American Journal of Pharmaceutical Education 2005; 69 (4) Article 72.

TEACHERS TOPICS The Pharmacotherapy of the Modern Day Epidemic Infection with Human Immunodeficiency Virus (HIV)
Frank Romanelli, PharmD
College of Pharmacy, University of Kentucky
Submitted August 19, 2004; accepted November 1, 2005; published September 8, 2005.

Infection with Human Immunodeficiency Virus (HIV) and the resultant Acquired Immunodeficiency Syndrome (AIDS) have reached pandemic proportions, causing approximately 20 million deaths worldwide. HIV pharmacotherapy is a complex and rapidly evolving area. Educators are challenged to provide pharmacy students with current, specific, and practical information in this highly specialized area. This paper describes a learning experience in HIV/AIDS which incorporates basic HIV epidemiology, pathophysiology, and pharmacotherapy. The experience also emphasizes the psychosocial aspects of the disease which can among other things impact adherence. Mini-cases and a clinic medication history form that are used to assist students in assimilating information and relating it to patient care are also discussed.
Keywords: Human Immunodeficiency Virus (HIV), Acquired Immunodeficiency Syndrome (AIDS), pharmacotherapy, epidemic

INTRODUCTION
The first cases of suspected Human Immunodeficiency Virus (HIV) infection in the United States were reported in 1981 in a case series describing 5 homosexual males presenting with Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP).1,2 Initially the syndrome associated with HIV infection was known as Gay Related Immune Disorder (GRID). Researchers and clinicians alike would soon recognize that, similar to most infectious diseases, HIV was not population specific. Thereafter, the term GRID was replaced with Acquired Immunodeficiency Syndrome (AIDS).3 An estimated 900,000 Americans were thought to have been infected with HIV as of the end of 2003, some of whom are completely unaware of their serostatus.4 Globally, some 40 million persons are estimated to be infected.5 Perhaps the most serious consequences and effects of the disease can be seen on the continent of Africa where in some nations life expectancies have been reduced from the mid-60s to the late 30s.5 Potent antiretrovirals have significantly impacted life expectancies of infected individuals living in industrialized nations.6 However, infection rates across the globe have continued to increase, making HIV a modern-day pandemic.5 Unintentionally, students, clinicians, and lay persons often loose sight of the significance and ongoing crisis associated with HIV disease. Many wonder what it
Corresponding Author: Frank Romanelli, PharmD. Address: 800 Rose Street, Lexington, KY 40536. Tel: 859257-4778. Fax: 859-323-0069. E-mail: froma2@uky.edu

would have been like to have lived during times when major diseases such as Yersinia pestis or influenza caused significant numbers of deaths, yet these same individuals may be unaware of the effects of the modern day plague of HIV disease. This learning experience is delivered to third-professional year pharmacy students and is intended to describe the current epidemiology and effects of HIV disease. Organization includes historical perspective, epidemiology, etiology, diagnosis, transmission, pathophysiology, and pharmacotherapy. Psychosocial and pharmacy-specific issues are also introduced. Several mini-cases are used to illustrate concepts discussed in class and to demonstrate approaches to patient care. Students also review and practice completing an HIV clinic medication history form. Etiology and Testing Scientific evidence indicates that HIV probably originated in other primates, most likely certain subspecies of chimpanzees.7,8 An HIV-like viron (eg, Simian Immunodeficiency Virus (SIV)) is suspected to have mutated and subsequently acquired the ability to infect humans. The HIV viron exists in 2 forms, HIV-1 and HIV2.9 HIV-1 is responsible for approximately 99% of all US cases, while HIV-2 is more predominant in the countries of West Africa. Patients found to be HIV seropositive are often designated as HIV+. AIDS is the acquired immunodeficiency syndrome often characterized by immune dysfunction and the presence of opportunistic infections. 525

