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The

NEW ENGLA ND JOURNAL

of

MEDICINE

Perspective
may 10, 2012

HIVHBV Coinfection A Global Challenge


Athena P. Kourtis, M.D., Ph.D., M.P.H., Marc Bulterys, M.D., Ph.D., Dale J. Hu, M.D., M.P.H., and Denise J. Jamieson, M.D., M.P.H.

uman immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) exact a high toll worldwide. Both can lead to chronic disease, cancer, and death, and neither can be eradicated with
the use of current therapies. Antiviral drug resistance often develops after patients have received treatment for some time and is usually followed by the loss of clinical benefit. Coinfection with the two viruses exacerbates the negative effects. Worldwide, HBV is the leading cause of chronic liver disease and a leading cause of death, accounting for up to half of all cases of cirrhosis and hepatocellular carcinoma.1 An estimated 400 million people are infected with HBV,1 with the majority of cases occurring in regions of Asia and Africa where the virus is endemic. There, up to 70% of adults show serologic evidence of current or prior infection, and 8 to 15% have chronic HBV infection.1 These staggering infection rates largely reflect a failure of maternal and child health programs. The majority of HBV infections in settings where the virus is highly endemic occur through perinatal transmission (predominant in East and Southeast Asia) or in young children, transmitted through close household contact or through medical or traditional scarification procedures (predominant in Africa).1 Perinatal HBV infection is associated with a 90% risk of chronic hepatitis B, as compared with a risk of less than 5% among adults with intact immunity.1 The risk of perinatal transmission is lower in Africa than in Asia, a disparity that could be due to a lower prevalence of hepatitis B e antin engl j med 366;19 nejm.org may 10, 2012

gen (HBeAg) and other differences in the pathogenic characteristics of circulating HBV genotypes.1 According to the Joint United Nations Program on HIV/AIDS (UNAIDS), about 33 million people are infected with HIV worldwide, and the majority of them live in Asia and Africa. Approximately 10% of the HIV-infected population has concurrent chronic hepatitis B,2 with coinfection more common in areas of high prevalence for both viruses. In countries where the viruses are highly endemic, the rate can be as high as 25%.2 In areas where HBV is less endemic (North America, Europe, and Australia), HBV and HIV are most often acquired during adolescence or adulthood through sexual transmission or injectiondrug use. The prevalence of HIV HBV coinfection in these regions is generally less than 10% of the HIV-infected population.2 However, up to half of injection-drug
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PERSPE C T I V E

HIVHBV Coinfection A Global Challenge

A HIV Prevalence (Population Age 1549, 2009)

0.1% 0.20.4% 0.53.1% 3.225.9% Data unavailable B Prevalence of HBV Surface Antigen Positivity (2006)

Low: <2% Intermediate: 27% High: 8%

Prevalence of HIV-1 and HBV Infection, According to Country. Data on HIV are from the United Nations Childrens Fund, the World Health Organization, and (in the case of province-level data for China) the China Centers for Disease Control; data on hepatitis B virus (HBV) are from the U.S. Centers for Disease Control and Prevention.

users infected with HIV are coinfected with HBV. Worldwide, there may be 3 to 6 million HIV-infected people living with chronic HBV (see maps).
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HIVHBV coinfection increases the morbidity and mortality beyond those caused by either infection alone. People coinfected with HIV have higher levels of

hepatitis B viremia, have progression to chronic hepatitis B that is approximately five times as fast as that among people infected with only HBV, and have a higher

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PERSPECTIVE

HIVHBV Coinfection A Global Challenge

risk of cirrhosis and hepatocellular carcinoma.1 HIV immunosuppression can even cause the loss of hepatitis B surface antibodies and reactivation to chronic hepatitis B.1 As compared with healthy, uninfected persons, those infected with HIV particularly the most immunocompromised mount poorer antibody responses to HBV vaccination. Managing hepatitis B in HIV-coinfected patients is further complicated by the dual activity of several nucleoside analogues, the emergence of resistant HIV or HBV strains, the limitations of and decreased response to interferons, and the more rapid development of lamivudine-resistant HBV.2 Very few studies have addressed coinfection with HBV among HIVinfected pregnant women. Studies in Africa indicate that they are three times as likely as HIV-negative pregnant women to test positive for HBV DNA and twice as likely to test positive for HBeAg. Both higher HBV DNA levels and HBeAg expression are associated with an increased risk of an HIVinfected pregnant womans transmitting HBV to her child.1 Vaccination of infants against hepatitis B is highly protective, reducing the risk of infection by more than 70% (the addition of hepatitis B immune globulin reduces the remaining risk by half. However, many countries with a high prevalence of HBV lack universal or timely vaccination coverage, and hepatitis B immune globulin is often unavailable or prohibitively expensive. In 2006, for example, the coverage rate for the vaccine dose at birth was only 36% in countries where the prevalence of chronic HBV infection exceeded 8%. Even with appropriate vaccination, 5 to 15% of infants born to

mothers who test positive for hepatitis B surface antigen (HBsAg) become infected. The proportion is much higher among infants whose mothers have high serum HBV DNA levels; transmission rates of 39% or higher have been noted.3 High HBV DNA levels are often seen in women with concurrent HIV infection, particularly in Southeast Asia, where HBV is highly endemic and perinatal transmission of HBV is already common. Additional approaches are needed to protect children of infected mothers. For example, the use of antiviral therapy in pregnant women with high HBV loads has been examined in a few small studies and has shown promise in decreasing perinatal transmission3; this strategy appears to be cost-effective and should be explored further.4 Women coinfected with HIV would be good candidates for this preventive approach. Even in areas with historically low rates of HBV, challenges exist. In the United States, the number of HBV-infected pregnant women is probably underestimated, with current methods relying on the expectation that certain ethnic groups are at high risk. In Europe, there is no consistent policy of testing women for HBV infection during pregnancy; some countries rely on assessment of risk factors alone. Immigration patterns in Europe and North America suggest that HBV prevalence will vary by region. There are a number of unanswered questions about disease pathogenesis in coinfected persons and the management of HIVHBV coinfection, especially in pregnant women. Pregnancy itself can trigger elevations of liver enzymes. The administration, during pregnancy, of antiretroviral

