HIV This Week

Welcome to the fiftieth issue of HIV This Week!  In this issue, we cover prevention of mother-to-child transmission (from Zambia: exclusive breastfeeding wins the day!; single-dose tenofovir and emtricitabine preserve mothers’ long-term therapeutic options by cutting resistance risk following single dose nevirapine), treatment (mathematical modelling shows it is time to diagnose earlier, time to treat earlier; beyond the scale-up numbers – a human rights lens), sexual and reproductive health (from Rwanda: high time for integration of sexual and reproductive health into antiretroviral treatment programmes; young South Africans need new social norms on communicating about sex, contraception, and condoms; marriage and fertility life projects come alive in Nigerians on antiretroviral treatment), molecular epidemiology (impress your friends with coalescent theory, molecular clock analysis, and phylogeography: findings from Albania), health system strengthening (how HIV treatment scale-up can benefit health systems), basic science (HIV and frailty: accelerated aging?), gender (bad combo: intimate partner violence, injecting drug use, and HIV in Baltimore, Miami, New York City, and San Francisco), paediatric treatment (to start or not to start – that is the question; from Cote d’Ivoire: unclear future for chronic hepatitis B, HIV, and antiretroviral treatment), biomedical trials (how to minimize and mitigate social harms of trial participation; human rights and ethics: what instrument for what?), and vaccines (shaking a multi-envelope cocktail for macaques).

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For full PDF acess to this issue:HIV This Week Issue #50

Kuhn L, Sinkala M, Kankasa C, Semrau K, Kasonde P, Scott N, Mwiya M, Vwalika C,Walter J, Tsai WY, Aldrovandi GM, Thea DM. High Uptake of Exclusive Breastfeeding and Reduced Early Post-Natal HIV Transmission. PLoS ONE. 2007; 2(12):e1363.

Photo credit: UNAIDS/ L.Alyanak

Empirical data showing the clear benefits of exclusive breastfeeding for HIV prevention are needed to encourage implementation of lactation support programs for HIV-infected women in low resource settings among whom replacement feeding is unsafe. Kuhn and colleagues conducted a prospective, observational study in Lusaka, Zambia, to test the hypothesis that exclusive breastfeeding is associated with a lower risk of postnatal HIV transmission than non-exclusive breastfeeding. As part of a randomized trial of early weaning, 958 HIV-infected women and their infants were recruited and all were encouraged to breastfeed exclusively to 4 months. Single-dose nevirapine was provided to prevent transmission. Regular samples were collected from infants to 24 months of age and tested by polymerase chain reaction. Detailed measurements of actual feeding behaviours were collected to examine, in an observational analysis, associations between feeding practices and postnatal HIV transmission. Uptake of exclusive breastfeeding was high with 84% of women reporting exclusive breastfeeding cumulatively to 4 months. Post-natal HIV transmission before 4 months was significantly lower (p = 0.004) among exclusively breastfed infants (0.040 95% CI: 0.024-0.055) than among non-exclusively breastfed infants (0.102 95% CI: 0.047-0.157); time-dependent Relative Hazard (RH) of transmission due to non-exclusive breastfeeding = 3.48 (95% CI: 1.71-7.08). There were no significant differences in the severity of disease between exclusively breastfeeding and non-exclusively breastfeeding mothers and the association remained significant (RH = 2.68 95% CI: 1.28-5.62) after adjusting for maternal CD4 count, plasma viral load, syphilis screening results and low birth weight. In conclusion, non-exclusive breastfeeding more than doubles the risk of early postnatal HIV transmission. Programs to support exclusive breastfeeding should be expanded universally in low-resource settings. Exclusive breastfeeding is an affordable, feasible, acceptable, safe and sustainable practice that also reduces HIV transmission providing HIV-infected women with a means to protect their children’s lives. TRIAL REGISTRATION: ClinicalTrials.gov NCT00310726.