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Not all patients who are HIV+ have AIDS. An HIV+ patient is considered to have AIDS when the CD4+ T lymphocyte count is or ever has been below the threshold of 200 cells/mm3 or if the patient develops one of a list of established AIDS defining illnesses (eg, Kaposis sarcoma, tuberculosis, Pneumocystis jiroveci pneumonia, toxoplasmosis, Mycobacterium avium).10 The screening test for HIV is the HIV ELISA (enzyme linked immunosorbent assay) test.11 This is an antibody detection assay that can, in certain situations (eg, co-infection with other viral illnesses, recent vaccination), produce false positive results. Positive results should be confirmed by repeat ELISA testing and subsequently through the use of a Western Blot assay. When combined, the HIV ELISA and Western Blot assays approximate 99% sensitivity and specificity in detecting HIV.11 One limitation of the ELISA and any antibody detection assay for HIV is that on average it may take upwards of 3-6 months for acutely infected individuals to seroconvert. Thus patients with negative ELISA tests who suspect a recent infection should consider being retested in 6 months. A CLIA (Clinical Laboratory Improvement Amendments)-waived rapid HIV ELISA test (OraQuick Advantage HIV-1/2) is now available and FDA approved for testing of either serum or oral fluids. A person who receives a positive result from the OraQuick test would still require confirmatory testing using the Western Blot assay. Transmission The virus itself is difficult to transmit. In the United States, sexual contact, particularly among men who have sex with men (MSM), remains the most common mode of transmission.4 Because of its traumatic nature, anal intercourse appears to be the riskiest form of sex. Vaginal intercourse is the next riskiest form of sex, with transmission from males to females being more effective. Coinfection with other sexually transmitted diseases (eg, syphilis, herpes simplex virus) often results in inflammation or ulceration of the genitourinary tract and has been reported to increase the likelihood of sexual transmission of HIV. The role of oral sex in the transmission of HIV is highly controversial.12 Some researchers have found little to no risk while others have reported some level of transmissibility. Most clinicians now agree that transmission of HIV is possible through oral sex. Following sexual contact, the second most common mode of transmission of HIV in the US is injection drug use.4 Injection drug use as a mode of transmission has decreased in the United States in recent years; this is believed to be a result of legalization of needle exchange 526 programs in some cities. Needle exchange programs reduce the availability of dirty needles and promote the use of sterile needles and syringes. Vertical transmission of HIV is believed to be the cause of the vast majority (>95%) of childhood HIV infections. The risk of transmission of HIV in untreated seropositive mothers is approximately 23%. In the landmark AIDS Clinical Trial Group (ACTG) study 076, researchers demonstrated that administration of zidovudine could reduce transmission risk by as much as 67.5% (from 22.6% to 7.6%).13 Women in the trial were administered zidovudine at a dose of 100 mg orally, 5 times per day, at 13 weeks gestation. During labor, women were treated with zidovudine 2 mg/kg intravenously over 1 hour, followed by a continuous infusion of 1 mg/kg until delivery. Beginning 8-12 hours after birth, newborns were administered zidovudine 2 mg/kg orally for the first 6 weeks of life. In most clinical cases, zidovudine will be employed as part of combination antiretroviral therapy with or without caesarian section to prevent perinatal transmission. With regards to combination therapy, certain antiretroviral medications should be avoided due to the propensity to either interact with zidovudine (ie, stavudine) or produce untoward effects on the fetus or mother (ie, efavirenz, didanosine). Some success in reducing perinatal transmission through the use of single oral doses of nevirapine delivered to both the mother and newborn has also been documented.14 Particularly, promising results have been seen in Africa, where simple, inexpensive perinatal preventative regimens are especially needed. Pathophysiology and Clinical Course HIV is a retrovirus belonging to the class of lentiviruses.9 Retroviruses possess RNA as their baseline genetic material and undergo reverse transcription, which allows for conversion of viral RNA to viral DNA. The 2 characteristics of HIV that make it most difficult to effectively treat and cure are its unparalleled ability to reproduce and its error-prone replication process, which often produces genetic variants. The virus possesses no mechanisms for the detection and repair of genetic errors occurring during replication. CD4+ cells, which are T lymphocytes, also known as T4 cells or helper cells, are key components of the immune system whose primary involvement is with the cell-mediated branch.9 While not primary mediators, the cells also play instrumental roles in humoral immunity. HIV infects these cells by way of CD4+ receptor-mediated fusion and binding, which also involves chemokine co-receptors.15 Once attached, HIV will insert its viral

