The Case for HIV self-testing in Zambia

M. Robin Ridley 6 November 2012

Statement of originality
In presenting this dissertation for assessment, I declare that it is a final copy including any last revisions. I also declare that it is entirely the result of my own work other than where sources are explicitly acknowledged and referenced within the body of the text. This dissertation has not been previously submitted for any degree at this or any other institution. M. Robin Ridley

List of abbreviations
AIDS ART ARV BCC CD4 CDC CHAI CSO DALY FDA GBV GRZ HBC HCT HIV HMIS HRH M&E MOH NAC NASF NGO OI OTC PEPFAR PITC PLHIV PMTCT POC ROI STI SRH SROI TB VTC UNAIDS WHO ZDHS ZSBS Acquired Immune Deficiency Syndrome Antiretroviral Therapy Antiretroviral Drugs Behavior Change Communication A protein encasing the white blood cells that fight against infection Center for Disease Control and Prevention Clinton Health Access Initiative Civil Society Organization Disability adjusted life years Federal Drug Administration Gender-based Violence Government of the Republic of Zambia Home-based care HIV Testing and Counseling Human Immunodeficiency Virus Health Management Information System Human Resources for Health Monitoring and Evaluation Ministry of Health National HIV/AIDS/STI/TB Council National AIDS Strategic Framework Non-Governmental Organization Opportunistic Infection Over-the-Counter Presidents Emergency Plan for AIDS Relief Provider-Initiated Counseling and Testing People Living with HIV Prevention of Mother-to-Child Transmission Point of Care Return on Investment Sexually Transmitted Infection Sexual and Reproductive Health Social Return on Investment Tuberculosis Voluntary Testing and Counseling Joint UN Programme on HIV and AIDS World Health Organization Zambia Demographic and Health Survey Zambia Sexual Behavior Survey

Table of contents
Statement of originality ................................................................................................................................ 2 List of abbreviations ...................................................................................................................................... 3 Table of contents .......................................................................................................................................... 4 List of graphs and figures .............................................................................................................................. 6 Executive summary ....................................................................................................................................... 7 1. The HIV and AIDS epidemic in Zambia .................................................................................................. 8 2. Structure of this dissertation by chapter ............................................................................................ 10 3. Literature review ................................................................................................................................. 11 3.1 History of HIV testing .................................................................................................................... 11 3.2 So why arent people testing? ...................................................................................................... 14 3.3 Why arent Zambians testing? ...................................................................................................... 14 3.4 Which testing methods seem to work best in sub-Saharan Africa? ............................................. 16 4. Methodology ....................................................................................................................................... 18 4.1 Whether HIV self-testing is an innovative solution for Zambia? .................................................. 18 4.2 Whether OraQuick is acceptable, easy to use, and accurate in Zambia? ................................... 19 4.3 Whether HIV self-testing is a value for money investment? ........................................................ 20 5. Analysis of the literature on HIV testing and evaluation of HIV self-testing ...................................... 21 5.1 HIV self-testing and the early debates on home pregnancy testing 1976.................................... 23 5.2 HIV self-testing debates I: a snap shot of the American debate 2005.......................................... 25 5.3 HIV self-testing debate part II: the developing world 2012 .......................................................... 26 6. Accuracy and acceptability of the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test ..................... 26 7. HIV testing 101: the basics .................................................................................................................. 30 8. Test and treat .................................................................................................................................... 31 8.1 The WHOs Rapid Advice takes baby steps toward test and treat 2009 ................................. 32 8.2 The CDC takes bigger steps toward test and treat 2011 ............................................................ 33

9. Cost benefit of implementing HIV self-testing in Zambia ................................................................... 33 9.1 Baseline cost-analysis of current HIV testing and ART interventions ........................................... 35 9.2 Cost and projections of introducing HIV self-testing in Zambia ................................................... 38 9.3 Social return on investment.......................................................................................................... 45 10. Discussion.......................................................................................................................................... 46 10.1 Is innovation enough? ................................................................................................................. 47 10.1 Does ease of use lead to abuse? ................................................................................................. 47 10.2 Some ethics around cost-effectiveness ...................................................................................... 48 Conclusion ................................................................................................................................................... 48 Study limitation ........................................................................................................................................... 49 Recommendations ...................................................................................................................................... 50 Bibliography ................................................................................................................................................ 50 Annex 1: Excerpts from OraQuick Customer Letter.................................................................................... 56

List of graphs and figures

Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Figure 9. Figure 10. Figure 11. Figure 12. Figure 13. Figure 14. Disease burden in rural versus urban areas in Zambia 2010 .................................................... 8 The cost of AIDS exceptionalism ........................................................................................... 13 Number > 15 years who received HTC and know their results 2006-2010 ............................ 15 A 1979 advertisement for a home pregnancy self-test kit ..................................................... 23 Approaches to OTC Home-Use HIV Test Kits debate within FDA ........................................... 25 Sample test accuracy using sensitivity, specificity, PPV and NPV ........................................... 27 Accuracy of OraQuick HIV test based on Zambian HIV prevalence and population .............. 28 OraSure Technologies OraQuick ADVANCE Rapid HIV-1/2 Antibody Test ............................ 29 Costing of OraQuick against current national algorithm in Zambia ..................................... 29 The relationship between CD4+ count and viral load......................................................... 31 Three stages in the Cascade of Positive Care...................................................................... 34 Lost to care in the cascade in US and segregated by age group ......................................... 35 Baseline costs of HIV testing and treatment....................................................................... 37 Cost of HIV self-testing scenario by cohort years ............................................................... 40

Executive summary
The problem : Zambia, one of the countries hardest hit by the AIDS epidemic, has aggressively
pursued global best practices in its treatment protocols and set ambitious targets to reverse the HIV epidemic and mitigate its impact. However, an estimated 115 new adult infections and 25 new child infections occur each day resulting in more than 50,000 new infections annually. While Zambia appears to have the expertise in place to provide life-saving antiretroviral treatment (ART) to everyone in need, low demand and uptake of HIV testing continues to bedevil any efforts to achieve an all-encompassing expansion of HIV services.

Research : In the wide-ranging literature review, we begin by positioning the HIV testing discourse
within the context of ethics and human rights. We explore the debates over HIV testing models, the notion of AIDS exceptionalism, the marriage of counseling to HIV testing, and the persistent barriers to use of HIV testing and counseling services. We review the early applications to the Food and Drug Administration for HIV self-testing kits and the reasons they were not approved. We draw comparisons with the early debates on home pregnancy testing. Finally, we highlight research showing that with safer, less toxic and more effective drug regimens available, earlier HIV diagnosis and treatment delivers substantial benefits to the individual and the successive impact at the population level is drastic reduction in transmission of the virus. We note that the entry point to realizing these benefits is the HIV test.

Findings : We demonstrate that the patterns and trends in the various HIV testing models support our
assessment that the closer HIV testing gets to households and families, the higher the uptake in services. This in turn validates our hypothesis that HIV self-testing is an innovative solution for Zambias testing conundrum. We evaluate the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test, an oral fluid HIV selftesting product for sensitivity and specificity, and find it to be accurate, easy to use and highly acceptable in the Zambian context. We show that an initial investment of less than $8 million in HIV self-testing kits has the potential to help Zambia reach 81% coverage of all its citizens in need of antiretroviral treatment virtual achievement of the universal access dream. We further demonstrate that the additional treatment costs of $234 million over five years are substantial yielding, nonetheless a modest 4% return on investment (ROI). However, by using a financial proxy for the value of lives saved; we can generate a social return on investment (SROI) of 23% making HIV self-testing an attractive investment.

Recommendations: Civil society groups and communities all over Africa are designing and
implementing community-based models for ART delivery, patient tracking, adherence support and home based care with great success. With the anticipation of over 500,000 people rapidly entering the treatment ranks over the next 5 years, expanding operations research around the implementation and piloting of innovative community models for service delivery will be a fundamental and worthy investment for Zambia.

Conclusion: HIV self-testing is here. The time for innovation is now.

1. The HIV and AIDS epidemic in Zambia

In June 2011, a Political Declaration on HIV/AIDS: Intensifying our Efforts to Eliminate HIV/AIDS was unanimously adopted by Member States. The declaration set forth bold new targets including having 15 million people living with HIV on antiretroviral treatment by 20151. At that time, an estimated 6.6 million people living with HIV were receiving treatment. One of the major barriers to achieving this ambitious goal is identifying the additional 7+ million people, most of who are living in sub-Saharan Africa2, in order to start them on lifesaving treatment. This can only be accomplished through a drastic increase in HIV testing. Globally, significantly less than half the people living with HIV are aware of their status. In sub-Saharan Africa, over 60% of people living with HIV are unaware that they are carrying the virus 3. Zambia, located in Southern Africa, is not only one of the poorest countries in the world, but also one of the countries hardest hit by the AIDS epidemic. The Zambia Demographic and Health Survey (2007) describes Zambias HIV epidemic as a mature, generalized, hyper-endemic HIV epidemic where heterosexual sex is the major mode of transmission. According to the most recent reporting on the epidemic (data from 2011), the adult HIV prevalence is 12.5%. Prevalence is calculated based on adults aged 15-49 years. According to UNICEF, the Zambian population <15 years of age is sizeable (46.7%). Zambia has an estimated 970,000 people living with HIV of which 170,000 are children below the age of 15 years. With approximately 38.8% of the population living in urban areas, Zambia is hailed as the most urbanized country in sub-Saharan Africa 4. Urbanization, however, has a downside in that the HIV prevalence in urban areas doubles that in the rural areas 20.1% vs. 10.8%. However, as shown in Figure 1 below, while big cities bear a disproportionate burden of the epidemic, rural areas, with a significant yet harder to reach number of people living with HIV (45.8%) cannot be ignored or excluded from program interventions. Figure 1. Disease burden in rural versus urban areas in Zambia 2010
Rural vs Urban disease burden in Zambia 2010 % Adult population est.

Zambia total rural urban

Population rural/urban 13,046,508 7,978,274 61.2% 5,068,234 38.8%

(53.3% >15) prevalence est. PLWH disease burden 6,953,789 13.5% 938,761 4,252,420 10.8% 459,261 45.8% 2,701,369 20.1% 542,975 54.2%

Data source: Zambia 2010 Census Population summaries, Central Statistical Office, Zambia

Knowledge of ones HIV status through testing is the entry point to HIV prevention, treatment, and care and support services5. An individual who tests positive for HIV is referred to important clinical and support services including access to antiretroviral therapy, clinical management of related illnesses, and psychological support. Knowing ones HIV status, whether positive or negative, is also considered to be a key motivating factor for positive behavior change by helping individuals make decisions to reduce risks and increase safer sex practices thereby demonstrating significant prevention gains6 7.

In the summer of 2011, a landmark study called HTPN 0052 demonstrated that early antiretroviral treatment (ART) reduces HIV transmission by 96%, in serodiscordant couples by vastly decreasing the viral load in people living with HIV 8. In effect, treatment is prevention. Co-Principal Investigator of HPTN 0052, Myron Cohen, claimed that "these new findings provide further confirmation of the health benefits of early antiretroviral therapy. The combined prevention and treatment benefits of antiretroviral therapy make broader testing and treatment urgent and imperative" 9. This is as true for Zambia as anywhere. Therefore, capitalizing on the full potential of antiretroviral therapy, calls for pioneering more effective approaches to HIV testing. Since 2003, the Government of Zambia has implemented a no fee policy for accessing antiretroviral therapy; both HIV testing and antiretroviral treatment are free of charge. Furthermore, multiple approaches exist in Zambia to increase knowledge of status including: workplace HIV testing services; home-based and mobile testing; fixed sites where clients can seek HIV testing services; testing and counseling in health facilities for pregnant women; testing of TB patients; and testing of in-patients and out-patients in health care facilities10. In fact, 1,563 public and private health facilities in Zambia provided counseling and testing services at the end of 2008 and this number increased to 1,784 in 201011. The 2009 Zambian Sexual Behavior Survey indicated that 94% of respondents knew where to go to get an HIV test and that 81% expressed a desire to be tested or re-tested12. Yet, only 25 per cent of sexually active adults know their HIV status in Zambia. Why is this so? The fact that most of those living with HIV in Zambia do not know it is obviously an enormous barrier to Zambia achieving its goal of providing universal access to HIV prevention, treatment, care and support. For a country with an estimated 115 new adult infections and 25 new child infections occurring each day11, Zambia desperately needs to realize the benefits of early initiation of treatment including: 1) at the patient level, less toxic and safer drug regimens, significantly reduced mortality, reduced morbidity from non-AIDS illnesses, and the opportunity to live a productive life; and 2) on a broader public health level, the drastic reduction of HIV transmission13-14. The sole entry point to these benefits is HIV testing. To dramatically increase the uptake of HIV testing, Zambia needs an innovative solution that is low cost and has a low need for infrastructure and human resources. This dissertation sets out to answer the following research questions: 1. Whether HIV self-testing is an innovative solution to address Zambias low uptake in HIV testing; 2. Whether an oral fluid HIV self-testing product, specifically the OraQuick ADVANCE Rapid HIV1/2 Antibody Test, would be acceptable, easy to use and accurate in the Zambian context; and 3. Whether HIV self-testing, with its potential to drastically increase the numbers of people in care, is a value for money investment for Zambia.