Editors’ note: Exclusive breastfeeding for at least 6 months when the AFASS criteria (acceptable, feasible, affordable, sustainable, and safe) are not met balances the protective infant survival benefits of breastfeeding against the low, sustained risk of HIV acquisition. Relaxing treatment guidelines to provide antiretroviral drugs to lactating mothers with CD4 counts under 350 cells already makes imminent sense now, but several clinical trials assessing this and infant prophylaxis during breastfeeding, have yet to report.

Intrapartum and neonatal single-dose nevirapine are essential components of perinatal HIV prevention in resource-constrained settings, but can induce resistance to other non-nucleoside reverse transcriptase inhibitor drugs. Chi and colleagues aimed to investigate whether this complication would be reduced with a single peripartum intervention of tenofovir and emtricitabine. The authors randomly assigned 400 pregnant women living with HIV who sought care at two public-sector primary health facilities in Lusaka, Zambia. One was excluded, 200 were assigned to receive a single oral dose of 300 mg tenofovir disoproxil fumarate with 200 mg emtricitabine under direct observation, and 199 to receive no study drug. Short-course zidovudine and intrapartum nevirapine were offered to all of the participant women living with HIV, according to the local standard of care. Women who met national criteria for antiretroviral therapy were referred for care and not enrolled. The primary study outcome was resistance to non-nucleoside reverse transcriptase inhibitors at 6 weeks after delivery. The authors used standard population sequencing to determine HIV genotypes and analyzed data as per protocol. Of the 200 women who were randomly assigned to the intervention, 14 were lost to follow-up or withdrew from the study, two did not take study drug according to protocol, and one specimen was lost; 23 of 199 controls were lost to follow-up or withdrew from the study, and three specimens were lost. Women given the intervention were 53% less likely than controls to have a mutation that conferred resistance to non-nucleoside reverse transcriptase inhibitors at 6 weeks after delivery (20/173 [12%] vs. 41/166 [25%]; risk ratio [RR] 0.47, 95% CI 0.29-0.76). The authors noted postpartum anaemia, the most common serious adverse event in mothers, in four women in each group. 20 of 198 (10%) infants in the intervention group and 23 of 199 (12%) controls had a serious adverse event, mostly due to septicaemia (n=22) or pneumonia (n=8); these events did not differ between groups, and none were judged to be caused by the study intervention. The authors’ interpretation of the results was that a single dose of tenofovir and emtricitabine at delivery reduced resistance to non-nucleoside reverse transcriptase inhibitors at 6 weeks after delivery by half; and therefore this treatment should be considered as an adjuvant to intrapartum nevirapine.

Editors’ note: Although there was no difference in rates of perinatal HIV transmission, adding a single dose of tenofovir (TDF) and emtricitabine (FTC) significantly reduced the risk of resistance from single dose nevirapine. As cited in Lockman et al (HIV This Week Issue #25), women who started antiretroviral treatment within 6 months of receiving a single dose of nevirapine are at risk for virological and clinical treatment failure because of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. Since both nevirapine and efavirenz are common NNRTI components of first line therapy and options for second-line treatment are limited, addition of single dose TDF-FTC makes a lot of sense for the mother’s health.

Hallett TB, Gregson S, Dube S, Garnett GP. The impact of monitoring HIV patients prior to treatment in resource-poor settings: insights from mathematical modelling. PLoS Med. 2008 Mar 11; 5(3):e53.