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RNA into the host cell along with other key enzymes involved in replication. The enzyme reverse transcriptase catalyzes the conversion of viral RNA to viral DNA. Once viral DNA is produced, HIV does not possess the enzymatic capability to convert the product to essential proteins. Therefore, using the enzyme integrase, the virus will insert its viral DNA into endogenous CD4+ cell DNA strands. When the endogenous DNA strands are transcribed by the host cell, inadvertent transcription of viral DNA to viral RNA also occurs. Subsequently, viral RNA is converted to viral polyproteins, which are cleaved and activated by protease enzymes. Once these essential proteins have been formed, new virons are enveloped and depart the host CD4+ cell. The eventual outcome is destruction of the CD4+ cell, accompanied by a rise in viral load as new cells become infected.15 In most cases, patients achieve a certain set-point viral load and may remain clinically stable for years before a more acute immune dysfunction ensues. Shortly following infection with HIV, most patients will experience a clinical syndrome characterized by constitutional symptoms (eg, headache, fever, malaise) which may or may not be accompanied by weight loss, diaphoresis, and a nonspecific rash.9 These initial symptoms usually represent an early and non-sustained surge in viral load. The increase in replication is eventually tempered by the immune system until some clinical viral load set point is reached. Some studies have indicated that a lower viral load set-point may be a predictor of slower disease progression. Following the initial viral surge associated with infection, HIV may remain dormant within lymphatic and other tissues (ie, retinal, testicular) for several years, with many patients being asymptomatic. At some time, viral load may once again increase and result in reduced immune competency with eventual opportunistic infection. In many cases, hospitalization with overt symptoms of an opportunistic infection often results in initial testing and diagnosis of HIV infection. As CD4+ cell counts decline, immune system function deteriorates and infection with serious opportunistic infections (ie, Pneumocysis jiroveci pneumonia, cytomegalovirus, tuberculosis, toxoplasmosis, etc) often results.9,10,15 In many cases, it is these opportunistic infections that ultimately lead to the death of infected individuals. Recently, early diagnosis and improved therapy have resulted in a reduced incidence of death as a result of opportunistic infections, with more individuals suffering morbidity associated with drug toxicity, organ dysfunction, and other causes. The onset of various opportunistic infections has been correlated to specific threshold CD4+ cell counts.16 A 527 normal CD4+ cell count is usually within the range of 8001,000 cells/mm3. Thrush and other topical candidal infections are common during early CD4+ cell decline (ie, < 500 cells/mm3). Pneumocystis jiroveci pneumonia usually occurs at CD4+ cell counts less than 200 cells/mm3, toxoplasmosis at counts less then 100 cells/mm3, and Mycobacterium avium infection at counts less than 50 cells/mm3. Central Nervous System (CNS) lymphoma, cytomegalovirus retinitis, and various invasive fungi (ie, Cryptococcus, histoplasmosis) are more likely to occur at CD4+ cells counts less than 50 cells/mm3. These corresponding CD4+ cell counts are often used to guide treatment decisions with regards to the initiation and discontinuation of opportunistic infection prophylaxis among patients infected with HIV.16 Pharmacotherapeutics Most treatment decisions regarding the initiation and alteration of antiretroviral medications are made based upon CD4+ cell count and viral load parameters. Viral load can be quantified using either polymerase chain reaction (PCR) or branch chain DNA (bDNA) technology.17 When comparing viral load values, clinicians should always compare values derived from the same testing method (either PCR or bDNA). Viral load testing is limited by its lower end of detection. Standard tests cannot quantify viral burden below 400 copies/ml, while ultra-sensitive testing cannot quantify viral burden below 50 copies/ml. When viral burden falls below these thresholds, results are reported as undetectable. Clinicians and patients should be aware that an undetectable viral load does not signify a cured or non-contagious patient. Since the early 1980s, a number of new antiretroviral medications have been introduced. Currently, 5 classes of antiretroviral medications are available (Table 1).18 The nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors (NNRTIs) all target the viral enzyme reverse transcriptase. Inhibition of this enzyme results in hampered viral replication. The protease inhibitors (PIs) act to prevent the cleavage and activation of viral polyproteins, thus reducing the infectivity and reproducibility of the virus. Only one agent is currently FDA approved in the class of fusion inhibitors. Fusion inhibitors interact with CD4+ cell receptors to prevent receptor-mediated entry and infection. Guidelines addressing the most opportune time to initiate antiretroviral therapy are controversial. Discussions surrounding the proper time to initiate therapy have focused on the potential immunological advan-