2. Structure of this dissertation by chapter

Chapter 1 provides an overview of the HIV and AIDS epidemic in Zambia and clearly articulates the three research questions this dissertation addresses. Chapter 2 outlines the structure of the dissertation by chapter. Chapter 3 begins with a wide-ranging review of the literature on HIV testing including its history distinction from other infectious disease testing protocols; the stigma and discrimination associated with the virus itself and how this continues to impede access to and uptake of HIV testing services; the specific aversion that Zambians have to HIV testing; and finally those methods of HIV testing that seem to surmount these challenges. Chapter 4 outlines the methodologies employed to answer each of the three research questions. Chapter 5 provides analysis of the literature reviewed and a summary of the few studies that employ or evaluate HIV self-testing as a testing method. It then explores the possible reasons for this paucity of studies by reviewing the long, slow process of approval in the United States of a home specimen collection kit for HIV diagnostics in the 1990s and more recently the debate on over-the-counter, homeuse HIV testing kits. It closes with a modern look at some of the legitimate concerns around HIV selftesting. Chapter 6 explains how the accuracy of a diagnostic test is evaluated using specificity, sensitivity, and predictive values. It then employs these elements to access the accuracy of the OraQuick ADVANCE Rapid HIV-1/2. Finally, it reviews the results of many field studies that evaluated this oral fluid diagnostic test for acceptability, ease of use and accuracy. Chapter 7 is a brief tutorial on the disease progression that explains the need for two other tests involved in the clinical management of HIV: the viral load and CD4 count tests. This basic knowledge is necessary as a prerequisite to the discussion and analysis in subsequent chapters. Chapter 8 analyzes the benefits of early diagnosis and treatment both for the individual and for the broader community thereby underscoring the need for innovation in HIV testing as the gateway to treatment. It also documents the revision of protocols by the CDC and the WHO in their slow march toward universal test and treat policies. Chapter 9 describes the cost benefit of implementing an HIV self-testing scenario by comparing projected five year costs of including HIV self-testing in the method mix weighed against a baseline assessment of Zambias current testing and treatment outcomes. It also looks at traditional return on investment calculations and argues for a social return on investment by establishing a financial proxy for lives saved to use in the calculation. Chapter 10 highlights some of the risks inherent in implementing an innovative HIV self-testing solution and discusses possible ways to mitigate each. To frame the discussion, each concern is aligned to one of the three research questions.

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3. Literature review
3.1 History of HIV testing
When the first HIV antibody test was developed in 1985, over a decade before treatment became available, opponents of its wide spread use questioned its relevance to the individual given the limited therapeutic options available for those diagnosed as positive15. In addition to limited clinical options, fear of mandatory testing, coerciveness in obtaining consent, discrimination, and social exclusion in the most at risk community largely gay men firmly positioned the entire discourse around testing within the context of ethics and human rights16. In their review of the history of HIV testing, Bayer and Edington (2009) examine the complex and politically charged relationships that have evolved between public health and human rights on the issue of HIV testing. Their research focuses primarily on the polemical debate around routine testing, also known as routine screening, provider-initiated testing and counseling (PITC), or opt-out testing wherein clients must refuse to take an HIV test. Conversely, with opt-in or voluntary counseling and testing (VCT), clients must request that an HIV test be administered. The notion of informed consent how stridently such consent should be pursued and how explicitly it should be affirmed is central to this debate. The move away from traditional public health practices in other communicable diseases (e.g. routine testing that presumed consent, partner identification, case reporting, and referral, etc) established the concept of HIV as an exceptional virus 17. Suddenly client autonomy, counseling and confidentiality (not just of the test result itself, but also of the fact of testing at all) became part and parcel of the testing model for HIV. Global HIV testing advocacy and policies centered around the Three Cs: consent, confidentiality and counseling as fundamental principles for ethical HIV testing18. Reichter (2010) informs us that the term AIDS exceptionalism was coined in the early 1990s to describe an approach to the AIDS epidemic that was explicitly located within a human rights and bioethics framework. She describes this new model of diagnosis as follows, VCT includes pre- and post-test counselling, express and informed consent that an HIV test would be conducted on the patient, and assurances of the confidentiality of the test result. Again, the emphasis is on the Three Cs. It is interesting to note the considerable variation in the naming of the Three C combinations. In a much referenced abstract, "Increasing the Acceptability of HIV Counseling and Testing with Three C's: Convenience, Confidentiality and Credibility," Angotti et al (2009), clearly have a different take on the characterization of the Three Cs, with Confidentiality as the only common denominator with the WHO (2004) and Reichter (2010) definitions. Furthermore, in a 2009 review of Zambias HIV testing and counseling policy and interventions, the Southern African Development Community and the African Development Bank noted that Zambias HIV testing and counseling programs adhere to set global standards following the 3 Cs (Consent, Confidentiality and Context)19. More on the multiple Cs will follow in the analysis section of this paper.

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As Bayer (2009) points out, in the early days before treatment, the HIV antibody test itself was seen to offer little, if anything. Therefore, throughout the discourse on HIV testing, counseling was deemed vital as an encouragement for behavior change since those who tested positive needed to change behavior to avoid transmission and those who tested negative needed to mitigate behavior to remain so. Even after the development of the first HIV antibody test, the testing focus continued to be primarily centered on pre- and post-test counseling; pre-test counseling to highlight the risks and benefits of testing and to explicitly obtain consent, and post-test counseling to interpret the implications of the results and advocate for behavior change for prevention. Once antiretroviral treatment became available in the mid-1990s, public health officials began to question the exceptionality construct for HIV testing and to call for a paradigm change in the testing model. The 2001 WHO consultation report on increasing HIV testing stated: The demanding procedures inherent in the VCT approach may now inadvertently draw a high level of attention to HIV in a way that impedes the normality of seeking and accepting HIV testing. Current approaches to voluntary HIV testing may ironically perpetuate the stigma associated with HIV and HIV testing, and limit its availability20. Thus the relevance and efficacy of AIDS exceptionalism in the context of the voluntary testing and counseling model a model that positions HIV testing as a parallel service to standard health service provision was called to account. The substantial push for PITC in all clinical settings once again unleashed the tensions between safeguarding individual rights and protecting public health. Of note is that both testing models are essentially voluntary and, more importantly, testing in both models continues to be yoked to counseling. In 2006, the Center for Disease Control and Prevention (CDC) recommended routine HIV testing in all clinical settings21 igniting a similar controversy among public health practitioners in the United States. In a review of the legal ramifications of implementing the CDC recommendation, Brown (2008) describes the controversy over opt out testing as one of the most contentious issues facing those involved in the interface of HIV screening and public health. Interestingly, Brown notes that both camps, although diametrically opposed, based their arguments on the same data and both had the best interest of their patients in mind. Noting that the ethical principle of respect for autonomy puts the patients rights at the forefront, Obemeyer (2007) warns that framing the testing debate in a rights discourse to begin with may not work in settings where individuals, far from feeling entitled to know their status, are fearful of results and ambivalent about tests. She recommends exploring complementary approaches to testing in these contexts, as in Zambia. According to the WHO, millions of people have learned their HIV status thanks to VCT over the past 20 years. Still global coverage of HIV testing and counseling programs remains low and efforts are urgently needed to increase the provision of HIV testing through a wider range of effective and safe options. Therefore, in 2007, in order to increase the proportion of persons who know their HIV status, the WHO and UNAIDS issued a Guidance on Provider-initiated HIV Testing and Counseling in Health Facilities

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that recommended routinely offered and delivered counseling and testing for everyone entering health care facilities in countries with generalized epidemics22. Nevertheless, VCT is still the dominant model for HIV testing in sub-Saharan Africa, including in Zambia23, and this model has increased awareness of and access to HIV testing services. However, despite an increase in testing rates, demonstrated willingness to test24, and the endorsement and promotion of an alternative model (PITC) of testing; most HIV-positive people remain unaware of their status, do not consider themselves at risk, and do not seek out HIV testing services3. By 2008, with the world economic crisis looming on the horizon and donor monies drying up or stagnating, the global health community began to focus on the costs of AIDS exceptionalism, specifically the vertical programming of AIDS interventions at country level. Achieving greater cost efficiencies by integrating services was the new global health mantra. Figure 2 shows the significant savings of integrating VCT services into already existing sexual and reproductive health services in three countries. Figure 2. The cost of AIDS exceptionalism

Data Sources: , , Population Council Frontiers reporting , and

25 26

27

28

The introduction of rapid HIV diagnostic kits, able to provide results in less than 30 minutes, has made testing easier to use and less costly to deliver in all testing settings15. Importantly, the advent of these kits also made it possible for people to know their test results in real time thus eliminating a significant barrier to knowing ones status i.e. the requirement to return to the clinic, often as much as two weeks later, to obtain test results. Obermeyer in a comparative analysis of the acceptability of testing with delayed results found that those willing to be tested frequently reached 80% - 90%; however, those who actually return for their results were about 60% of those tested. In Zambia the acceptability of testing was much lower at 50% with only 12% returning for their results29.

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Today most countries make use of both client- and provider-initiated testing and counseling interventions and these have conclusively contributed to raising the awareness of HIV status in the general population and among key populations at higher risk of HIV infection. Nonetheless, this uptake is still insufficient as the majority of people living with HIV do not know it5. The advances in testing technology coupled with the wide availability of treatment and a suite of testing models should lead to a growing demand for HIV testing.

3.2 So why arent people testing?

The WHO/UNAIDS/UNICEF 2010 progress report on scaling up HIV interventions indicates unequivocally that knowledge of HIV status remained inadequate and that testing and counselling programmes are not always tailored to local contexts. The report reveals that in sub-Saharan Africa, the median percentage of people living with HIV who know their status is below 40%3. Findings in study after study show that stigma and discrimination against people living with HIV is pervasive worldwide30-32. In addition to the fear of stigma and discrimination, other barriers to use of counseling and testing services include low awareness of personal risk, reluctance to get tested while still healthy, fear of a breach of confidentiality on the part of service providers, and economic costs (largely in transport and lost hours of work)24,31 Institutional barriers associated with testing uptake include clients having to initiate testing themselves, lengthy pre- and post-test counseling, and patient concerns about confidentiality. Finally there are numerous emotional barriers to testing most based on fear e.g. fear of rejection by loved ones, fear of loss of job or housing, fear of discrimination and violence, etc33. Obermeyer (2007) maintains the major barrier [to utilization of testing and counseling] is individuals reluctance to acknowledge that they are at risk even when in fact they are. She claims that this is universally documented whether one looks in rural Tanzania, northern Thailand, among poor women in Brazil, or pregnant women in the United Kingdom.

3.3 Why arent Zambians testing?

Acknowledging that HIV counseling and testing services are the cornerstone of all HIV interventions in Zambia, the Zambian National AIDS Strategic Framework 2005-2010 (NASF) included a target to increase the percentage of the adult population using voluntary counseling and testing services from a cumulative 13% in 2005 to a cumulative 30% by 2010. To accommodate this target increase, Zambia also underscored the need to increase the number of health facilities and centers that provide HIV services. The NASF targeted a 100% increase from 420 facilities in 2005 to 840 by 2010 11. Interestingly, Zambia vastly exceeded its target of 840 health facilities offering HIV services (a 420% increase) with 1,690 health facilities offering HIV services at the end of 2010. Yet it failed to meet the target of 30% of adults tested by 2010 testing only 19.1%. Figure 3 shows testing trends over time for adults older than 15 years.

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Figure 3. Number > 15 years who received HTC and know their results 2006-2010
Zambia Trends in HIV Testing
8,000,000 7,000,000 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 -

Adult Population

No. Tested 4% 6% 8% 16% 19% 25% Adult Population Percent 2006 2007 2008 2009 2010 2011 Year

Data source: Zambia Country Progress Report UNGASS Reporting 2010, 2012

In a 2005 proposal application to the Global Fund to Fight AIDS, TB and Malaria, the Zambian Country Coordinating Mechanism for the three diseases wrote that stigma in Zambia was apparent in many forms of discrimination due to beliefs that AIDS is associated mainly with illicit sex, and is the result of sin. The application goes on to state that because of stigma, many people shun HIV services including HIV testing 34. Bond (2011) agrees that HIV testing in Zambia is most often a protracted, courageous and painful decision as HIV testing carries a degree of moral disclosure due to the association among Zambians between HIV and sex, and at the epidemics apex in the mid 1990s between HIV and Death. Introducing the notion of HIV as a long-term chronic disease is difficult because, as Bond writes, it is weighted with such extraordinary baggage - that of sex and sin. In a 1996 constitutional amendment, Zambia declared itself a Christian nation. Current estimates are that over 85% of Zambians profess some form of Christianity with Roman Catholic and Protestant among the highest, with a recorded surge in Pentecostalism35. Therefore, the concepts of respectability and moral integrity are strongly infused into the national and personal identities are engraved in ones public persona 36. Both Bond and Simpson (2010) document the fear of gossip as a pronounced and major form of HIV-related stigma throughout sub-Saharan Africa noting that gossip is inherently bound up with scandal, lack of decency or morality, and shame30,36. One of the significant findings in Jorgensens 2012 study was the concept that voluntary counseling and testing in Zambia is used more as a diagnostic tool once a person has fallen ill rather than as preventive measure. To know ones status meant confirming an expected diagnosis and gaining access to ART 37.

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Gender inequalities and sexual violence are also seen as barriers to HIV testing uptake among women in Zambia and most females know the perpetrator of the violence 12. Analysis of the Demographic Health Survey (DHS) in 2007 shows correlation between domestic violence by husbands or intimate partners and the fear among women of starting and continuing antiretroviral treatment, including HIV testing services. The Zambian Sexual Health Survey of 2009 shows that only 34% of all people surveyed expressed accepting attitudes toward people living with HIV. This of course means that 76% expressed negative attitudes. The survey also found that almost one in five (18%) of survey respondents reported that they knew of someone who had experienced discrimination or verbal abuse in the past year due to known or suspected HIV status. These percentages were higher in urban versus rural areas; however, those living with HIV in rural areas were (32%) more likely to experience negative judgments 38. Despite the seemingly rampant stigma and discrimination, 1,772,043 Zambians (25%) were reportedly tested in 201111. Yet, Zambias targets for HIV testing remain unmet. A Partnership Framework signed between The Government of the Republic of Zambia and The Government of the United States of America to support the implementation of the Zambian national response to HIV and AIDS from 2011 2015, sets the following targets for HIV testing: Females and males aged 15-49 who received an HIV test in the last 12 months and know their results is increased from 15.4 per cent in 2008 to 30 per cent in 2013 and 50 per cent by 2015. 39 As mentioned earlier, the Zambian governments National Strategic AIDS Framework had even more ambitious but ultimately unrealized HIV testing targets: Increase the percentage of the adult population using voluntary counseling and testing from a cumulative 13 per cent in 2005 to a cumulative 30 per cent by 2010 11. Finally, in December 2008, the Ministry of Health, with technical assistance from the U.S. Agency for International Developments (USAID) Deliver Project and funding from the Presidents Emergency Program for AIDS Relief (PEPFAR), conducted a national long-term forecast of rapid HIV tests for 2009 201540. Stakeholders set similar targets to those already agreed culminating in the assumption of reaching 50% of the adult population with testing by 2015. Zambia is currently not on track to meet its HIV testing targets and this will impact its ability to meet other HIV treatment and prevention targets.