The roll-out of antiretroviral treatment in developing countries concentrates on finding patients currently in need, but over time many HIV-infected individuals will be identified who will require treatment in the future. Hallett and colleagues investigated the potential influence of alternative patient management and antiretroviral treatment initiation strategies on the impact of antiretroviral treatment programmes in sub-Saharan Africa. The authors developed a stochastic mathematical model representing disease progression, diagnosis, clinical monitoring, and survival in a cohort of 1,000 hypothetical HIV-infected individuals in Africa. If individuals primarily enter antiretroviral treatment programmes when symptomatic, the model predicts that only 25% will start treatment and, on average, 6 life-years will be saved per person treated. If individuals are recruited to programmes while still healthy and are frequently monitored, and CD4(+) cell counts are used to help decide when to initiate antiretroviral treatment, three times as many are expected to be treated, and average life-years saved among those treated increases to 15. The impact of programmes can be improved further by performing a second CD4(+) cell count when the initial value is close to the threshold for starting treatment, maintaining high patient follow-up rates, and prioritising monitoring the oldest (> or = 35 y) and most immune-suppressed patients (CD4(+) cell count < or = 350). Initiating antiretroviral treatment at higher CD4(+) cell counts than the World Health Organization recommends leads to more life-years saved, but disproportionately more years spent on antiretroviral treatment. In conclusion, the overall impact of antiretroviral treatment programmes will be limited if rates of diagnosis are low and individuals enter care too late. Frequently monitoring individuals at all stages of HIV infection and using CD4 (+) cell count information to determine when to start treatment can maximise the impact of antiretroviral treatment.

Editors’ note: When testing a full range of treatment approaches is cumbersome, time consuming and potentially unethical, mathematical modelling can help inform policy-makers. This model shows that 15 additional years of life after starting treatment, rather than six years, can be achieved by early diagnosis, frequent CD4 count monitoring, and early initiation of treatment before the immune system is irreversibly damaged. This has implications for “knowledge of serostatus” campaigns, low-cost CD4 count monitoring, revision of treatment guidelines, and increased resource mobilisation.

Human rights analyses, concepts, and in particular rhetoric have played a consistent role in the global response to HIV for over two decades. Despite the longstanding recognition of human rights as essential to an effective response, recent global guidance, particularly with respect to the implementation of antiretroviral treatment scale-up efforts, falls short of meaningfully incorporating human rights norms and concepts. Applying human rights to antiretroviral treatment scale-up draws attention to who is gaining access to antiretroviral treatment, how they are gaining access, and over what period of time, not just how many people gain access. Deliberate consideration of the human rights principles of the interdependence of rights (including attention to the legal and policy environment), participation, non-discrimination, accountability, and key aspects of the right to health can help to identify and overcome some of the challenges to increasing and sustaining access to treatment and needed services, as well as to promote accountability and transparency for what is done and how it is done. Whereas a need remains to document evidence of the ways in which a lack of attention to human rights negatively influences the long-term outcomes of scale-up programmes, this paper focuses on the positive role human rights can play in antiretroviral treatment scale-up efforts, and offers suggestions for research and action moving forward.

Editors’ note: Identifying the challenges and overcoming barriers to increasing access to antiretroviral treatment services, and enabling people to make informed and appropriate choices, are rights-based actions. Monitoring and evaluation for accountability can foster change to ensure equitable access.

Allen S, Stephenson R, Weiss H, Karita E, Priddy F, Fuller L, Declercq A. Pregnancy, hormonal contraceptive use, and HIV-related death in Rwanda. J Womens Health (Larchmt) 2007; 16:1017-27.

Few studies have examined the influence of pregnancy and hormonal contraception on HIV-related deaths in African women. Rwanda is a country with high fertility, high HIV prevalence, and frequent use of hormonal contraception in urban areas. Data from a prospective cohort study of 460 urban childbearing (18-35 years) women living with HIV followed at 6-monthly intervals for 6 years in Kigali, Rwanda, were analyzed. The relationship of time-dependent measures of pregnancy and hormonal contraceptive use to death from HIV disease was assessed with multivariate models. Incident pregnancy was not associated with elevated risk of death among women living with HIV. Oral and injectable hormonal contraceptive use had borderline protective effects associated with reduced mortality (HR 0.40, 95% CI 0.15-1.07 and HR 0.48, 95% CI 0.21-1.08 for mortality, respectively) in a multivariate model including time-dependent measures. In conclusion, the results point to the benefits of integrating family planning and HIV services. In a highly pronatalist society, such as Rwanda, which is experiencing high HIV prevalence, service integration affords an opportunity to provide HIV testing to women at risk of pregnancy and to promote family planning among women living with HIV.