prophylaxis containing one agent with anti-HBV activity may be associated with later development of HBV resistance. For pregnant women who, to prevent perinatal HIV transmission, take antiretroviral prophylaxis containing one or two agents with anti-HBV activity, the safety of stopping treatment after delivery is unknown. The administration of antiretrovirals without HBV activity in coinfected pregnant women may leave their infants unprotected against HBV. Finally, infection of the infant with HIV threatens the benefits of HBV immunization for perinatal prevention. What will it take to address this crisis? First, we must acknowledge that HBVHIV coinfection represents a major global public health threat. Because each virus affects the others natural history and response to therapy, HIVHBV coinfection requires dedicated research. A willingness to rapidly implement new scientific evidence is critical. Preventing transmission of both viruses to the next generation should be a priority for health policymakers. Ideally, all pregnant women should receive early prenatal care with voluntary HIV and HBV testing to permit timely interventions aimed at preventing perinatal transmission.5 Use of antiretroviral agents with dual antiviral activity is a promising preventive approach one limited, however, by a paucity of data on important agents (e.g., tenofovir) regarding safety during pregnancy, for both the fetus and the mother. As regimens including tenofovir become first-line therapy for many HIVinfected people (and are used as preexposure prophylaxis for the uninfected), determining the safety of these medications during pregnancy becomes a critical re1751

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PERSPE C T I V E

HIVHBV Coinfection A Global Challenge

search need. Evaluating the HBV viral load in HIV-infected pregnant women should be an essential step of prenatal evaluation, so that the mothers health can be managed appropriately. Continued improvements in the coverage and timeliness of HBV vaccination and the education of clinicians about its importance should be priorities everywhere. Making such improvements will require substantial advocacy and political and financial commitment. Now is the time to provide the best care we can for coinfected people and to protect a future generation of children from the

largely hidden epidemic of HBVrelated liver disease, which is being further fueled by the HIV epidemic.
The opinions expressed in this article are those of the authors and do not necessarily reflect the position of the Centers for Disease Control and Prevention. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion (A.P.K., D.J.J.), the Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (D.J.H.), and the Division of Global HIV/AIDS, Center for Global Health (M.B.), Centers for Disease Control and Prevention, Atlanta; and the CDC Global AIDS Program, Beijing, China (M.B.).

1. Hoffmann CJ, Thio CL. Clinical implications of HIV and hepatitis B co-infection in Asia and Africa. Lancet Infect Dis 2007; 7:402-9. 2. Thio CL. Hepatitis B and human immunodeficiency virus coinfection. Hepatology 2009;49:Suppl:S138-S145. 3. Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebocontrolled study. J Viral Hepat 2009;16: 94-103. 4. Unal ER, Lazenby GB, Lintzenich AE, Simpson KN, Newman R, Goetzl L. Cost-effectiveness of maternal treatment to prevent perinatal hepatitis B virus transmission. Obstet Gynecol 2011;118:655-62. 5. Kourtis AP, Bulterys M, Nesheim SL, Lee FK. Understanding the timing of HIV transmission from mother to infant. JAMA 2001; 285:709-12.
Copyright 2012 Massachusetts Medical Society.

Statins: Is It Really Time to Reassess Benefits and Risks?


Allison B. Goldfine, M.D.

o drug provides health benefits without some degree of risk, and riskbenefit assessments require ongoing review as new data become available. This is certainly the case for the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors statins and the risk of new-onset diabetes. Cardiovascular disease is the leading cause of illness and death in patients with type 2 diabetes. There is no doubt that for persons who have had an acute coronary syndrome or who have other risk factors for atherosclerotic coronary artery disease, statins effectively reduce the risks of death from any cause, death due to cardiovascular disease, fatal myocardial infarction, the need for revascularization, and stroke (see figure). Over a period of 4 years of statin use, a reduction of 1 mmol per liter (39 mg per deciliter) in the level of low-density lipoprotein (LDL) cholesterol translates into
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a 9% reduction in the risk of death from any cause among patients with diabetes and a 13% reduction among those without diabetes.1 Benefits are realized within the first year of use but increase over time. Few drugs have had such a dramatic effect on health outcomes. In the JUPITER study (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; ClinicalTrials .gov number, NCT00239681), involving 17,802 participants without diabetes but with LDL cholesterol levels below 3.4 mmol per liter (130 mg per deciliter) and highsensitivity C-reactive protein levels of 2.0 mg per liter or higher, the hazard ratio for newly diagnosed diabetes was increased 25% in the rosuvastatin group than in the placebo group.2 Despite the increase in the risk of new-onset diabetes, the participants previously considered to have low cardiovascular risk had
n engl j med 366;19 nejm.org may 10, 2012

clinically important health improvements over a median followup period of only 1.9 years, with a hazard rate 44% lower than that of the placebo group for the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. In addition, rates for the key secondary outcomes were lower in the treated participants: 54% lower for myocardial infarction, 48% for stroke, 46% for revascularization, and 20% for death from any cause. A meta-analysis of six statin trials that included 57,593 participants revealed a 13% increase in the relative risk of new-onset diabetes3 a more modest effect than that seen in the JUPITER study, perhaps because the diagnostic criteria differed. Similarly, a meta-analysis of 13 randomized statin trials with 91,140 participants showed an odds ratio of 1.09 for a new diagnosis of

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