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Table 1. Antiretroviral Medications Trade Generic Adult Dosing Name Adverse Effects Nucleoside Reverse Transcriptase Inhibitors Bind to and inhibit the enzyme responsible for the conversion of viral RNA to viral DNA. Zidovudine (AZT) 300 mg PO twice daily Retrovir Marrow suppression Didanosine EC (ddI EC) 400 mg every day Videx EC Pancreatitis Peripheral neuropathy Zalcitabine (ddC) 0.75 mg three times daily Hivid Pancreatitis Peripheral neuropathy Stavudine (d4T) 40 mg twice daily Zerit Peripheral neuropathy Lamivudine (3TC) 150 mg twice daily Epivir Nausea,vomiting or 300 mg every day Emtricitabine (FTC) 200 mg every day Emtriva Headache, diarrhea Abacavir (ABC) 300 mg twice daily Ziagen Hypersensitivity reaction, rash Zidovudine (AZT) 1 capsule twice daily Combivir Marrow suppression Lamivudine (3TC) Peripheral neuropathy Pancreatitis Zidovudine AZT) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) Tenofovir (TF) 1 capsule twice daily Trizivir Marrow suppression Peripheral neuropathy Hypersensitivity reaction, rash Diarrhea, nausea, vomiting Nausea, vomiting, hypersensitivity reaction, rash

1 tablet every day

Truvada

Lamivudine (3TC) 1 tablet every day Epzicom Abacavir (ABC) Nucleotide Reverse Transcriptase Inhibitors Bind to and inhibit reverse transcriptase enzyme; structurally distinct from NRTIs.

Tenofovir DF 300 mg every day Viread Diarrhea, nausea, vomiting Non-nucleoside Reverse Transcriptase Inhibitors Bind to and inhibit reverse transcriptase enzyme; structurally distinct from NRTIs. Nevirapine 200 mg every day X2 weeks, Viramune Rash, diarrhea, hepatitis then twice daily Delavirdine 400 mg three times a day Rescriptor Rash, headache Efavirenz 600 mg at bedtime Sustiva Rash, CNS disengagement Protease Inhibitors Bind to and inhibit protease enzyme. Protease enzyme normally cleaves and activates HIV poly-proteins. Saquinavir (Hard gel) 500 mg twice daily (boosted) Invirase Nausea, vomiting, diarrhea Ritonavir 600 mg twice daily Norvir Potent CP 450 inhibitor, GI distress, perioral tingling Indinavir 800 mg every eight hours Crixivan Nephrolithiasis, increased bilirubin Nelfinavir 1250 mg twice daily Viracept Diarrhea, nausea Fosamprenavir 700 mg twice daily Lexiva Nausea, vomiting, diarrhea Lopinavir/Ritonavir 3 Capsules twice daily Kaletra GI Upset Tipranavir 500 mg twice daily (boosted) Aptivus GI upset Atazanavir 400 mg every day Reyataz Increased bilirubin Fusion Inhibitors Prevent CD4+ receptor medicated fusion between HIV and CD4+ cells. Enfuvirtide 90 mg SQ twice daily Fuzeon Injection site reactions
Alternate doses may be employed depending upon specific concurrent drugs being employed as part of an antiretroviral regimen.