Editors’ note: Women (and men for that matter) when diagnosed HIV-positive, and when starting on antiretroviral therapy, should be asked about their fertility intentions and counselled concerning their options. More attention is needed urgently to integrate reproductive health and HIV services to ensure that unplanned pregnancies are avoided and HIV transmission risk during pregnancy, childbirth, and breastfeeding is minimised.

Adolescent reproductive health has not continued to receive the attention it deserves since the start of the HIV epidemic. In South Africa, high numbers of adolescent women report pregnancies that are unwanted and yet few have accessed available termination of pregnancy services. Enabling contraception use is vital for meeting the goals of HIV prevention. A nationally representative survey of South African 15-24 year olds was undertaken. Participants completed a questionnaire on sexual behaviour and provided an oral fluid sample for HIV testing. Analysis of the data was restricted to women (n = 6 217), particularly those who reported being sexual active in the last 12 months (n = 3 618 ) and was conducted using methods allowing for sample strata, primary sampling units and population weights in the program STATA 8.0. Univariate and multivariate analyses were conducted to explore factors associated with contraceptive use. Two thirds of all women reported having ever been sexually active and among these 87% were sexually active in the past 12 months. Among women who reported currently being sexually active, 52.2% reported using contraceptives. There was evidence of association between contraceptive use and being employed or a student (vs unemployed); fewer sex partners; type of last sex partner; having talked to last partner about condom use, and having ever been pregnant. The authors conclude that specific emphasis must be placed on encouraging young women to use contraceptive methods that offer protection against pregnancy and STIs/HIV. The consistent finding of a relationship between discussing condom use with partners and condom use indicates the importance of involvement of male partners in women’s contraceptive decisions.

Editors’ note: Male partners are more likely to get involved and young women are more likely to involve them in both HIV prevention and contraception decision making if they develop communication skills in sexual relationships. Behaviours that result in unwanted pregnancy are also those that lead to HIV transmission. Breaking the silence to talk about protection must become the social norm among young, sexually active people everywhere.

Smith and colleagues aimed to examine and understand the marital and fertility aspirations and behaviours of individuals receiving antiretroviral therapy in Nigeria and evaluate the effects on sexual behaviour, disclosure, and adherence. The study used ethnographic methods of participant observation and in-depth interviews of individuals receiving antiretroviral therapy through a government-supported programme in southeastern Nigeria. Interviews and observations of individuals on treatment demonstrate that marriage and childbearing are paramount desires for people whose health is restored by antiretroviral therapy. The concept of life projects is introduced and combined with the established idea of therapeutic itineraries to show how participation in and adherence to treatment, disclosure of HIV status, and decisions about sexual behaviour cannot be understood in purely biomedical terms. Marital and reproductive aspirations routinely impinge on and often trump clinical and public health priorities. Emblematic case studies are provided to illustrate the social dynamics that motivate and explain behaviour seemingly inimical to individual and public health. In conclusion effective antiretroviral programme design and therapy management will require acknowledging and often enabling rather than discouraging the marital and reproductive goals of individuals if issues of disclosure, adherence, and prevention are to be realistically addressed.

Editors’ note: Antiretroviral treatment can lead to the restoration of life projects that may have been abandoned, such as developing long-term partnerships and having children. Enabling people to navigate these new horizons with joy and satisfaction in ways that are safe for themselves and others is a welcome challenge.

Salemi M, de Oliveira T, Ciccozzi M, Rezza G, Goodenow MM. High-Resolution Molecular Epidemiology and Evolutionary History of HIV-1 Subtypes in Albania. PLoS ONE. 2008 Jan 2;3(1):e1390.