3.4 Which testing methods seem to work best in sub-Saharan Africa?

Two studies in Botswana and Tanzania, neighboring countries with similar generalized epidemics and high prevalence showed that 95% (Botswana) and 83% (Tanzania) of study participants very much agreed that routine testing makes it easier for people to get tested, is likely to reduce the barrier of community level stigma, and to increase access to antiretroviral treatment41. Following a government

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decision to integrate routine counseling and testing into primary health care facilities in Zambia in 2008, a study demonstrated that PITC dramatically increased the number of people testing (97%) above that associated with VCT alone which means that PITC did not replace VCT, but offered another route to testing. Furthermore, the study showed an increased acceptability of testing over time from 53% agreeing to test in the first month to 85% agreeing 30 months later in nine urban clinics in the study. Importantly, this gradual acceptance shows that patients were not coerced, but exercised free will in the decision to test and that testing became more normalized over time42. Kankasa et al. (2009) found similar uptake of testing with routine screening among pediatric inpatients in the Zambia University Teaching Hospital with a gradual increase in counseled children (care givers/parents) who agreed to HIV testing from 76 % to 88.2% at the studys end 43. Evans et al. (2011) found that while health workers reported an increased workload with the provider initiated testing and counseling model, they also felt that this additional work was offset by a decrease in HIV-related admissions (e.g. STIs and other opportunistic infections) that led to a newfound enthusiasm in working with healthier clients 44. Finally, an abstract highlighting the results of focus group discussions among HIV clients in five US cities revealed that participants compared non-health care settings unfavorably to health care settings regarding privacy, competency, confidentiality, and test accuracy and that routine HIV testing was preferred because focus group discussants believed that selfselecting by high risk factors e.g. drug use, homosexuality, sex work, is in itself stigmatizing45. Two studies have shown that HIV testing opportunities in the workplace increase uptake of testing among employees. In one cluster-randomized trial in Zimbabwe, Corbett et al. (2006) found that uptake to VCT services by employees who were offered on-site VCT was 12 times higher than the uptake by employees offered vouchers for off-site HIV testing. Just over half of the employees in the on-site arm tested for HIV while only one fifth of the employees in the offsite arm accepted vouchers but of these only 20% actually used their vouchers and tested. Interestingly, in both of the intervention arms, young people (<25 years old) were most likely to test46. In 2001, Heineken, the multinational brewing company, began offering confidential in house VCT to its employees and their dependents. Van der Borght et al., in a longitudinal study of uptake dynamics from 2001-2007, found that annual uptake of testing increased over time of between 15-32% per year47. A strategy to bring the VCT package closer to the people by using mobile testing units in Cameroon was effective in reaching a great number of people with limited access to facility-based testing services48. In Zambia, people were much more likely to undergo community facility based testing when the messaging and interventions were developed by and for their own communities11. Because uptake was similar between men and women, a study in Soweto, South Africa concluded that men would be more likely to access VCT in a community-based setting49. Significantly, in a study in neighboring Malawi, Angotti et al. (2009) found that even when voluntary counseling and testing facilities offer services free of charge, the number of people coming forward to take advantage of these services is disappointingly low [] despite high numbers reporting that they would like to be tested24. Oddly, people seemed to want to be tested, but didnt use the free services. Conversely, the same study findings indicate that fear of knowing their results may not be the

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underlying reason for low uptake of VCT services as an overwhelming majority was willing to be tested and learn their results immediately when presented with the opportunity to do so during a door-to-door longitudinal study in the same area in Malawi. Door-to-door or home-based testing includes door-to-door visits by community health workers or lay counselors who employ rapid diagnostic HIV tests on any adult members of the household who consent and read the results within 20 minutes all in the clients home. Several studies in Uganda have demonstrated the feasibility and acceptability of the home-based HIV testing and counseling method. One study showed that home testing increased acceptance of testing from 10% to 46% and eliminated differences in acceptance between women and men50. Another study compared stand-alone testing; hospital-based testing; household-member testing; and door-to-door testing and found that while the hospital testing identified the most treatment ready people, household member and door-to-door testing reached the greatest proportion of previously undiagnosed people and people with higher level CD4 counts25. A third study found that home-based testing showed significantly higher numbers of people interested in knowing their results and an increased uptake in testing services, particularly among people between the ages of 25-54. Subsequent interviews and focus group discussions demonstrated that home based testing eliminated the inconvenience, fears, and costs of facility-based tests51. A randomized controlled trial in Zambia in which clients were offered the option of testing in the clinic or another location, found that 84% chose home as the preferred venue for testing29. Finally, new rapid diagnostic technologies have made mass testing drives practical and these have been rolled out with great success in South Africa and Kenya. South Africa launched a 15 month HIV counseling and testing campaign that tested and screened 14 million people for HIV and other chronic diseases with another 1.5 million tested through the private sector. Of the people tested, two million were diagnosed as HIV positive and were referred for further care52. In Kenya, a similar multi-disease testing campaign was launched in the largely rural, but densely populated Western part of the country. In just 7 days, 47,311 people attended the campaign and 99.7% of these were given HIV tests with 4% of these testing positive53 and referred for further care. Importantly, both these primary HIV testing campaigns were integrated with broader national health goals to provide multiple-disease preventative services thereby increasing coverage, access and cost efficiencies.

4. Methodology
4.1 Whether HIV self-testing is an innovative solution for Zambia?
The first objective of this paper is to demonstrate whether HIV self-testing can be an innovative solution to Zambias problem of low uptake of HIV testing. We note here that, while not a new concept, HIV selftesting has not been applied at scale anywhere in the world. This lack of real data has had considerable impact on the consideration of methodological approaches to answer what remains a theoretical research question. We began with a review of the recent HIV testing literature in order to understand the behavior around HIV testing and counseling and identify patterns and trends that might support our hypothesis. By combining and contrasting the research findings at various levels of aggregation e.g. gender, geographical location, age, etc.we developed a situation analysis of the current state of the art

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in HIV testing. The literature on HIV testing is massive. Computerized searches on any of the major databases retrieved thousands of articles even with restrictions on the period e.g. since January 2008 and use of limiting key words e.g. Sub-Saharan Africa in the search criteria: PubMed returned 2,427 articles; JAIDS, over 5,000 ; EBSCO 472; and The Lancet, 570. We tried as much as possible to include sources where research was carried out in sub-Saharan Africa, particularly in Zambia or its neighboring countries. We searched for sources on all the different approaches to testing e.g. voluntary testing and counseling, provider initiated testing and counseling, home-based testing and counseling, testing and counseling with mobile units, and HIV testing campaigns. To further narrow the search, we used keywords such as behavior, acceptability, and attitude to retain articles dealing with social and behavioral information rather than largely biomedical studies. In order to understand why Africas HIV testing rates are so low, and those of Zambia in particular, we included several searches with the key words stigma and discrimination another vast area of literature review as these issues were consistently raised as primary barriers to the uptake of HIV testing in the literature review. Finally, we excluded many of the articles on HIV testing approaches for men who have sex with men because, unless there is a vast and silent crossover MSM community in Zambia and there very well may be, this group is not currently seen as a driver of what is essentially understood as an heterosexual epidemic in Zambia largely driven by multiple concurrent sexual partnerships. While this was not a meta-analysis per se, we did employ a common measure or size effect in the review which was the relative increase in the uptake of HIV testing in any given intervention. Because an HIV self-testing intervention is purely speculative, we could not formulate a statistical method to evaluate the evidence that would provide either predictive, population or construct validity to our question. We also cross-analyzed the Zambian Demographic Health Surveys of 2002 and 2007, and the Zambian Sexual Behavior Survey of 2009 against the literature review to gain a better understanding of the reasons why people in high endemic countries in Africa and in Zambia in particular do not seem to want to know their HIV status, and why some HIV testing interventions might have larger uptake and appeal than others.

4.2 Whether OraQuick is acceptable, easy to use, and accurate in Zambia?

When we began this research, HIV self-testing was not officially sanctioned anywhere in the world. However, in July of 2012 two events significantly changed the direction of this paper: the FDA approval of OraQuick ADVANCE Rapid HIV-1/2 antibody tests for home use; and the International AIDS Conference held in Washington, DC, that showcased several studies clearly demonstrating the large scale impact from early ARV treatment. These events combined with the WHO and the CDC revision of treatment guidelines in order to promote early treatment because of the individual patient benefits, not necessarily broader public health gains, and Zambias 2011 decision to adopt an aggressive treatment protocol, all created a sense of urgency around the question of HIV self-testing in Zambia. The led our research in two directions. First, whether an oral fluid self-testing product would be acceptable, easy to use and accurate in the Zambian context. We researched the accuracy and acceptability of oral fluid rapid HIV diagnostics through a mix of focused computerized retrieval, hand 19

searching, web review, and review of the bibliographies of the principal articles on oral HIV testing. We also reviewed the national testing algorithms for Zambia and its neighbors, their HIV policies, and testing and treatment protocols. Second, the overwhelming acceptability of HIV self-testing in these few studies led us to consider whether the empowerment of claiming health as a right through the act of HIV selftesting might also motivate self-testers to enter treatment earlier and to remain in care. Research around this second question on product acceptability moved us toward the assumption that large numbers of people empowered by an HIV self-testing opportunity would self-diagnose, enter the compendium of care earlier, and remain there.

4.3 Whether HIV self-testing is a value for money investment?

Our third objective is to determine what would be the broader cost-effectiveness and cost-affordability if indeed large numbers of people entered into lifetime treatment and care in Zambia? Clearly, the impact of HIV self-testing in Zambia has the potential to exceed the small scale efficiencies of lower human resource and infrastructure costs that we initially hoped to document. First, in order to understand whether HIV self-testing, and importantly the increased demand and uptake of HIV services self-testing has the potential to generate, would be value for money investments, we began by documenting the new protocols recommended by standard-setting hubs such as the CDC and the WHO noting the research and expert opinions on which these institutions based their policy changes and how Zambias policy environment adapted these accordingly. Second, in order to understand how a surge in HIV self-testing might impact the numbers of people entering treatment in Zambia, we conducted focused searches largely on PubMed and JAIDS of the HIV treatment literature dealing with issues of the compendium of HIV treatment and care, its components, and barriers to retention in care in general and in Zambia using key words such as retention, mortality, Pre-ART and lost to follow up. The size effect or common measure for this second quasi meta-analysis was the percentages of patients retained in each of the stages of care. The wide variety of interpretation on how the stages of care are calculated and the dire lack of data in retention in Pre-ART made any statistical method of review too complex for our purposes. Third, in order to evaluate the relative cost-effectiveness we began by establishing a baseline of the current testing levels, resultant patient numbers and estimated costs based on Zambia-specific data in as much as was possible. We searched the websites of the many collaborating universities currently involved in HIV research in Zambia e.g. University of Alabama, University of Boston, London School of Hygiene and Tropical Disease, etcand collected documents by other agencies with offices in Zambia e.g. UNAIDS, WHO, PEPFAR and the CDC. We were also privy to some as yet unpublished research, personal emails, and costing data used by the Ministry of Health in Zambia to roll-out its Elimination of Mother-to-Child Transmission Strategy. Unfortunately, this access did not include data on HIV testing rates, data which is irregularly monitored and often contradictory perhaps another consequence of AIDS exceptionalism as many of the testing venues are stand-alone structures not connected to specific health facilities.

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Finally, in order to conclude the cost benefit analysis, particularly the introduction of HIV self-testing and its corresponding assumptions, we researched models that forecast economic and health benefits in the short and long term tied to retention in care and subsequent averted HIV transmissions. We evaluated the return on investment using the standard financial measure of gains less costs divided by costs. However, given that a nations health is not a business enterprise and should not be measure as such, we re-calculated using a financial proxy for the costs of HIV infections averted to measure the social return on investment (SROI) for a much improved outcome.

5. Analysis of the literature on HIV testing and evaluation of HIV self-testing

Walensky (2011) reminds us that whatever the next hottest, scientifically proven HIV treatment or prevention strategies are, they will share a common denominator for implementation: the HIV test. With more than 100,000 facilities in low- and middle-income countries providing HIV testing and counseling, the fact that only 34% of women and 17% of men have ever had an HIV test in these settings3 is to Walensky, astonishing54. The literature review on HIV testing has clearly demonstrated that the closer HIV testing gets to households and families, the higher the uptake in services. Community-based testing is preferable to clinic-based; home-based testing is preferable to community-based and so on. The obvious assumption here is that HIV self-testing would significantly increase uptake, but there is little to no data on whether this is true. Why is this so? Throughout the literature review on HIV testing, the public health community has been called upon to identify novel and far-reaching approaches to HIV screening54; complementary approaches to HIV testing in contexts where stigma is widespread33; a wider range of effective and safe options55 that are tailored to local contexts3. Yet the paucity of research into the feasibility and acceptability of HIV selftesting in sub-Saharan Africa where it is perhaps most needed leads one to assume that, even today with antiretroviral treatment widely available, public health and academic communities continue to be staunchly paternalistic in their insistence on supervised settings for an HIV testing model where 1) faceto-face counseling remains an integral part of the model, and 2) someone is on hand to know and record the test result. For example, the WHO in 2011 reviewed literature and discussions of current practices of HIV self-testing among health workers and recommended that perhaps, a well-implemented and regulated [italics my own] self-testing programme might be a cost-effective way to increase the prevention value of HIV testing and ensure earlier entry into care for health workers. The 2010 Ministry of Health National Guidelines for HIV Testing and Counseling in Kenya includes HIV self-testing using oral fluids as a separate option that is different from the standard HTC models due to the absence of pre and post-test counseling56. However, the onus of providing information, counseling and referral to the purchaser is on the vendor of the test kits, generally pharmacies. There are also regulatory standards and approvals in place for test kits and their storage. However, as of now, no selftest kits have been approved for over-the-counter sales in Kenya57.