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tages of early therapy versus quality of life and drug resistance issues surrounding prolonged exposure to multiple antiretroviral medications. Clinicians should recognize that guidelines regarding the initiation of antiretroviral therapy are dynamic and the most up-to-date reports should always be consulted. Currently, US Department of Health and Human Services guidelines advocate that treatment be initiated for all symptomatic HIV+ patients and patients who are asymptomatic with CD4+ cell counts below 200 cells/mm3.18 Treatment should be offered to asymptomatic patients with CD4+ cell counts in the range of 200-350 cells/mm3. Some clinicians and patients may select to initiate therapy when the CD4+ cell count is greater then 350 cells/mm3 or viral load is greater then 100,000 copies/ml. An additional consideration in making treatment decisions regarding antiretroviral medications is patient readiness. Some antiretroviral regimens will involve multiple medications with complex dosing schemes and significant adverse effects. These regimens also demand near perfect adherence in order to maximize efficacy and reduce the likelihood of drug resistance.19 Additionally, regimens entail significant financial burden. Patients should be aware of these issues and the life changes that may be involved. When a decision to initiate antiretroviral therapy is reached, clinicians are faced with the dilemma of designing effective multi-drug regimens. Patient-specific factors such as co-morbidities and concurrent medications should be considered when selecting specific antiretroviral regimens. Mono and duel antiretroviral regimens rapidly select for resistant virus and are not advised. Three-drug combinations are the most commonly employed regimens, particularly for treatment nave patients. Some commonly employed antiretroviral combinations include 2 NRTIs, plus either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor.18 Previously, triple NRTI regimens had been considered appropriate initial antiretroviral therapy, but recent clinical evidence has demonstrated that some of these regimens may not produce potent anti-HIV effects regardless of baseline viral burden. Therefore, triple NRTI regimens should not be employed as initial therapy for HIV unless it is not possible to use either an NNRTI or a protease inhibitor. Due to pools of latently infected CD4+ cells, complete eradication of HIV through the use of antiretroviral therapy does not appear possible. Once therapy is initiated, treatment goals consist of maximum and durable suppression of viral load (ie, <400 copies/ml or <50 copies/ml depending upon the testing method employed), restoration and preservation of immune 529 function, improvement of quality of life, and reduction of HIV-related morbidity and mortality.18 These goals must be balanced with the concept of preserving future antiretroviral drug options. Alterations in therapy to achieve treatment goals should not be undertaken without serious consideration of implications on future treatment options. Once therapy is initiated, the clinical goal is to achieve an undetectable viral load (< 400 copies/ml at 24 weeks; <50 copies/ml at 48 weeks). Cases in which an undetectable viral load is not achieved following an adequate trial of appropriate antiretrovirals or in which levels become detectable are considered treatment failures. In managing treatment failures and before making therapy-altering decisions, clinicians should consider a number of other factors. Adherence to the medication regimen is critical for success in suppressing viral replication and avoiding the acquisition of resistance. If the patient has inherent barriers to adherence, failure is likely regardless of the specific regimen selected. Patients with concurrent infections may experience minor elevations in viral load known as blips during the acute phase of their infection.21 These blips do not typically represent treatment failures and usually return to baseline following resolution of the acute infection. Lastly, clinicians should be aware that routine vaccine administration may also cause minor and temporary increases in viral replication and burden.18,20 This is believed to be a result of immune stimulation and is not cause for altering antiretroviral therapy. In cases of treatment failure, ideally antiretroviral regimens should be altered to include a minimum of 3 new drugs to which the patient is treatment nave and to which the least propensity of cross-resistance is likely.18 The sequencing of certain antiretroviral drugs should be considered as the order and length of use of specific agents may contribute to antiretroviral resistance. Newer antiretroviral agents usually possess unique resistance profiles and may therefore provide some additional durability. In cases involving several treatment failures accompanied by significant resistance to existing antiretroviral agents, salvage therapy may be employed. Salvage therapy typically involves the use of more unorthodox antiretroviral combinations and may involve more then 3 simultaneous antiretroviral agents.18 Enfuvirtide is often reserved for use as salvage therapy because the drug is administered subcutaneously and is expensive (eg, approximately $1,200 per month of therapy). Additionally, the drug possesses a novel mechanism of action involving the inhibition of attachment and entry of HIV particles into CD4+ cells.21 While usually effective resistance to this agent has been described and involves substitutions in the gene encoding for the gp41 protein of HIV.