The HIV-1 epidemic in Western Europe is largely due to subtype B. Little is known about the HIV-1 in Eastern Europe, but a few studies have shown that non-B subtypes are quite common. In Albania, where a recent study estimated a ten-fold increase of AIDS incidence during the last six years, subtype A and B account for 90% of the known infections. Salemi and colleagues investigated the demographic history of HIV-1 subtype A and B in Albania by using a statistical framework based on coalescent theory and phylogeography. High-resolution phylogenetic and molecular clock analysis showed a limited introduction to the Balkan country of subtype A during the late 1980s followed by an epidemic outburst in the early 1990s. In contrast, subtype B was apparently introduced multiple times between the mid-1970s and mid-1980s. Both subtypes are growing exponentially, although the HIV-1A epidemic displays a faster growth rate, and a significantly higher basic reproductive number R(0). HIV-1A gene flow occurs primarily from the capital Tirane, in the center of the country, to the periphery, while HIV-1B flow is characterized by a balanced exchange between center and periphery. Finally, the authors calculated that the actual number of infections in Albania is at least two orders of magnitude higher than previously thought. The analysis demonstrates the power of recently developed computational tools to investigate molecular epidemiology of pathogens, and emphasize the complex factors involved in the establishment of HIV-1 epidemics. The authors suggest that a significant correlation exists between HIV-1 exponential spread and the socio-political changes occurred during the Balkan wars. The fast growth of a relatively new non-B epidemic in the Balkans may have significant consequences for the evolution of HIV-1 epidemiology in neighboring countries in Eastern and Western Europe.

Editors’ note: Phylogenies reconstructed from randomly sampled viral gene sequences can give insight into population-level changes and epidemic dynamics. This study of treatment-naïve subjects who had no major mutations associated with drug resistance was able to describe the quite different trajectories of both subtype A and subtype B during a time of socio-political turmoil in the region. It has implications for further epidemic monitoring and for intensified prevention programmes.

El-Sadr WM, Abrams EJ. Scale-up of HIV care and treatment: can it transform healthcare services in resource-limited settings? AIDS. 2007 ;21 Suppl 5:S65-70.

The rapid expansion of HIV care and treatment in resource-limited settings will undoubtedly ameliorate conditions in communities ravaged by this epidemic around the world and enable persons living with HIV to live longer, more productive lives. Concerns have been raised, however, regarding the possible deleterious effects on other health services. This paper argues that efforts to scale up HIV care and treatment in resource-limited countries, if designed and implemented with the additional goal of achieving broad health benefits, may serve as a catalyst for the establishment of more effective and responsive health systems. In order to determine these broader effects, mechanisms need to be established that enable relevant research and evaluation questions to be answered.

Editors’ note: HIV treatment programmes have the potential to decongest medical clinics, emergency services, and hospital wards as well as to increase laboratory support, health care personnel job satisfaction, and health care infrastructure. Programmatic monitoring and evaluation frameworks need to be modified to detect both improvement in outcomes for people living with HIV and effects on the broader healthcare system.

Desquilbet L, Jacobson LP, Fried LP, Phair JP, Jamieson BD, Holloway M, Margolick JB: Multicenter AIDS Cohort Study. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty J Gerontol A Biol Sci Med Sci. 2007;62(11):1279-86

Older healthy and adults living with HIV exhibit physiological similarities. Frailty is a clinical syndrome associated with aging that identifies a subset of older adults at high risk of mortality and other outcomes. Desquilbet and colleagues investigated whether HIV infection increases the prevalence of a frailty-related phenotype that approximates a clinical definition of frailty. The authors first defined the frailty-related phenotype and assessed its prevalence among HIV-uninfected men followed in the Multicenter AIDS Cohort Study (MACS) between 1994 and 2004. Using repeated measurements logistic regression models, they then assessed the association between frailty-related phenotype and HIV infection before the era of highly active antiretroviral therapies, adjusting for covariates among HIV-uninfected (N = 1905) and incident HIV infections (N = 245). HIV infection was strongly associated with frailty-related phenotype prevalence. Compared to men without HIV of similar age, ethnicity and education, men with HIV were more likely to have the frailty-related phenotype for all durations of infection: for < or =4 years, the adjusted odds ratio (OR) was 3.38, with 95% confidence interval (CI), 1.25-9.11, and for 4.01-8 years and 8.01-12 years the corresponding figures were ( OR = 12.95, 95% CI, 6.60-25.40) and ( OR = 14.68, 95% CI, 7.60-28.35), respectively. The frailty-related phenotype prevalence for 55-year-old men infected with HIV for < or =4 years (3.4%; 95% CI, 1.3-8.6) was similar to that of uninfected men > or =65 years old (3.4%; 95% CI, 1.5-7.6). The authors conclude that in this cohort, HIV infection was associated with an earlier occurrence of a phenotype that resembles the phenotype of frailty in older adults without HIV infection. Studies of frailty in the setting of HIV infection may help to clarify the biological mechanism of frailty.