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Of the available data on HIV self-testing in sub-Saharan Africa is a 2011 study by Kalibala et al. of the Population Council who reviewed the feasibility and acceptability of HIV self-testing among Kenyan healthcare workers and their families58. As healthcare workers are often at risk for HIV due to occupational hazards of exposure in their work environments, it is assumed that many of the staff members in health clinics and hospitals routinely self-administer HIV test kits. Findings unsurprisingly demonstrated a high demand for HIV self-testing, appreciation of the privacy and confidentiality, ease of use of the test kits, and, importantly, that most healthcare workers discussed their results with someone else. A study in Blantyre, Malawi, led by Dr. Liz Corbett of the London School of Hygiene and Tropical Medicine, found that when compared with door-to-door VCT conducted by health care workers, the possibility of self-testing was much more attractive59. The study demonstrated that 92% of randomly chosen participants offered the opportunity to self-test chose to, and with modest instruction were able accurately administer oral HIV tests with minimal supervision. Of note is that almost half of the participants were men, a significantly harder to engage demographic in sub-Saharan Africa. Building on this research, Corbett and Choko hope to demonstrate a substantial increase in the uptake of HIV testing in these self-testing communities where individuals can effectively test themselves for HIV/AIDS in the privacy of their own homes using mouth swabs. It is hoped too that HIV self-testing will help Malawi improve detection and early treatment of people living with HIV 60. This current study will not be concluded until 2015. These studies are finding that the use of HIV self-test kits is overwhelmingly popular among potential users worldwide. Not only can the offer of HIV self-testing increase acceptability and uptake of testing resulting in more people knowing their HIV status, but HIV self-testing also mitigates most of the issues raised in the multiple Cs discussion of the previous section as follows: Confidentiality would no longer be a barrier to uptake of self-testing as the test is taken in private Consent would no longer be a barrier to uptake as the test is self-administered Convenience would no longer be a barrier to uptake as the individual can test when and where he/she would like Credibility would not be a barrier to uptake as shown in the Malawi study where the oral HIV rapid diagnostic kits were 99% concordant with the commonly used finger-stick kits. (More on sensitivity and specificity of rapid diagnostic HIV test kits in the next section). Cost (to consumer) would continue not to be a barrier to uptake as the Government of Zambia would presumably continue to pay for the cost of HIV test kits. Cost (to Government and donors) we will show in a subsequent chapter that the modest investment in HIV self-testing will have an enormous return on investment. Counseling while a few studies list counseling (and the time it consumes) as an actual barrier to the uptake of HIV testing, it is the waiver of the opportunity to provide counseling that is widely viewed as both an ethical and public health concern. Overall, however, counseling (or lack thereof) would not in and of itself be a barrier to the uptake of self-testing.

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Can we not challenge the resolute marriage of counseling and testing by offering separate models for each? Might there not be equally effective models to provide HIV prevention information and counseling, for example via hotline telephone centers? What are the potential benefits of HIV selftesting to public health and to individual wellbeing? In the absence of evidence, what might be the risks, costs and unintended consequences of a Government of Zambia decision to proceed in favor of selftesting? It is towards an evolution in the direction of HIV self-testing that this paper hopes to propel current thinking in Zambia.

5.1 HIV self-testing and the early debates on home pregnancy testing 1976
As a forward to this section, we would like to underscore the similarities between the on-going debates on HIV self-testing with those in the early days of home pregnancy testing. In 1976 the FDA approved an over-the-counter early pregnancy test kit known as e.p.t., manufactured by Warner-Chilcott. The test took two hours and the woman was required to mix her urine with several test tube solutions and wait two hours for results. The public and professional controversy that surrounded the launch of e.p.t. was based largely on fear fear of adverse consequences: that teenage girls would become more promiscuous since they could discover and possibly terminate a pregnancy without informing their parents; that the product would not be accurate; that suicide was imminent if the pregnancy was not intended; etc. The advertisement in Figure 4 below reassures a wary public health community that pregnant women will in fact seek care earlier in their pregnancies. Figure 4. A 1979 advertisement for a home pregnancy self-test kit

Data source: Advertisement for ACU-TEST, American Journal of Public Health, January 1979.

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Tone writes that home pregnancy tests have encouraged women who use them to seek medical attention once the results are known often as early as within the first weeks 61. An estimated six million women will get pregnant in the United States this year and, according to the manufacturers, two thirds of them will find out with a pregnancy self-test kit and these data are just for America fuelling my assumption that HIV self-testing will increase earlier uptake of ART services in Zambia. The notion of HIV self-testing is not new. As early as 1996, the FDA approved a home specimen collection kit system for HIV antibody testing. The kit, called Confide, was developed by Direct Access Diagnostics, a subsidiary of Johnson & Johnson. To use the system the client obtained a dried blood sample from a finger prick and simply mailed the sample to a laboratory for analysis. Anonymous results were available by telephone in one week. Counseling and referral were offered during the telephone call, if desired62. Remarkably, the FDA took nine years to approve Confide. Direct Access Diagnostics first submitted the application in 1987. Elliott J. Millenson, former CEO of Direct Access Diagnostics, testified before the FDA Blood Products Advisory Committee in 2005 in a meeting in which approval of an over-the-counter rapid HIV test was being debated. According to his testimony, the FDA approval for this product was a battle that began when the initial 1987 application for Confide prompted an FDA ban on all home AIDS tests63. Millenson testified that strong science sometimes meets stronger politics. Apparently, AIDS testing was appropriate for professional use and only in a health care environment. According to Millenson, opponents of home testing conjured up the scare tactic that suicides could not be prevented without face-to-face counseling. This claim, he states, had no scientific basis. (Not then, not now). Clinicians were also concerned that they would lose federal funding should home testing catch on. The other rational for the ban a rationale that was only made public by a CBS report of a private meeting of the Advisory Committee was that approval of this testing method would lead to a landslide of referrals that would overwhelm the already overburdened health care system. Oddly enough, Millenson had initially contemplated developing a rapid HIV diagnostic test given the technology was available back in 1987, but it was clear the FDA would not approve such a test. As shown below, the FDA Blood Products Advisory Committee first debated over-the-counter, home-use HIV test kits in 2005, but it wasnt until 3 July 2012 (seven years later) that OraQuick ADVANCE Rapid HIV-1/2 Antibody Test, an HIV self-test kit, was formally and unanimously approved the first over-thecounter HIV test licensed for home use 64. It is expected to be on sale at major pharmacies in the United States as early as October 65. Between 1996 and the present and in the absence of any evidence on whether HIV self-testing would be feasible and safe, or what the adverse consequences might be many academics, public health authorities, journalists and development workers have voiced their concerns; many, too, have voiced their enthusiasm and optimism. The following is a distillation of the pros and cons compiled from news articles, journal opinion editorials, and studies on the theoretical acceptance of HIV self-testing.

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5.2 HIV self-testing debates I: a snap shot of the American debate 2005
Quick Minutes recorded during the Blood Products Advisory Committees 85th Meeting 3-4 November 2005 and Open Public Hearing document the debate on Approaches to Over-the-Counter (OTC) HomeUse HIV Test Kits following the test kit manufacturer, OraSure Technologies Inc.s, original application for FDA approval66. Figure 5 shows a snap shot of the debate on HIV self-testing and how the final votes lined up in 2005. Figure 5. Approaches to OTC Home-Use HIV Test Kits debate within FDA In favor of home-use HIV test kits Test kits will significantly increase the number of individuals who know their HIV status. These benefits far outweigh the risk Lower sensitivity may be tolerated for a home-use kit compared to professional kits given the benefit of more people knowing their status Suited for young people who do not want to confront a live person with a test result especially true in small towns where social stigma prevents people from getting tested People have a right to make choices about how to be tested and how to understand their HIV status Test kits will lessen the stigma of testing and allow it to become more routine Against HIV home-use test kits No assurance that the person self-testing will take appropriate follow-up actions that would be taken if counseling were involved Home-use test kits could be used for inappropriate purposes without legal limitations on the use of the results Untrained individuals should not be performing tests for an agent that has significant implications for the individual and public health. Incorrect test results due to improper performance or interpretation has the potential for significant risk of harm to patients and public health Unable to make a recommendation What is the utility of such a test who will most likely use it? Price will be a factor if test is >$20

Will measures be in place to prevent bulk sales of a home-use kit to entities attempting to establish themselves as counseling and testing sites? Information should be provided in as many languages as possible and at an appropriate educational level and should recommend follow-up testing Need for an assessment of impact of such a test on public health reporting Quality counseling available 24/7 as well as appropriate referrals

Data source: FDA Quick Minutes http://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4190M1_quick%20minutes.pdf

Of note, only two groups opposed the HIV self-test kit during the open public hearing: American Medical Technologists and the American Society for Microbiology. Many more were in favor: community-based organizations; the AIDS Healthcare Foundation; an epidemiologist; the National Association of People with AIDS; the American Social Health Association; and individuals. Perhaps it was due to the substantial number of representatives who were unable to make a recommendation including State Departments of Health; American Association of Clinical Chemistry; National Association of State and Territorial AIDS Directors; AIDS Institute; and the San Francisco AIDS Foundation, that the FDA did not approve OraSure Technologies Inc.s application at this time.

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5.3 HIV self-testing debate part II: the developing world 2012
It is 2012. We now understand that ARV treatment is an integral part of any package of HIV prevention interventions; that early initiation at a higher CD4 threshold is healthier and safer; that the new combination drug regimens are less toxic, more effective, and have fewer side effects; that HIV rapid diagnostic tests are accurate, acceptable and easy to use; that stigma surrounding HIV and HIV testing hasnt dissipated; that most resource-constrained countries can no longer afford to counsel negative people individually; that counseling by telephone hotline has always been an acceptable and well-used method and is now a reality in most parts of Africa; that referral doesnt have to happen face-to-face either; and that test and treat is already a partial reality in the U.S. and is on the horizon in Africa. Furthermore, Zambia and its Cooperating Partners have demonstrated success in scaling up treatment thus far and have implemented reasonably reliable drug regulatory and delivery systems. So what now are the legitimate concerns around HIV self-testing? There are three: 1. Ethics: assuming that HIV self-testing will drastically increase the numbers of people entering the compendium of positive care, can Zambia afford this? Can Zambia commit to providing free ART throughout the lifespans of the cohorts entering into care each year? 2. Referral and retention: will the healthcare-seeking behavior of these motivated self-testers translate into retention in the compendium of positive care in Zambia? What alternative counseling and referral systems could be put in place in order to ensure this? 3. Coercion: as heard from a female delegate in a debate on self-testing in South Africa, if women cant even negotiate condom use, what will they do when their man wants them to test?60 How do we prevent the possible misuse and abuse of HIV self-testing? These risks are valid and are considered in more depth in the discussions section at the end of the paper. Nonetheless, the assumption that the opportunity to self-test for HIV infection would drastically increase not only the numbers of people who test in Zambia, but also, building on the empowerment of self-diagnosis, that more Zambians who test positive would seek care earlier before becoming symptomatic is equally valid and powerful. Therefore, the strategic value of expanding HIV testing to include self-testing in order to expand ART coverage becomes extraordinarily salient.

6. Accuracy and acceptability of the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test
The accuracy of a rapid diagnostics test is clearly important to the consumer. Credibility is one of the multi-Cs discussed earlier in this paper. Ideally, all people who have HIV will test positively and all people who do not have HIV will test negatively. In reality, however, the ability to classify individuals correctly by serostatus depends on the accuracy of the test. To assess the accuracy of a medical diagnostic device, diagnosticians compare the test for sensitivity and specificity against an agreed Gold Standard test a

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best available test that is generally more expensive and/or invasive and requires laboratory analysis. In the case of HIV, the gold standard test is the Western Blot. Sensitivity refers to a test's ability to correctly identify HIV infection in people who are infected a true positive result. It is calculated by the number of positive results divided by the total number of people infected with HIV. Specificity refers to a tests ability to correctly identify the absence of infection in people who are not infected with HIV a true negative result. It is calculated by the number of negative results divided by the total number of people who do not have HIV infection. Alternatively, Positive and Negative Predictive Values describe the proportion of those infected by HIV among all who tested positive (PPV) and the proportion of those without HIV among all who tested negative (NPV). For example: The gold standard test confirms that in a population of 1000 people, 100 are HIV+ and 900 are without HIV infection, an HIV prevalence of 10% in that population. If the screening (diagnostic) test reports that 99 are positive and 895 are negative, we would have a table that looks like Figure 7. Figure 6. Sample test accuracy using sensitivity, specificity, PPV and NPV

HIV present test positive True positives (a) 99 False negatives (c) 1 Total with HIV (a+c) 100 Sensitivity = a / (a+c) 99.0%

No HIV False positives (b) 5 True negatives (d) 895 Total without HIV (b+d) 900 Specificity = d / (b+d) 99.4%

Total Total Positives (a+b) 104 Total negatives (c+d) 896 Total screened (a+b+c+d) 1000 PPV = a / (a+b) 95.2% NPV = d /(c+d) 99.9%

test negative

Data Sources: Johns Hopkins School for Public Health and HealthKnowledge.org UK

While Sensitivity and Specificity are independent of the HIV prevalence in a testing population (test specific); PPV and NPV are not fixed characteristics, but are dependent on HIV prevalence within the given population tested (population specific). Prevalence is important because as the number of HIV positive people in a given population increases, the numerator will also increase thereby making the positive predictive value stronger. Lets apply the sensitivity and specificity characteristics of the recently FDA approved OraQuick ADVANCE Rapid HIV-1/2 Antibody Test (oral fluids) to Zambias adult population with an estimated HIV prevalence of 12.5%. According to the Performance Characteristics in the Customer Letter that is

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inserted into the packaging of OraQuick ADVANCE Rapid HIV-1/2 Antibody Tests for oral fluids (see Annex 1), sensitivity is calculated to be 99.3% and specificity at 99.8% as shown in Figure 8. Figure 7. Accuracy of OraQuick HIV test based on Zambian HIV prevalence and population
Estimated Adult Population Prevalence 12.5% test positive test negative HIV present True positives (a) 868,875 False negatives (c) 6,125 Total with HIV (a+c) 875,000 Sensitivity = a / (a+c) 99.3% 7,000,000 No HIV Total PPV = a / (a+b) 99% NPV = d /(c+d) 100%