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Table 2. Genotypic and Phenotypic Resistance Assays Relative Advantages Genotypic Ease of availability Shorter time to results (days) Less technically demanding Mutations will likely precede phenotypic resistance Less costly when compared to phenotyping Relative Limitations Indirect measure of susceptibility May not correlate directly with phenotype Expert interpretation required Insensitive for the detection of minor species Reliance upon known mutations in mapped areas of the HIV genome Lack of laboratory standardization Limited availability Longer time to results (weeks) Technically demanding Insensitive for detecting minor species Clinically significant breakpoints undefined Lack of laboratory standardization

Phenotypic Direct measure of susceptibility More familiar reporting results (IC50 or IC90)

Clinicians may use resistance-testing technology to assist in drug selection, particularly in cases of multiple treatment failures.22 Resistance testing can be accomplished either genotypically or phenotypically and requires that the patient be tested while continuing on the failing regimen (Table 2). Many inherent limitations to resistance testing exist (Table 2). Despite these limitations, most clinicians agree that antiretroviral resistance testing should play some role in the management of HIVinfected patients. No consensus guidelines regarding whether to specifically employ genotypic or phenotypic assays exist, but clinicians should be consistent in the assay method they select and be aware of cost. While economics is a consideration, clinicians should recognize that if used appropriately resistance testing can be cost effective in producing efficacious viral strain-specific antiretroviral regimens. Once antiretroviral therapy is initiated, proper monitoring is essential. At a minimum, viral burden and CD4+ cell counts should be assessed every 90 days.18 As previously mentioned, antiretroviral therapy is associated with a number of adverse effects, some of which may affect adherence and/or be serious or life-threatening. The lipodystrophy syndrome is a complex multifaceted condition characterized by peripheral fat wasting, central fat accumulation, and elevations in serum lipids which may or may not be accompanied by glucose intolerance.23 Etiology of the syndrome remains elusive, but has been correlated to treatment with NRTIs (particularly stavudine), treatment with PIs, and to HIV disease itself. Patients with a previous history of lipid dysfunction or cardiovascular disease should be closely monitored. All patients should undergo fasting lipid profiles at 3-month intervals. Treatment of HIV-infected patients with lipid and/or metabolic disorders should mirror guidelines for 530

non-infected patients. Initial treatment typically involves diet and exercise and in some cases the use of hydroxymethyl glutaryl coenzyme A reductase inhibitors (HMG CoA RI) or fibrates may become necessary.23 Because of their lower propensity to interact with antiretrovirals, pravastatin, and atorvastatin are the preferred HMG CoA RI for concurrent use with HIV therapy.18,23 The NRTIs are associated with several well-recognized adverse effects.18 Zidovudine is known to cause bone marrow suppression, with anemia being very common. Patients receiving zidovudine often complain of extreme malaise and fatigue, a result of the anemia induced by the drug. Often anemia may become so severe that drug discontinuation is necessary. Didanosine, zalcitabine, and particularly stavudine have been associated with the development of peripheral neuropathies that in some cases may become so severe that potent pain relievers such as narcotics become necessary. Peripheral neuropathies are believed to be a result of NRTI-induced damaged to mitochondrial DNA synthesis in affected muscle groups. Other interventions for the management of neuropathies besides drug discontinuation include amitriptyline and gabapentin therapy. Abacavir, which is available as a single agent or as part of certain combination antiretroviral products, has been associated with a serious and potentially life-threatening hypersensitivity reaction in 2%-9% of patients.24 Symptoms most commonly associated with this hypersensitivity reaction are fever (70%-80%), rash (approximately 70%), gastrointestinal effects (approximately 50%; nausea, vomiting, diarrhea or abdominal pain), lethargy or malaise (40%-60%), and upper or lower respiratory effects (18%-30%). Rechallenge to abacavir is not advised since fatal hypotension has occurred in patients where this has been attempted.