Editors’ note: Aging is associated with both increased risk of certain diseases and frailty involving enhanced vulnerability to stressors and impairments of immunological and inflammatory regulation. Similar mechanisms seem to be operation in HIV infection. This long-term cohort study found that the duration of HIV infection, low CD4 count, and high viral load were associated with a higher likelihood of frailty-like manifestations, suggesting that earlier treatment could potentially slow down the aging-like effects of HIV infection.

Frye V, Latka MH, Wu Y, Valverde EE, Knowlton AR, Knight KR, Arnsten JH, O’Leary A; INSPIRE Study Team. Intimate partner violence perpetration against main female partners among HIV-positive male injection drug users. J Acquir Immune Defic Syndr. 2007;46 Suppl 2:S101-9.

Intimate partner violence against women is a serious public health and social problem and is associated with a host of adverse health outcomes and behaviours, HIV risk behaviours included, among women who are victimized. Historically, research has focused on correlates of intimate partner violence victimization among women; thus, there is less information on the role of men in perpetrating intimate partner violence, particularly among men at risk for transmitting HIV to their female partners. Frye and colleagues assessed the self-reported prevalence and correlates of perpetration and threat of perpetration of physical and/or sexual intimate partner violence against a main female partner among 317 men with HIV who were current injection drug users. More than 40% of men reported perpetrating physical (39%) and/or sexual (4%) violence against their main female partners in the past year. Multivariate analyses revealed that low education, homelessness, psychologic distress, and unprotected sex with main and non-main HIV-negative female partners were positively associated with intimate partner violence perpetration against main female partners. These findings reveal that intimate partner violence perpetration is prevalent among HIV-positive male injecting drug users and associated with sexual HIV transmission risk behaviours. Intimate partner violence assessment and treatment among HIV-positive men in HIV care is recommended as a way to prevent intimate partner violence perpetration andvictimization and to reduce potential HIV transmission.

Editors’ note: Although more research is needed to better understand how HIV and drug involvement influence the natural history of intimate partner violence across the life span, programmes are needed now to address the dynamics of abusive relationships, reduce the violence, and prevent HIV transmission. HIV care services need to integrate the assessment and treatment of both violence experience and violence perpetration.

Welch SB, Gibb D. When should children with HIV infection be started on antiretroviral therapy? PLoS Med. 2008;5(3):e73.

Background to the debate: The advent of highly active antiretroviral therapy dramatically improved the prognosis for both adults and children infected with HIV who had access to treatment. However, the optimal timing for initiating treatment remains controversial, particularly in children. This debate lays out the case for deferred treatment against the case for early initiation of highly active antiretroviral therapy in children.

Editors’ note: This open access article is a debate with each author arguing his or her point of view for or against early initiation of antiretroviral treatment in children. Research into paediatric antiretroviral treatment has lagged behind that of adults, the effects of antiretroviral medication on growth and development are unknown, and there are adherence problems. On the other hand, there are new paediatric drug formulations and there is good evidence for starting early. Kids will be on treatment for life so it is important to consider the wishes and circumstances of individual children and their families, in addition to biomarkers, in the decision to initiate antiretroviral treatment. There is a clear need for clinical trials that address the ‘where to start’ question.