False positives Total test positives (b) (a+b) 12,250 881,125 True negatives Total test negatives (d) (c+d) 6,112,750 6,118,875 Total without HIV Total screened (b+d) (a+b+c+d) 6,125,000 7,000,000 Specificity = d / (b+d) 99.8%

Data source: OraSure Technologies, Inc. OraQuick ADVANCE Rapid HIV-1/2 Antibody Test Customer Letter (Advance Package Insert English)

Although the high HIV prevalence in Zambia increases the positive predictive value of the OraQuick test to 99%, we see that the test will incorrectly diagnose 12,250 HIV negative people as positive. With a negative predictive value of 100% and only 6,125 HIV positive people diagnosed as negative (.088% of the population); therefore, a negative diagnosis is most likely correct. For those testing positive, the slightly less accurate predictive value should be a motivating factor for individuals with a positive result to seek a confirmatory test through the health care system. A pilot study in an emergency room in Baltimore, Maryland designed to find out whether money could be saved through a reduction in staff time spent on HIV testing, found that 85% of patients agreed to use a point-of-care self-test and that a large majority opted for an oral fluid test over the finger prick method. Furthermore, the results were 99.6% concordant with those obtained by health care professionals and 94% of the oral fluid testers claimed to trust their results. Importantly, over 80% of the volunteer testers reported feeling in control of own health67. In a head-to-head comparison of accuracy, Pant Pai et al. (2012) found the overall sensitivity of the oral fluids method of diagnosis using OraQuick ADVANCE Rapid HIV-1/2 Antibody Test to be slightly less (1.55%) than that of the finger prick method (98.03% vs. 99.68%) and the overall specificity to be similar between the two (99.74% vs. 99.91%). The PPV was also similar among populations in high prevalence areas, but was somewhat lower in the oral fluid method in areas with a lesser prevalence. Pant Pai also conducted a study in rural India showing 100% sensitivity and specificity of the oral fluid OraQuick ADVANCE Rapid HIV-1/2 test demonstrating its accuracy even in less developed settings68.

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As mentioned previously, the research in Blantyre, Malawi on the uptake and accuracy of rapid diagnostic kits using a swab found the method to be highly acceptable 59. Equally important in that study, was the finding that the oral self-testing results were 99% concordant with rapid finger-stick tests collected in parallel. Figure 8. OraSure Technologies OraQuick ADVANCE Rapid HIV-1/2 Antibody Test

Data source: AP Photo/OraSure Technologies and Zambia Times online advertisement

A very recent study in Zambia compared the accuracy of OraQuick ADVANCE Rapid HIV-1/2 under field conditions in randomly sampled individuals from twelve communities and calculated the cost differentials should OraQuick ADVANCE Rapid HIV-1/2 replace one of the two currently used blood based antibody assays in the national testing algorithm. Findings show the sensitivity and specificity of the OraQuick test to be 98.7% and 99.8%, respectively. However, while the costs were somewhat higher with the oral fluid assay in the algorithm, the researchers concluded, from our field experience, oral fluid based testing offers many advantages over blood-based testing, especially with self-testing on the horizon.69 Figure 10 shows the results of this costing exercise (note: Zambia is currently using the Determine/Uni-Gold algorithm at $3.76). Figure 9. Costing of OraQuick against current national algorithm in Zambia ZAMSTAR Costed HIV testing algorithms Screening assay Confirmatory assay Price/per combination Determine HIV-1/2 Uni-GoldTM Recombigen HIV-1/2 $3.76 Determine HIV-1/2 OraQuick $4.03 OraQuick Determine HIV-1/2 $7.35 OraQuick Uni-GoldTM Recombigen HIV-1/2 $7.67
Data Source: (Zachary 2012)

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Optimally, we would want an oral fluid assay to be the screening test because of user preference, ease of use, disposal (no sharps), and the model is ideal for self-testing. Two things are important in the costing study above: first, the cost of each algorithm includes infrastructure, overhead and set up costs (assumed to be constant for all four combinations); and second, the confirmatory assay is only used on those with reactive (positive) first tests. For example, with an HIV prevalence of 12.5%, one would assume that for every 1000 screening tests, we would need only 125 confirmatory tests (1000 x 12.5%).

7. HIV testing 101: the basics

The primary interest of this paper is the rapid diagnostic HIV antibody test and the individual and public health benefits stemming from its use. However, in order to understand the longer-term benefits (financial, individual and public health) of getting people on treatment and getting them on treatment earlier it is important to understand the basics of two other tests used for clinical diagnosis, the viral load and CD4+ cell count assays, and how they are used and interpreted. This understanding is also pivotal to linking the business case for HIV self-testing to the broader return on investment as discussed later in this paper. The following is a simplified version of the information found on the Center for Disease Control and Prevention (CDC) website AIDSinfo under the tag HIV/AIDS (www.cdc.gov.hiv) An HIV antibody test detects the presence of antibodies to HIV in a persons blood or saliva to determine whether an HIV infection is present. It is important to note that after the original infection, it takes anywhere from 2-14 weeks for the body to begin to generate antibodies to HIV that will appear in the blood or saliva. The period between initial infection with HIV and the point at which testing can detect antibodies in the blood is called the seroconversion period also referred to as the window period. During this period, an HIV-infected person can still spread the disease even though a test will not detect any antibodies in his or her blood or saliva. If a person has an HIV positive result from an antibody test, a confirmatory test is always conducted. HIV infects a persons CD4+ cells. CD4 is a protein that encases the white blood cells that fight against infection and are part of the bodys immune system. When a person is diagnosed with HIV, a CD4+ cell count test is taken to help doctors assess the strength of the immune system and to determine whether the person is treatment ready. Another recommended test is the viral load test to measure the amount of HIV RNA in a patients blood to assess how quickly the virus is reproducing. The viral load test helps doctors to assess how long the patient will stay healthy and whether antiretroviral treatment is working. Generally, the initiation of treatment will decrease a patients viral load by 90% in the first two weeks, bringing it down to fewer than 20 copies (per ml plasma) within 6 months of treatment. Figure 6 shows the interplay between viral load and CD4+ cell count.

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Figure 10. The relationship between CD4+ count and viral load

Data Source: HIV i-base, treatment activist group http://i-base.info/ttfa/section-2/214-how-cd4-and-viral-load-are-related/

Of note in this diagram is the spike in the viral load that occurs just after infection with HIV. This is during the window period when the person is most infectious and, regrettably, least likely to know it. Also of note, is the indefinite period (2 -12 years) of clinical latency when the patient is asymptomatic; this period varies in duration from one person to the next. Once a person is no longer asymptomatic and has begun to exhibit any of a series of opportunistic infections, he/she is considered to have AIDS. Prior to this, the patient is simply living with HIV.

8. Test and treat

Following the groundbreaking news that ART reduces the viral load to almost non-transmissible levels and early treatment delivers considerable health benefits at the patient-level, concerns began to be raised about the expanded costs of putting people on treatment earlier, particularly in resourceconstrained countries. This concern led health economists, researchers and policy makers to investigate the potential cost savings of earlier ART initiation based on the patient-level cost savings largely avoidance of costly opportunistic infections combined with the broader public health savings of new HIV infections averted. Using a variety of modeling and costing projections, researchers began to calculate the short term (5 years hence) immediate gains as well as the longer term (40-50 years) returns on investment. What they are finding is that early treatment can drastically reduce long term costs while also decreasing the overall HIV burden in any given country. Intuitively, when fewer people acquire HIV infection and more people take antiretroviral therapy, we understand that there will be a correlated reduction in HIV-related health care costs and in the HIVrelated encumbrance to what in many countries is an already struggling primary health care system. We also understand that late presentation for HIV clinical care (CD4 < 200 cells/) means that ones immune system is so weakened that it cannot respond as well to ART and that this engenders health care costs,

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and not just in the short-term. A US study found that higher direct medical costs for late presentation ranged from $27,000-$61,000 and the differences in costs were still large even after 7-8 years in care70. A study in South Africa, assuming an annual testing rate of 90%, found that initiating patients on ART with CD4 counts <350 cells/ would prevent an estimated 265,000 new HIV infections in five years and 1.3 million over 40 years; would bring down the number of HIV-related deaths from 12.5 million to 10.6; and disability adjusted live years (DALY) would increase from 109 to 93 million over 40 years. According to the modeling, HIV related cost savings would be $504 million over 5 years and 3.9 billion over 40 years14. It is worth noting that an annual HIV testing rate of 90% may not be realistic; however, as mentioned before, South Africas HIV testing and counseling campaign resulted in over 15 million people knowing their HIV status. In another study modeled in South Africa and India, researchers projected the clinical impact, costs, and cost-effectiveness of early ART and found that protocols for increasing the CD4 threshold for initiation of treatment would increase survival, prevent costly opportunistic infections, avert further HIV transmission and save money9. Unfortunately, neither the clinical benefit to the individual nor the broader cost effectiveness of earlier treatment will be realized unless a large proportion of Zambians get tested for HIV and do so earlier. As described in the previous section, when a person moves out of the clinical latency period and begins to exhibit symptoms of illness, antiretroviral treatment has long been proven to boost the immune system and limit the course of these AIDS-defining illnesses. However, clinicians were hesitant to begin treatment when the initial HIV infection was diagnosed, due to the toxicity of the drug regimens and concern over their long term use. With the development of new antiretroviral treatment combinations, emerging data is showing that untreated HIV infection leads to a range of other conditions including cardiovascular disease and kidney disease, and that the virus begins damaging the body even when its impact on the immune system is shown to be minimal71. Furthermore, expanded analysis of the HPTN 052 study is revealing that individual patient outcomes are also greatly enhanced by the early initiation of ART; data show that the overall incidence of clinical events (both AIDS and non-AIDS) was much lower in study participants in the early therapy arm 9. The broader public health benefits of earlier ART as demonstrated in the HTPN 052 study showing a reduction in transmission by 96% for people on ART combined with the evidence of improved patientlevel outcomes led to calls for a universal test and treat approach to ART delivery72.

8.1 The WHOs Rapid Advice takes baby steps toward test and treat 2009
The World Health Organization 2006 guidelines recommended waiting to initiate treatment until the patients CD4 count was <200 cells/. However, the 2009 Rapid Advice recommendations, noting the progress in developing better, less toxic drug regimens and the mounting evidence that with these less toxic drugs, earlier treatment is more beneficial to the patient, upped the threshold for treatment initiation to <350 cells/ (irrespective of clinical symptoms) so that more people could access the benefits of earlier treatment. Further recommendations encouraged countries to start ART in all

32

individuals who: 1) have active tuberculosis or hepatitis B; 2) are pregnant (note: initially the WHO guidelines for pregnant women used the <350 cells/ threshold, but this was quickly amended to immediate initiation irrespective of CD4 count in a 2010 guide for the elimination of mother-to-child transmission73; 3) are HIV positive in a serodiscordant relationship (where one partner is HIV positive and the other HIV negative) irrespective of clinical symptoms or CD4 count74. The ramifications of this advice for HIV testing (i.e. the need to rapidly scale up the treatment entry point to a level where most people know there status and can start treatment) are obvious.

8.2 The CDC takes bigger steps toward test and treat 2011
Based on data from randomized controlled trials, well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes, and expert opinion, the Center for Disease Control updated its antiretroviral treatment guidelines in 201175. These data demonstrated the following: Effective ART has been shown to prevent transmission of HIV from an infected individual to a sexual partner (HIV Prevention Trials Network 052 study 2011) Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life Untreated HIV infection or uncontrolled viremia (when the virus enters the bloodstream and can circulate freely in the body) may be associated with development of many non-AIDS-defining diseases, including cardiovascular disease, kidney disease, liver disease, neurologic complications, and malignancy.

A study on the optimal time to initiate ART that included 45,691 patients from 18 cohort studies found that when therapy was delayed until CD4 counts fell to the 251-300 cells/ range, the rate of progression to AIDS and/or death was higher than when ART was started at the 351-450 cells/ range 75. Therefore, the CDC 2011 treatment guidelines essentially upped the ART initiation threshold to <500 cells/ and recommended immediate therapy for pregnant women, people with active TB or Hepatitis B, and patients at risk of transmitting HIV to a sexual partner. While the impact of these higher thresholds have yet to be measured, high endemic countries like Zambia are hurrying to cost and implement these new treatment modalities. Implementation begins with an HIV test.

9. Cost benefit of implementing HIV self-testing in Zambia

Zambia has aggressively pursued global best practices in its treatment protocols and set ambitious targets to reverse the HIV epidemic and mitigate its impact. However, the low rate of HIV testing continues to bedevil these efforts. In addition to getting individuals to take an HIV test, two other challenging barriers to expanded ARV care in Zambia exist. They are: 1) getting positive testers into care early; and 2) retaining those already

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enrolled in care throughout the continuum of positive care i.e. for the rest of their lives. Figure 11 shows three stages in the cascade of positive care as defined by Rosen and Fox (2011). Figure 11. Three stages in the Cascade of Positive Care

Data Source: Rosen and Fox (2011).http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2012.03055.x/pdf

Rosen and Fox define the three stages as follows: Stage 1 begins with a positive diagnosis and continues until the patient has taken and returns for his/her CD4 results. The CD4 results determine whether a patient will enter Stage 2 Pre- or is eligible for Stage 3 ART initiation. Stage 2 (Pre-ART) begins with a CD4 result showing a count >350 cells/ and continues until the CD4 count drops to 350 cells/. Note: in Zambia the mean CD4 count at the time of ART initiation is 158 cells/, only 35% of patients initiate with CD4 > 200 cells/, and 28% initiate with CD4 < 100 cells/; therefore, a great proportion (~70%) of positive patients is already eligible for treatment and enters Stage 3 (ART initiation) immediately76. Stage 3 begins with the initiation of ART and continues throughout the patients life.