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The NRTIs have also been associated with the development of rare but clinically significant and potentially life threatening lactic acidosis.25 One theory surrounding the etiology of lactic acidosis involves NRTI-associated mitochondrial toxicity. NRTIs have been demonstrated to bind and inhibit DNA polymerase gamma, which is the enzyme responsible for mitochondrial DNA synthesis. As previously mentioned, this mechanism might also be responsible for the peripheral neuropathies caused by some of the NRTIs. Initial symptoms are variable but may include complaints of nausea, vomiting, fatigue, myalgias, or gastrointestinal discomfort. Elevations in hepatic transaminases may accompany symptomatology. Routine serum lactate levels should be performed in high-risk patients (every 3-6 months) or in those describing any of the above symptoms.23,25 Serum lactate levels greater then 5 mmol/dl are considered abnormal and levels greater then 10 mmol/dl are considered serious and potentially life threatening. Treatment generally consists of withdrawal of NRTIs accompanied by symptomatic management. In cases of serious lactic acidosis, re-challenge with NRTIs is not recommended. Other clinical adverse effects of antiretrovirals with which clinicians should be familiar include hepatotoxicity, which may or may not be accompanied by lactic acidosis.18,26 Hepatoxicity has been correlated with all currently available NNRTIs and PIs. The NNRTI nevirapine has particularly been associated with a higher incidence of hepatic effects.26 The majority of patients who develop elevations in transaminases are asymptomatic; however, fulminate hepatitis is possible. Osteonecrosis and osteopenia are now recognized as emerging metabolic complications of HIV infection that may be related to antiretroviral therapy.18,27 Most of the data linking these symptoms to therapy involve the PIs. Among the NNRTIs, a high incidence of rash that often progresses to Stevens-Johnson syndrome has been reported.18 The NNRTI efavirenz has been shown to cause vivid nightmares and CNS disengagement associated with dizziness and confusion.18 These symptoms usually subside following ongoing treatment beyond 4 to 6 weeks. Pharmacists should also carefully monitor medication profiles for drug interactions. Drug interactions can involve prescription and nonprescription medications as well as complementary medications or herbal/natural products.28,29 Among antiretroviral medications, ritonavir is known to be a very potent cytochrome (CP) 450 inhibitor and extreme caution with regards to drug interactions should be exercised whenever the drug is being prescribed. Withstanding ritonavir, significant CP 450 interactions exist with almost every protease inhibitor 531 and most NNRTIs. A number of therapy compromising herbal/antiretroviral drug-drug interactions have been reported including those involving protease inhibitors and the herbal products St. Johns wort and garlic.29 Numerous other potential interactions exist and up-todate sources including tertiary and primary references should always be consulted when analyzing medication regimens for drug-drug interactions. This is particularly important in the area of HIV pharmacotherapeutics since accepted therapy is rapidly changing and drug-drug interactions have a high likelihood of affecting the efficacy of current as well as future treatment options. Psychosocial Considerations HIV/AIDS is a complex disease state with many physical as well as psychosocial manifestations.30 Clinicians caring for these patients must understand the pscychosocial aspects of the disease and the constraints they place on care and quality of life. Diagnosis alone can result in clinical depression and lead to serious questions regarding life expectancy and death. Another serious concern for patients infected with HIV are prospects for relationships. Often an HIV diagnosis can put external strains on existing relationships and raise concerns regarding the need for disclosure to past or current partners. HIV seropositive patients should receive extensive counseling regarding the need to practice safer sex when they are involved in any type of sexual encounter or relationship. This is both to protect themselves from superinfection with another strain of HIV and to protect their partners from initial disease acquisition. Among female patients, discussions of contraception and perinatal screening should occur. All patients presenting with HIV should be initially and routinely screened for coinfection with other sexually transmitted diseases and coinfections such as hepatitis B and C. Clinicians should recognize the sensitive nature of HIV information and maintain the highest level of confidentiality in this regard. Chemical dependency (ie, ethanol, club drugs, methamphetamine, etc) is an issue for many HIV-infected patients. Chemical dependency may have particularly detrimental effects on patients abilities to adhere to antiretroviral regimens.19 Pharmacists may play a role in the identification of patients with dependencies and referral to treatment programs. Other environmental factors such as homelessness and poor nutritional status are issues that may need to be addressed in the overall care plan of certain HIV-infected patients. In these cases, it may be especially helpful to enlist the assistance of social workers, case managers, and dieticians. As previously described, the pharmacotherapeutics of HIV disease requires the use of multiple medications