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The percentages used in my assumptions on loss to follow-up in the continuum of care (Assumption 4 in the next chapter) are based on the data shown in Figure 12. Figure 12. Lost to care in the cascade in US and segregated by age group

Data Source: Clinical Care Options highlights AIDS 2012 Conference, 2012, Washington, DC http://www.clinicaloptions.com/HIV/Conference%20Coverage/AIDS%202012/Tracks/Highlights%20From%20AIDS%202012/ Capsules/FRLBX05.aspx

I use the U.S. data specifically to show that retention is a challenge not only for developing countries with poor health infrastructures, but also for those with relatively well-functioning health systems. Also, in as much as is possible, it is representative of the range in averages in retention found across subSaharan Africa31. The distinction between those who do not return for their CD4 results and those who have higher CD4 counts and are lost to care (Rosen/Fox Stage 2) is not disaggregated in the US data of Figure 12 instead these numbers are combined in the 29% lost after linked to care. As both groups are lost to care, this will not affect the outcome of our costing exercise in the next section.

9.1 Baseline cost-analysis of current HIV testing and ART interventions

In order to assess the cost-benefit of implementing an HIV self-testing model, we will start with a baseline assessment of the current HIV testing and treatment programs in Zambia. Unless otherwise indicated, this costing exercise reflects prices used by the Ministry of Health to cost its Prevention of Mother-To-Child Transmission (PMTCT) Strategy (unpublished); data from the National ART Facility-Based Costing Study 76; data from the Zambia: National Annual Long Term ARV Forecast Report 2013 -2015 (unpublished); and data from Zambias UNGASS reporting 2010 and 201210,11. Data from these studies include:

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Population in 2012 = 14,309,466 (World Bank) Adult population (53.3%) = 7,626,945 (UNICEF) Number of adults in care as of 2012 = 366,649 Annual live births = 500,000. ANC HIV testing coverage = 94% HIV prevalence in pregnant women = 13.25% ANC ART coverage = 85% ART mortalities 11% within 12 months of initiation CD4 test kit cost = $8.31; ART/PPPY = $278; HIV test algorithm $3.76 (Figure 10); Pre-ART/PPPY = $96; Treatment of opportunistic infections (OIs) = $11.40/PPPY (included in ART cost) Average human resources costs in ART $73/PPPY (included in ART costs) Mean CD4 at ART initiation = 158; with 35% > 200; and 28% < 100

Following are the assumptions and their corresponding costs: Assumption 1: HIV testing levels continue at 25% of the adult population. Cost: 1,906,736 x $3.76 = $7.1 million Assumption 2: Zambias PMTCT program will test 94% of the estimated 500,000 pregnant women or 470,000 women (already accounted for in Assumption 1) and 13.5% or 62,275 of these will test positive. 85% or 52,934 of these pregnant women will initiate ART immediately (regardless of CD4 count). Cost: 52,934 x $278 = $14.7 million Assumption 3: Of the 1,436,736 testers who are not pregnant (1,906,736 - 470,000), 12.5% or 179,592 will test positive. Of these, 16% or 28,735 individuals will be lost to follow up and not receive a CD4 count. Leaving 150,857 (179,592 - 28,735) positive testers who will receive a CD4 count. Cost: 150,857 x $8.31 = $1.25 million. Assumption 4: Of the 150,332 positive testers that received a CD4 count, 29% or 43,749 will either not return for their results or will return and not be eligible for ART (CD4 > 350). In either case, they will be lost to follow up leaving 107,109 retained in care. Mean CD4 count at ART initiation will continue to be 158 cells/ and 25% will initiate ART with CD4 counts <100. Therefore 95% or 101,753 not lost to follow up will have CD4 counts <350 and be immediately eligible for ART (from Figure 12). Cost: 101,753 x $278 = $28.2 million

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Assumption 5: The 5% or 5,355 of people who remain enrolled and have CD4 counts >350 will enter into Pre-ART until they are eligible to initiate treatment. Cost: 5,355 x $96 = $0.5 million Assumption 6: Lamentably, 11% or 11,193 of all those initiating treatment will die within 12 months (largely from opportunistic infections due to late presentation in care). Cost: None Total baseline costs are $51.9 million. Figure 13. Baseline costs of HIV testing and treatment

Description

Baseline Scenario Data

14,309,466 7,626,945 953,368 366,649 586,719 1,906,736 $3.76 $278 $96 $8.31 470,000 62,275 52,934 11,804 1,436,736 179,592 28,735 150,857 43,749 107,109 101,753 5,355 11,193 148,238

Costs

Total population Baseline Adult population (53.3%) Estimated adult PLHIV (12.5%) Adult PLHIV already in Care Need to identify (unknown HIV status) # HIV tested Baseline (25%) Cost of testing algorithm ART cost PPPY Pre-ART cost PPPY CD4 test kit ANC testing pregnant women # Positive pregnant women (13.25%) PW+ immediate ART (85%) # PW+ lost to care in 12 mos. (22.3%) Non pregnant testers # Positive testers (12.5%) Lost to follow up in Stage One (16%) Receive CD4 test Loss to follow up Stage Two (29%) # retained in care CD4 <350 (95%) Pre-ART care (5%) Death within 12 months of ART (11%) Total cost of baseline scenario # PLHIV in care baseline

7,169,329

$14,715,583

$1,253,624

$28,287,406 $514,122 $51,940,063

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9.2 Cost and projections of introducing HIV self-testing in Zambia

We hypothesize that when Zambians are given the opportunity to self-test for HIV in the privacy of their own homes, the likelihood that they will do so and correlated assumptions and notes are as follows: Assumption 1: Inclusion of HIV self-testing in the method mix of testing options will increase the total number of people testing by 10% in the year 1, and in each subsequent year by an increase in 10% in the number of new self-testers. Note: In the first year, the number of self-testers will reflect a 10% increase in market share and also a 10% cannibalization of the market share from traditional testing methods thus making the entire market more efficient. In years 2 4, HIV self-testing will be responsible for all of the market increase in testing. Assumption 2: See Figure 9. In a personal email from the ZAMSTAR team, Dr. Zachary confirmed using 18.5% HR costs in the OraQuick/Determine algorithm (almost 50% less than the 37.7% HR costs in the Determine/Unigold algorithm). This includes daily salary cost, number of clients seen daily, time spent on average with each client for pretest counseling, testing, and post-test counseling, and time spent by each counselor to walk from each house on average. We will discount the HR costs completely 7.35 - (7.35 x 18.5%) = $5.99 and use $5.99 for the OraQuick/Determine algorithm. Assumption 3: Many of those who are empowered to HIV self-test will be more likely to do so with their partner. We will assume that 25% of the total self-testers will do so with their partners. Any discordant positive testers will initiate ART immediately. Note 1: According to data from the Zambia DHS 2007, the couples testing will result statistically as follows: both partners positive = 15.6%; discordant couples = 18% Assumption 4: We assume the proven benefits of earlier diagnosis and treatment; therefore, we will discount the costs for opportunistic infections of $11.40/PPPY from all treatment years 278 11.40 = $267 and reduce the costs for human resources from $73/PPPY to $35/PPPY in treatment years 2-5 (269 38 = $229). Assumption 5: We assume a higher prevalence among the self-testers because they have self-selected based on knowledge of their own risk of HIV infection and that of their sexual partners. Therefore 20% prevalence will be found in the HIV self-test group. Assumption 6: Those who self-diagnose have taken a significant step in claiming their right to health; they will be more likely (80%) to seek confirmatory tests and 75% of those will be retained in the compendium of positive care.

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Note: this assumption, while fundamentally logical, has no supporting data given that HIV self-testing is not widely practiced anywhere in the world. However, studies from urban, high-prevalence communities in Blantyre to urban, emergency room settings in Baltimore have articulated the acceptability and empowerment of HIV self-testing.59,67 Assumption 7: Those who self-test for HIV and test positive will have a significantly higher CD4 count than HIV positive individuals currently seeking care in health facilities. We will assume 60% will have a CD4 count >350 and will enter Pre-ART for one year and 40% will have a CD4 count <350 and initiate treatment immediately. Note 1: these CD4 averages are based on data from current CD4 counts of pregnant women entering ANC facilities from the Prevention of Mother-To-Child Transmission (PMTCT) Strategy (unpublished). They are as follows: 19% <200; 21% 200-350; 27% 350500; and 33% >500; pregnant women have long been a barometer of the sexually active population in HIV surveillance. Assumption 8: In reference to assumption 4 above, we consider 11% of those with CD4 count <350 will as lives saved due to early presentation and enrollment. Lets run the numbers. Figure 14 shows the five year self-testing scenario by cohort years.

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Figure 14. Cost of HIV self-testing scenario by cohort years Cohort 1st Year Data Costs Year 1 Costs Year 2 Costs Year 3 Costs Year 4 Costs Year 5 14,309,466 7,626,945 1,906,736 2,097,410 381,347 (190,674 baseline testers who switch + 190,674 new self-testers) 18% $5.99 2,284,270 $267 $229 $96 $8.31 286,010 95,337 14,873 (Reduced HR costs $229 after year 1) 8,580 2,287,512 1,964,892 1,964,892 1,964,892 1,964,892 57,202 72,075 (Total # in care x CD4 $8.31 x2) 57,660 479,152 957,163 957,163 957,163 957,163 8,649 49,011 29,406 2,823,019 6,734,077 6,734,077 6,734,077 6,734,077 19,604 5,226,506 4,489,385 4,489,385 4,489,385 4,489,385 66,240 2,156 13,100,462

Description Total population baseline Adult population (53.3%) # HIV tested baseline (25%) Increase no tested by 10% Actual number self-testing Percentage of market share Cost of testing ART cost PPPY (less 11.40 in OI costs) ART cost PPPY years 2-4 (less 50% HR) Pre-ART cost PPPY CD4 test kit # Singles self-tested (75%) # self-tested w/ partner (25%) Both partners positive (15.6%) Discordant partners (18%) immediate ART Positive single self-testers (20%) Total positive self-testers (partners + singles) Seek CD4 (80%) Lost to follow up Stage 2 (15%) Retained in care (85%) CD4 count >350 Pre-Art (60%) CD4 <350 immediate ART (40%) # PLHIV in care self-testing scenario # of deaths averted (11% of CD4<350) Total cost year 1

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Cohort 2nd Year Description Data Costs Year 1 Costs Year 2 # HIV tested Year 1 2,097,410 Increase by 10% increase in # self-testers 2,516,892 381,347 + (381,347 x 10%) Actual number self-testing 419,482 Percentage of market share 17% Cost of testing $5.99 2,512,697 # Singles self-tested (75%) 314,611 # self-tested w/ partner (25%) 104,870 Both partners positive (15.6%) 16,360 Discordant partners (18%) immediate ART 9,438 2,516,263 Positive single self-testers (20%) 62,922 Total positive self-testers (partners + singles) 79,282 Seek CD4 (80%) 63,426 527,067 Lost to follow up Stage 2 (15%) 9,514 Retained in care (85%) 53,912 CD4 count >350 Pre-Art (60%) 32,347 3,105,321 CD4 <350 immediate ART (40%) 21,565 5,749,157 # PLHIV in care self-testing scenario 63,350 # of deaths averted (11% of CD4<350) 2,372 Total cost year 2 (includes costs from cohort 1 in year 2) 28,556,023

Costs Year 3

Costs Year 4

Costs Year 5

2,161,381

2,161,381

2,161,381

(Total # in care x CD4 $8.31 x2) 1,052,880 1,052,880 1,052,880

7,407,485 7,407,485 7,407,485 4,938,323 4,938,323 4,938,323 (Reduced HR costs $229 after year 1)

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Cohort 3rd Year Description Data Costs Year 1 Costs Year 2 HIV Tested Year 2 2,516,892 Increase by 10% increase self-testers 2,978,322 419,482 + (419,482 x 10%) Actual number self-testing 461,430 Percentage of adult population 15% Cost of testing $5.99 # Singles self-tested (75%) 346,073 # self-tested w/ partner (25%) 115,358 Both partners positive (15.6%) 17,996 Discordant partners (18%) immediate ART 10,382 Positive single self-testers (20%) 69,215 Total positive self-testers (partners + singles) 87,210 Seek CD4 (80%) 69,768 Lost to follow up Stage 2 (15%) 10,465 Retained in care (85%) 59,303 CD4 count >350 Pre-Art (60%) 35,582 CD4 <350 immediate ART (40%) 23,721 # PLHIV in care self-testing scenario 69,685 # of deaths averted (11% of CD4<350) 2,609 Total cost year 3 (includes costs from cohorts 1 and 2 in year 3)

Costs Year 3

Costs Year 4

Costs Year 5

2,072,975

2,767,889

2,377,519

2,377,519

579,774

(CD4 maintenance) 1,158,168 1,158,168

3,415,853 6,324,073

8,148,233 8,148,233 5,432,156 5,432,156 (Reduced HR cost ART)

44,866,151

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Cohort 4th Year Description Data Costs Year 1 # HIV tested in Year 3 2,978,322 Increase by 10% increase self-testers 3,485,895 Actual number self-testing 507,573 Percentage of market share 15% Cost of testing $5.99 # Singles self-tested (75%) 380,680 # self-tested w/ partner (25%) 126,893 Both partners positive (15.6%) 19,795 Discordant partners (18%) immediate ART 11,420 Positive single self-testers (20%) 76,136 Total positive self-testers (partners + singles) 95,931 Seek CD4 (80%) 76,745 Lost to follow up Stage 2 (15%) 11,512 Retained in care (85%) 65,233 CD4 count >350 Pre-Art (60%) 39,140 CD4 <350 immediate ART (40%) 26,093 # PLHIV in care self-testing scenario 76,654 # of deaths averted (11% of CD4<350) 2,870 Total cost year 4 (includes costs from cohorts 1, 2, and 3 in year 4)

Costs Year 2

Costs Year 3

Costs Year 4

Costs Year 5

2,280,273

3,044,678

2,615,271

637,752

1,273,985

3,757,439 6,956,480

8,963,057 5,975,371

63,498,283

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Cohort 5th Year Description Data Costs Year 1 #HIV tested Year 4 2,213,503 Increase no tested by 10% 3,349,983 Actual number self-testing 1,136,481 Percentage of adult population 38% Cost of testing 5.99 # Singles self-tested (75%) 418,748 # self-tested w/ partner (25%) 139,583 Both partners positive (15.6%) 21,775 Discordant partners (18%) immediate ART 12,562 Positive single self-testers (20%) 83,750 Total positive self-testers (partners + singles) 105,524 Seek CD4 (80%) 84,420 Lost to follow up Stage 2 (15%) 12,663 Retained in care (85%) 71,757 CD4 count >350 Pre-Art (60%) 43,054 CD4 <350 immediate ART (40%) 28,703 # PLHIV in care self-testing scenario 84,319 # of deaths averted (11% of CD4<350) 3,157 Total cost year 5 (includes costs from cohorts 1, 2, 3, and 4 in year 5) Total cost all years all cohorts 234,014,545 13,100,462 Total PLHIV in care self-testing scenario 351,599 57,591

Costs Year 2

Costs Year 3

Costs Year 4

Costs Year 5

3,349,146

701,527

1,427,956

4,133,182 7,652,128

28,556,023 63,350

44,866,151 69,685

63,498,283 76,654

83,993,629 83,993,629 84,319

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Figure 14 shows us that at a cost of $234 million, we have put 351,599 adults on ART in five years. This is almost equal to the number of adults currently in care in our baseline data after decades of interventions and billions of dollars invested. The National AIDS Strategic Framework 2011 2015 estimates funding for 2012 at $371 million, if we assume this funding continues at a flat rate over the next five years it would amount to $1.88 billion. Our investment of $234 million would consume 12.6% of the total. What are the risks Zambia takes in not investing in this method? An initial investment of less than $8 million is all that is needed to reach a substantial number of individuals who are not currently using any of the HIV testing methods. The cost of not investing in HIV self-testing is a tragically missed opportunity. First, the human tragedy is that over 350,000 individuals would not receive the care and services they need. Figure 14, further documents the number of lives saved (deaths averted) for each cohort; these total 13,165 individuals who statistically would not survive the first 12 months after initiation leaving bereaved loved ones faced with loss of income and potential orphaned children for the state to tend to. But is $234 million over five years a sound financial investment?

9.3 Social return on investment

In the business world, return on investment (ROI) is used to evaluate the efficiency of an investment by calculating the benefit of the return. The standard measurement of ROI is the gain from the investment less the cost of the investment divided by the cost of the investment or: ROI = Gains from investment Cost of investment Cost of investment

We have identified the cost of the investment, but what are the benefits? Granich et al. (2009) estimated the number of HIV transmissions (infections) averted as follows, we assumed that the epidemic is in a steady state so that each person with HIV infects one other person before they die. A one to one treatment to infection averted ratio. Given that the average lifespan for a positive untreated person is about ten years and we are only looking at the next five years, we will use a ratio of 1:2 and assume that for every two people on treatment, we avert one transmission. Therefore, 531,599/2 = 175,800. The cost benefit would be 175,800 x 278 x 5 or $244,361,450 in treatment costs averted. The financial ROI on our testing scenario would be this: ROI = Cost of infections averted Cost of investment Cost of investment Or 244 million 234 million = 0.04 or 4% 234 million 45

ROI =

4% growth in five years is not an ideal investment in the business world; however, there is often a social return on the investment (SROI) that is non-financial. For example, in our self-testing scenario how would we measure the value of the health and wellbeing of the individuals themselves beyond the costs of treatment avoided? How should we value the lives saved? We would need to monetize the related benefits from the activity of testing and treatment by using a financial proxy or estimate of the financial value of one life. In this case, we will use Zambias gross national income (GNI) to estimate the lost income generation from those who would not have survived the first year. Our financial proxy would translate as follows: ((GNI x # deaths averted x # cohort years remaining) + Cost of infections averted) Cost of investment Cost of investment GNI =$ 1,160 (World Bank 2011) Financial proxy = (3157 x 1160) + (2870 x 1160 x2) + (2609 x 1160 x 3) + (2372 x 1160 x 4) + (2156 x 1160 x5) = 64,374,201 Therefore, SROI = (64,374,201+ 244,361,450) 234,014,545 = 0.23or 23% 234,014,545

The social benefits make a tremendous difference to the efficiency and soundness of our investment and to the lives and health of the Zambian people. Finally and importantly, this initial investment of $8 million to implement HIV self-testing has the potential to add 351,599 individuals into the compendium of care. With this addition plus the baseline 148,238, Zambia will attain 81% coverage of all people in need of treatment and care, effectively achieving the goal of universal access only dreamed of a few years back. Zambia can scarcely afford to incur the costs both human and financial of not taking this innovative step.

10. Discussion
As with any move forward in innovation, there are risks involved. In this section, we want to differentiate the risks to the health and safety of the Zambian consumers from venture risks i.e. business challenges in implementation, uptake and sustainability. Raising capital, marketing and promotion, distribution and delivery systems, management and leadershipthese are standard business practices full of risks and opportunities. This section, however, addresses the risks inherent in the use (or abuse) of the product described in the HIV self-testing part II: global debates section earlier because they are intricately correlated to the health and safety of the consumers who will use the product. In the following sub-chapters, we align each of the three primary concerns with one of the three research questions. Our intention in this chapter is not to provide definitive answers or to resolve each of these concerns, but to identify and recommend a few possible solutions and indicate areas for further research.

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10.1 Is innovation enough?

We have demonstrated that HIV self-testing is an innovation with the potential to greatly augment the numbers of Zambians testing for HIV and learning their status; however is this enough? The link between HIV testing and enrollment at a health facility has been documented as the stage where the largest number of positive clients are lost to care. Although, studies have shown that knowledge of HIV status often leads to behavior change to mitigate the risk of transmission, the recent evidence of both the individual and population-level benefits (as well as cost benefits) of early HIV treatment means that resolving the barriers to referral and linkage to care is paramount. How do we get Zambian positive selftesters out of the privacy of their homes and into the health care system for a confirmatory HIV test? What systems can we put in place and or strengthen in order to ensure this important linkage? There are many documented successes of HIV hotlines that can be enjoined to provide assistance with test interpretation and referral to care. Zambia launched a Toll-free, 24 hours, HIV Talkline in 2003 to overwhelming demand averaging 850 calls per day. Researchers claim that the hotline was desperately needed and filled a critical niche in the HIV service arena. According to the United States Agency for International Developments website in Zambia, between the launch in December 2003 and March 2007 more than 420,000 people called the Talkline and over 123,000 Zambians received services. Expansion of the Talkline to address concerns and issues around HIV self-testing with its ongoing referral services may help to build an important bridge to care. However, if Zambia is to achieve universal access to prevention, treatment, care and support with hundreds of thousands more individuals accessing treatment, a move toward community-centered treatment, adherence and support will also be necessary. Civil society groups and communities all over Africa are designing and implementing community-based models for ART delivery, patient tracking, and care and support with great success. We have demonstrated that as more individuals begin to access treatment earlier, their health needs will not be as labor-intensive as those who accessed treatment with already compromised immune systems; therefore, these new models of community care and support can be more cost-effective and less burdensome to the health care systems. We know that Zambian people are much more likely to embrace community centered activities when the messaging and interventions are developed by and for their own communities. Expanding operations research around the implementation and piloting of innovative community models of service delivery and adherence support of this kind will be a fundamental and worthy investment.

10.1 Does ease of use lead to abuse?

We clearly demonstrated that the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test is an acceptable method in no small part because it is simple to use; however, can availability combined with simplicity lead to abuse? As noted in the opening chapter of the HIV literature review, the entire discourse around HIV testing has always been firmly positioned within the context of ethics and the safe-guarding of human rights. The fears around mandatory testing, coerciveness in obtaining consent, discrimination, and social exclusion do not necessarily arise from the act of HIV self-testing itself. It is the notion that self can easily be taken out of the self-testing equation that incites the apprehensions of misuse and abuse. The idea that simple to use oral swabs intended for HIV self-testing can be misappropriated and

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misused under a broad range of circumstances is perhaps the primary cause for HIV self-testings lack of large scale patronage. It is not that HIV self-testing has opened up Pandoras Box, but the act of freely distributing the testing kits that has. What amount of abuse and coercion, particularly levied against already vulnerable women in developing countries like Zambia, would be tolerable on behalf of the greater good? What recourse will wrongfully and/or coercively tested individuals have? What litigation and court representation services are in place to provide access to justice? We know that programs to protect the rights of people living with HIV and increase their access to justice make basic HIV services more effective. We posit that the very act of HIV self-testing can be empowering and lead to a feeling of control over ones health, even to demanding the right to health. If Zambias policy environment doesnt allow for human rights violations to be addressed, then amendments that make the law accessible and actionable should be put in place not for HIV or public health reasons, but because the state is obligated to guarantee the protection of its weakest and most vulnerable citizens. This is one of the basic rights of man.

10.2 Some ethics around cost-effectiveness

We have demonstrated that Zambia could very well witness an enormous uptake of HIV testing when the offer of free self-testing is provided along with the mix of testing methods already available. While this is a good thing, we hypothesize that those who take the affirmative step to HIV self-test in the first place and who test positive will be equally be empowered to seek, yea demand follow up care. The success of the free ART program in Zambia to date has contributed to the understanding that ARV treatment comes with a life-long entitlement of HIV positive citizens on their governments. Each individual newly initiated on ART is told that adherence is a lifelong necessity. This creates an expectation that the current regimen, or an improved one, will be consistently and freely available throughout ones lifetime. This expectation and the Governments ability to afford lifelong care for all people living with HIV is often called the treatment time bomb. Governments, especially those in high HIV prevalence countries, bear an important moral responsibility to meet these expectations. So do donors. This is at the heart, or should be, of the shared responsibility agenda currently in vogue in the global health arena. The Government of Zambia has commissioned several studies to explore different approaches to longterm sustainable financing for AIDS including: an AIDS trust fund; a social health insurance scheme for the formal sector; earmarking tax revenues for AIDS treatment spending; and increasing the private sector contribution to AIDS. Zambian decision makers would do well to select a method (or several) and begin to increase its share of AIDS funding. In the short term however, it is clear that Zambia must continue to rely on financing by Cooperating Partners for more than half of its HIV treatment and care program.

Conclusion
This dissertation set out to examine whether HIV self-testing is an innovative solution to address Zambias low uptake in HIV testing. The literature review on HIV testing demonstrated that the closer

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HIV testing gets to households and families, the higher the uptake in services. We have demonstrated that this evidence is extraordinarily supportive of our hypothesis that HIV self-testing would greatly increase the uptake of HIV testing in the Zambian population. We discussed the benefits of early HIV testing and treatment from the aspect of the individuals health and the broader public health gains in reduced transmission of the virus noting the HIV test as the gateway. A second research objective was to determine whether an oral fluid HIV self-testing product, specifically the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test, would be acceptable, easy to use and accurate in the Zambian context. We demonstrated how to assess the credibility of a medical diagnostic device by comparing its sensitivity and specificity against an agreed gold standard. We show that in a number of head-to-head comparisons of the accuracy of oral-fluid based versus blood (finger prick) specimen HIV testing kits from a teaching hospital in rural India to an Emergency Room in the United States including under field conditions in Zambia, the oral fluid-based assay OraQuick ADVANCE Rapid HIV-1/2 was not only comparable in accuracy, but was preferable. To calculate our third objective, whether HIV self-testing, with its potential to drastically increase the numbers of people in care, is a value for money investment for Zambia; we used a baseline scenario of the cost of Zambias current testing and treatment outcomes. We then applied conservative assumptions around the uptake of HIV self-testing over a five year period, the retention of the selftesters by cohort through the compendium of care, and their initiation on antiretroviral treatment according to the Zambian national protocols. We then calculated the combined the costs for each cohort over the five year period and weighed this investment against the financial benefits of the treatment costs avoided due to reduced transmission. Our return on investment was a modest 4%. However, by using a financial proxy for the almost 20,000 lives saved, we recalculated the cost benefits and found that, in the short term and with a very small initial investment of $8 million, the social return on investment was a healthy 23%. The benefits of implementing an HIV self-testing approach and the subsequent provision of treatment to all those in need will more than offset the program costs to deliver these services. Of course there are many other social, non-financial benefits to be gained by getting HIV positive people diagnosed and on treatment earlier including increased labor productivity, better quality of life, better school attendance, stronger public health systems, and stronger families and communities. HIV self-testing is here. The time to act is now.

Study limitation
There is a conspicuous lack of primary data in this dissertation. However, we believe that interviews, surveys and questionnaires would be anecdotal at best given the novelty of the notion of HIV selftesting in Zambia. While plausible, many of the assumptions around HIV self-testing in Chapter 9 are not evidence based.

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Recommendations
Further research to prove the many assumptions and theories articulated throughout this dissertation is highly recommended. As countries raise the thresholds of treatment initiation and begin to drastically increase the numbers of people in care before they become symptomatic and ill, piloting community-based initiatives for service delivery, adherence and support will be imperative. There are many operational and ethical factors that should be addressed before HIV self-testing is implemented including how counseling and referral services can be provided to those who require more information and support; how to prevent abuse and misuse of the testing kits without impeding access; and what sustainability plans Governments and their Cooperating Partners need to put in place to assure life time access to and affordability of the most effective ARV drugs.

Bibliography
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. United Nations General Assembly, Political declaration on HIV and AIDS: Intensifying our efforts to eliminate and AIDS. 2011, United Nations: New York. UNAIDS, Together we will end AIDS. 2012, UNAIDS: Geneva. WHO/UNAIDS/UNICEF (2010) Towards Universal Access: Scaling up Priority HIV Interventions in the Health Sector. Central Statistical Office, Zambia 2010 Census of Population and Housing: Preliminary Population Figures. 2011, Ministry of Finance and National Planning: Lusaka. WHO/UNAIDS/UNICEF, Global HIV/AIDS Response Epidemic update and health sector progress towards Universal Access: Progress Report 2011. 2011, WHO: Geneva. Weinhardt, L.S., et al., Effects of HIV counseling and testing on sexual risk behavior: a metaanalytic review of published research, 1985-1997. Am J Public Health, 1999. 89(9): p. 1397-405. Arthur, G., et al., Behaviour change in clients of health centre-based voluntary HIV counselling and testing services in Kenya. Sex Transm Infect, 2007. 83(7): p. 541-6. Cohen, J., HIV Treatment as Prevention. Science, 2011. 334(6063): p. 1628. HIV Prevention Trials Network, Additional benefits of early HIV treatment revealed, in Science Daily. 2012. Republic of Zambia, M.o.H., National AIDS Council,, Zambia Country Reoprt: Monitoring the Declaration of Commitment on HIV and AIDS and the Universal Access: Biennial Report. 2010, National AIDS Council: Lusaka. Zambia, G.o., Zambia Country Report: Monitoring the Declaration of Commitment on HIV and AIDS and Universal Access. 2012, National HIV/AIDS/STIs/TB Council/Ministry of Health: Lusaka. Central Statistical Office (CSO), M.o.H.M., Tropical Diseases Research Centre (TDRC), and a.M.I.I. University of Zambia, Zambia Demographic and Health Survey 2007. 2009, CSO and Macro International Inc.: Calverton, Maryland, USA.