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Table 3. HIV Specific Mini Bullet Cases AA is a 25YO WM who presents to student health for his yearly physical exam. AA requests he be tested for HIV. Is HIV testing indicated? If so what screening test should be employed? What are the advantages of OraQuick? BB is a 28YO WF who works as an RN at the UK Neurology clinic. While drawing blood this AM at 0900 she stuck herself with a needle that had just been used for a venipuncture blood draw. She now phones the pharmacy asking how to proceed. CC is a 28YO BM who was recently diagnosed with HIV. He regularly engages in sex with both men and women. His medication regimen consists of AZT 300 mg BID, Didanosine EC 400 mg QD, and Nelfinavir 1250 mg BID. What counseling points/side effects can this patient anticipate? DD is a 35YO WM who presents to clinic for his 3 month follow-up. The patient is HIV+ with a viral load of <50 copies/ml and a CD4+ cell count of 290 cells/mm3. The patient is in need of a tetanus booster. Can he receive this or other immunizations? EE is a 28YO WF with HIV. Her visit 3 months prior to today revealed a viral load of <400 copies/ml and a CD4+ cell count of 200 cells/mm3. Today: viral load is 25,600 copies/ml and her CD4+ cell count is 181 cells/mm3. What interventions should be made to the regimen if any? Why or why not? FF is an HIV- WM whose wife is HIV+ with a viral load of <50 copies/ml and a CD4+ cell count of 400 cells/mm3. FF and his wife wish to remain sexually active. Is this advisable and what if any precautions should be undertaken? A physician asks what are the side effects expected from the following regimen: D4T, AZT, Kaletra? A 36YO HIV+ female reports she is pregnant. She is at 15 weeks of gestation. She is currently on therapy with Truvada and Nelfinavir. What if any interventions should be undertaken to reduce the risk of perinatal transmission to the child? GG is a 42YO BF who presents to clinic today for the initiation of HIV therapy. She was recently diagnosed after being admitted for PCP infection. Today her viral load is 79,900 copies/ml and her CD4+ cell count is 88 cells/mm3. The patient has NKDA besides antiretrovirals what other medications should be initiated? HH is a 22YO WM with HIV who practices unsafe sex with his partner who is also HIV positive. Why is this not a recommended practice despite the fact that both persons are already HIV seropositive? A physician asks what if any advantages exist for FTC over 3TC? A physician asks in what patient populations is Fuzeon appropriate and what are its advantages and disadvantages compared to other antiretrovirals? A patient using Epzicom develops a serious reaction which is described as throat tightness, rash, and SOB. What is the most likely cause? Can this drug be used again in this patient? What other drugs should be avoided following this reaction?

with some of which with high pill burdens and serious adverse effect profiles. These medications often require substantial financial commitments by patients. In some cases, access to drugs can be hampered by individual financial situations. Alternative sources of drug acquisition such as AIDS Drugs Assistance Programs (ADAP) or drug manufacturer compassionate use options should be considered in those situations. Instructional Methods This instructional module is part of the required course Integrated Pharmacotherapeutics. The historical perspective of HIV/AIDS is introduced to students by viewing and discussing aspects of the documentary film, And the Band Played On. Content is delivered using a didactic format. Assimilation of information is emphasized through the use of a number of mini-bullet cases (Table 3). These bullet cases are distributed and assigned to students at the completion of the didactic portion of the learning experience. Some of these cases specifically review points that were discussed in class, while others will require students to search for new information. This is meant to direct students to drug information and 532

other resources discussed in class. At the following session, students are expected to have completed the minicases and be prepared to discuss various issues surrounding the patients involved in the cases. Students are randomly called upon to discuss their answers and approach to the cases. While discussing these cases, students are also given an HIV-specific medication history form used by the Universitys HIV clinic (available by request from the author). The form is used to further demonstrate the complexity of antiretroviral regimens. Students practice completing these forms using information from the mini-cases. In addition to this learning experience, students are assessed on their abilities to manage HIV pharmacotherapy through the use of a structured clinical instructional module (SCIM) involving a pregnant patient who is HIV seropositive.

SUMMARY
HIV is a modern day pandemic with no realistic hopes for a cure in the immediate future. Education and instruction in this area is particularly challenging given the complexity of both the disease and antiretroviral medications. Additionally, treatment guidelines are rap-

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idly evolving. Various teaching methodologies, including the one presented in this manuscript, can be used to instruct various aspects of disease management. Regardless of the mechanism of instruction selected, students should be exposed to basic information regarding the disease and its pharmacotherapy. The importance of adherence and other psychosocial aspects of care should also be stressed. Lastly, students should be afforded an opportunity to assimilate this information using cases, mini-cases, or other patient-centered simulations.
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