11. 12.

50

13.

Weber, J., R. Tatoud, and S. Fidler, Postexposure prophylaxis, preexposure prophylaxis or universal test and treat: the strategic use of antiretroviral drugs to prevent HIV acquisition and transmission. AIDS, 2010. 24: p. S27-S39 10.1097/01.aids.0000390705.73759.2c. Granich, R., et al., Expanding ART for treatment and prevention of HIV in South Africa: estimated cost and cost-effectiveness 2011-2050. PLoS One, 2012. 7(2): p. e30216. Rietmeijer, C.A. and M.W. Thrun, Mainstreaming HIV testing. AIDS, 2006. 20(12): p. 1667-1668 10.1097/01.aids.0000238414.21066.4c. Bayer, R. and A.L. Fairchild, Changing the Paradigm for HIV Testing The End of Exceptionalism. New England Journal of Medicine, 2006. 355(7): p. 647-649. Bayer, R. and C. Edington, HIV Testing, Human Rights, and Global AIDS Policy: Exceptionalism and Its Discontents. Journal of Health Politics, Policy and Law, 2009. 34(3): p. 301-323. WHO/UNAIDS (2004) UNAIDS/WHO Policy Statement on HIV Testing. http://www.who.int/hiv/pub/vct/en/hivtestingpolicy04.pdf [accessed on 5 August 2012] Agu, V.e.a., The Development of Harmonized Minimum Standards for Guidance on HIV Testing and Counselling and Prevention of Mother-to-Child Transmissino of HIV in the SADC Region: HTC Country Report Zambia. 2009, Southren African Development Community and African Development Bank: Cape Town. WHO (2001) Increasing Access to Knowledge of HIV Status: conclusionis of a WHO Consultation. http://www.who.int/HIV/pub/vct/en/HIV_2002_09_en.pdf [Accessed on 7 August 2012] Center for Disease Control and Prevention (2006) Revised Recommendations for HIV TEsting of Adults, Adolescents, and Pregnant Women in Health-Care Settings. MMWR Morb Mortal Wkly Rep., 1-17. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm [Accessed on 18 August 2012] WHO/UNAIDS, Guidance on provider-initiated HIV testing and counselling in health facilities. 2007, WHO/UNAIDS: Geneva. Matovu, J.K.B. and F.E. Makumbi, Expanding access to voluntary HIV counselling and testing in sub-Saharan Africa: alternative approaches for improving uptake, 20012007. Tropical Medicine & International Health, 2007. 12. Angotti, N., et al., Increasing the acceptability of HIV counseling and testing with three C's: convenience, confidentiality and credibility. Soc Sci Med, 2009. 68(12): p. 2263-70. Menzies, N., et al., The costs and effectiveness of four HIV counseling and testing strategies in Uganda. AIDS, 2009. 23(3): p. 395-401 10.1097/QAD.0b013e328321e40b. Liambila, W., et al., Feasibility, Acceptability, Effect and Cost of Integrating Counseling and Testing for HIV within Fmaily Planning Services in Kenya. 2008, FRONTIERS Final Report, Population Council: Washington, DC. Das, R., et al., Strengthening Financial Sustainability through Integration of Voluntary Counseling and Testing Services with Other Reproductive Health Services. 2007, Population Council: Frontiers, New York. Forsythe, S., et al., Assessing the cost and willingness to pay for voluntary HIV counselling and testing in Kenya. Health Policy Plan, 2002. 17(2): p. 187-95.

14. 15. 16. 17. 18. 19.

20. 21.

22. 23.

24. 25. 26.

27.

28.

51

29. 30.

Fylkesnes, K. and S. Siziya, A randomized trial on acceptability of voluntary HIV counselling and testing. Trop Med Int Health, 2004. 9(5): p. 566-72. Bond, V.A., "It is not an easy decision on HIV, especially in Zambia": opting for silence, limited disclosure and implicit understanding to retain a wider identity. AIDS Care, 2010. 22 Suppl 1: p. 6-13. Fox, M.P., et al., Barriers to initiation of antiretroviral treatment in rural and urban areas of Zambia: a cross-sectional study of cost, stigma, and perceptions about ART. J Int AIDS Soc, 2010. 13: p. 8. MacPherson, P., et al., Stigmatising Attitudes among People Offered Home-Based HIV Testing and Counselling in Blantyre, Malawi: Construction and Analysis of a Stigma Scale. PLoS One, 2011. 6(10): p. e26814. Obermeyer, C.M. and M. Osborn, The Utilization of Testing and Counseling for HIV: A Review of the Social and Behavioral Evidence. American Journal of Public Health, 2007. 97(10): p. 17621774. The Global Fund, SCALING-UP ANTIRETROVIRAL TREATMENT FOR HIV/AIDS IN ZAMBIA. ZAM405-G24-H; HIV/AIDS Round 4. 2005, Country Coordinating Mechanism, : Zambia http://portfolio.theglobalfund.org/en/Grant/Index/ZAM-405-G24-H [accessed on 29 August 2012] Simuchimba, M., Religious Education in a Christian Nation: The Case of Zambia. British Journal of Religious Education, 2001. 23(2): p. 107-116. Simpson, A., Christian identity and men's attitudes to antiretroviral therapy in Zambia. African Journal of AIDS Research, 2010. 9(4): p. 397-405. Jurgensen, M., et al., The burden of knowing: balancing benefits and barriers in HIV testing decisions. a qualitative study from Zambia. BMC Health Services Research, 2012. 12(1): p. 2. Central Statistical Office, M.o.H., Univeristy of Zambia, and MEASURE Evaluation,, Zambia Sexual Behaviour Survey 2009. 2010, Central Statistical Office and MEASURE Evaluation: Lusaka. Government of the United States of America and Government of the Republic of Zamiba (2010) Partnership Framework between the Government of the Republic of Zambia Ministry of Finance and Naitonal Plannign and Minsitry of Health and the Government of the United States of America to support implementation of the Zambian national response to HIV and AIDS from 2011-2015. http://www.pepfar.gov/documents/organization/153133.pdf [accessed on 25 June 2012] Sikasote, J., S. Chanda, and W. Nicodemus, Zambia: National Quantification of HIV Test Kits (2009-2015). 2008. Weiser, S.D., et al., Routine HIV testing in Botswana: a population-based study on attitudes, practices, and human rights concerns. PLoS Med, 2006. 3(7): p. e261. Topp, S.M., et al., Opt-out provider-initiated HIV testing and counselling in primary care outpatient clinics in Zambia. Bulletin of the World Health Organization, 2011. 89: p. 328-335. Kankasa, C., et al., Routine offering of HIV testing to hospitalized pediatric patients at university teaching hospital, Lusaka, Zambia: acceptability and feasibility. J Acquir Immune Defic Syndr, 2009. 51(2): p. 202-8.

31.

32.

33.

34.

35. 36. 37. 38. 39.

40. 41. 42. 43.

52

44.

Evans, C. and E. Ndirangu, Implementing routine provider-initiated HIV testing in public health care facilities in Kenya: a qualitative descriptive study of nurses' experiences. AIDS Care, 2011. 23(10): p. 1291-7. Joseph, H.A. et al., 'The Anticipation Alone could Kill You': Past and Potential Clients' Perspectives on HIV Testing in Non-Health Care Settings. AIDS Education & Prevention, 2011. 23(6): p. 577594. Corbett, E.L., et al., Uptake of workplace HIV counselling and testing: a cluster-randomised trial in Zimbabwe. PLoS Med, 2006. 3(7): p. e238. Van der Borght, S.F., et al., Long-term voluntary counseling and testing (VCT) uptake dynamics in a multicountry HIV workplace program in sub-Saharan Africa. AIDS Care, 2010. 22(2): p. 195205. Mbopi-Kou, F.-X., et al., High impact of mobile units for mass HIV testing in Africa. AIDS, 2007. 21(14): p. 1994-1996 10.1097/QAD.0b013e3282f006c3. Robertson, G., et al., Reaching out to men in Soweto through a community-based VCT approach, in 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 2011: Rome, Italy. Lugada, E., et al., Comparison of Home and Clinic-Based HIV Testing Among Household Members of Persons Taking Antiretroviral Therapy in Uganda: Results From a Randomized Trial. JAIDS Journal of Acquired Immune Deficiency Syndromes, 2010. 55(2): p. 245-252 Wolff, B., Evaluation of a home-based voluntary counselling and testing intervention in rural Uganda. Health policy and planning, 2005. 20(2): p. 109-116. South Africa.info (2011) South Africa makes progress on HIV/AIDS. http://www.southafrica.info/about/health/aids-150811.htm#ixzz25g0tIGPy [Accessed on 10 September 2012] Lugada, E., et al., Rapid Implementation of an Integrated Large-Scale HIV Counseling and Testing, Malaria, and Diarrhea Prevention Campaign in Rural Kenya. PLoS One, 2010. 5(8): p. e12435. Walensky, R.P. and I.V. Bassett, HIV Self-testing and the Missing Linkage. PLoS Med, 2011. 8(10): p. e1001101. WHO HIV Testing and Counselling. 2012. http://www.who.int/HIV/topics/vct/en/ [Accessed on 4 August 2012] National AIDS and STI Control Programme, M.o.P.H.a.S., Guidelines for HIV Testing and Counselling. 2010: Nairobi, Kenya. Mavedzenge, S.N., et al., HIV self-testing among helath workers: a review of the leterature and discussion of current practicies, issues and optoins ofr increasing access to HIV testing in Subsaharan Africa. WHO Library 2011. Kalibala, S., et al., Knowing myself first: Feasibility of self-testing among health workers in Kenya,. 2011. Choko, A.T., et al., The Uptake and Accuracy of Oral Kits for HIV Self-Testing in High Prevalence Setting: A Cross-Sectional Feasibility Study in Blantyre, Malawi. PLoS Med, 2011. 8(10): p. e1001102.

45.

46. 47.

48. 49. 50.

51. 52.

53.

54. 55. 56. 57.

58. 59.

53

60.

Masina, L. (2012) Malawi: HIV Self-Testing Study Yuields Promising Results. Think Africa Press. http://thinkafricapress.com/malawi/hiv-self-testing-study-yields-promising-results [accessed on 3 September 2012] Tone, A., Medicalizing reproduction: the pill and home pregnancy tests. The Free Library, 2012. AIDSinfo, Home-Use HIV Test Kits, in HIV/AIDS News, N.I.f. Health, Editor. 1996. http://aidsinfo.nih.gov/news/243/home-use-hiv-test-kits/ [Accessed on 4 September 2012] Millenson, E. (2005) Testimony of Elliott J. Millenson: 85th Meeting of Blood Products Advisory COmmittee Meeting. http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4190t1.htm [accessed on 23 September 2012] U.S. Food and Drug Administration, FDA approves first over-the-counter home-use rapid HIV test, H.H. Services, Editor. 2012, U.S. Food and Drug Administration: Washington, DC. Arnold, C., At-home HIV test poses dilemmas and opportunities. The Lancet, 2012. 380(9847): p. 1045-1046. Federal Drug Administration, Approaches to OVer-the-Counter (OTC) Home-Use HIV Test Kits, in Blood Products Advisory Committee 85th Meeting. 2005: Gaithersburg. Gaydos, C.A., et al., Will patients "opt in" to perform their own rapid HIV test in the emergency department? Ann Emerg Med, 2011. 58(1 Suppl 1): p. S74-8. Pant Pai, N., Oral fluid-based rapid HIV testing: issues, challenges and research directions. Expert Rev Mol Diagn, 2007. 7(4): p. 325-8. Zachary, D., et al., Field comparison of OraQuick(R) ADVANCE Rapid HIV-1/2 antibody test and two blood-based rapid HIV antibody tests in Zambia. BMC Infect Dis, 2012. 12(1): p. 183. Fleishman, J.A., et al., The economic burden of late entry into medical care for patients with HIV infection. Med Care, 2010. 48(12): p. 1071-9. Thompson M., J.A. Aberg, and P. Cahn, Antiretroviral treatment of adult hiv infection: 2010 recommendations of the international aids societyusa panel. 2010. 304(3): p. 321-333. Mugavero, M.J., et al., Early Retention in HIV Care and Viral Load Suppression: Implications for a Test and Treat Approach to HIV Prevention. JAIDS Journal of Acquired Immune Deficiency Syndromes, 2012. 59(1): p. 86-93 World Health Organization, Programmatic Update: Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. 2012, World Health Organization: Geneva. World Health Organization (2009) Rapid Advice: Antiretroviral therapy for HIV infection in adults and adolescents.World Health Organization: Geneva. Center for Disease Control (2011) Guidelines for the USe of Antiretroviral Agents in HIV-1Infected Adults and Adolescents. Clinical Guidelines Portal. http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatmentguidelines/10/initiating-antiretroviral-therapy-in-treatment-naive-patients [Accesssed on 4 September 2012] Ministry of Health, National Facility-Based Anti-Retroviral Treament Costing Study in Zambia, in Draft copy - Unpublished. 2012, Clinton Health Access Initiative, University of Zambia, Ministry of Health: Lusaka. 54

61. 62. 63.

64. 65. 66. 67. 68. 69. 70. 71. 72.

73.

74. 75.

76.

Annex 1: Excerpts from OraQuick Customer Letter

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