The aim of this study, conducted in Ivory Coast, was to evaluate the prevalence and evolution of viral hepatitis in children coinfected with human immunodeficiency virus type 1 (HIV-1). Hepatitis B virus (HBV) and hepatitis C virus (HCV) markers were retrospectively and longitudinally assessed among 280 HIV-1-infected children enrolled in the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales B et C 1244/1278 cohort. Among these, 173 (61.8%) received highly active antiretroviral therapy, including lamivudine (3TC) for 122 children. Detection of the hepatitis B s antigen (HBsAg) was performed on specimens collected at inclusion and 6 months later. If results of both tests were positive, hepatitis B e antigen (HBeAg)/hepatitis B e antibody (HBeAb) and HBV DNA levels were measured at inclusion and during follow-up. A fourth-generation HCV enzyme immunoassay was used for HCV screening at inclusion. In Rouet and colleagues’ paediatric cohort, no patients were infected with HCV, but the prevalence of HBsAg at inclusion was 12.1% (34 of 280; 95% confidence interval [CI], 8.6-16.6). Among the HBV-HIV-1-coinfected children, a high rate of positive HBeAg chronic hepatitis B (CHB) was noted at inclusion (82.4% [ 28 of 34]; 95% CI, 65.5%-93.2%) and after a median follow-up of 18 months (78.3%; 95% CI, 45.5%-92.7%), with no significant difference between children treated with highly active antiretroviral therapy (with or without 3TC) and untreated ones. These children showed high HBV DNA levels (usually >8.0 log(10) copies/mL) and viral populations consisting of nearly exclusively wild-type HBeAg-positive HBV strains, strongly suggesting that most of them were in the initial immunotolerant phase of chronic hepatitis B. The authors conclude that in sub-Saharan Africa, children with chronic hepatitis B and who are treated with 3TC-based highly active antiretroviral therapy are at risk of developing 3TC resistance. Further studies are required to guide the management of HBV-HIV-1-coinfected children.

Editors’ note: Three anitretrovirals - lamivudine (3TC), tenofovir (TDF), and emtricitabine (FTC) - can suppress both HIV and HBV replication, preventing hepatitis B progression to cirrhosis and liver cancer. However, severe reactivations are possible when these drugs are stopped or when resistant HBV mutants emerge with prolonged exposure to them. Resistant HBV could even possibly infect people who have been vaccinated against hepatitis B. However, HBV testing is simply not available in most low- and middle-income settings.

Allen M, Lau CY. Social impact of preventive HIV vaccine clinical trial participation: A model of prevention, assessment and intervention. Soc Sci Med. 2008;66(4):945-51

Preventive HIV vaccine trial participants may experience problems related to trial participation, including difficulties with personal relationships, employment, education, health care, housing, health insurance, disability insurance, life insurance, travel or immigration. During the 19 years that the U.S.-based National Institute of Allergy and Infectious Diseases (NIAID) has conducted preventive HIV vaccine trials, Allen and colleagues have developed a model to prevent and resolve social impact related to study participation and assist study participants who report such events. Key elements of the model include: informing potential volunteers of risks prior to enrollment; standardizing data collection methods on social impact events; reviewing and following-up on reported social impact events; assisting participants, including provision of free HIV testing to differentiate HIV infection from vaccine-induced HIV antibody; implementing broad-based and targeted community education programs for achieving community support; communicating with scientific and health care communities; and working with government agencies, non-government agencies and industry on mechanisms to address social impact. This approach, established in collaboration with NIAID-funded clinical trial groups, serves as a model for prevention, assessment, monitoring, and intervention for social impact related to preventive HIV vaccine clinical trial participation. Although further research is necessary, this model could be adapted for use in different clinical trials.

Editors’ note: All clinical trials have the potential to cause social harms and these can be anticipated. Plans should be drawn up, in consultation with community and other research stakeholders prior to trial onset, to monitor, minimize, and mitigate them.

Clinical trials evaluating interventions for infectious diseases require enrolling participants that are vulnerable to infection. As clinical trials are conducted in increasingly vulnerable populations, issues of protection of these populations become challenging. In settings where populations are forseeably oppressed, the conduct of research requires considerations that go beyond common ethical concerns and into issues of international human rights law. Using examples of HIV prevention trials in Thailand, hepatitis-E prevention trials in Nepal and malaria therapeutic trials in Burma ( Myanmar), Mills and Singh address the inadequacies of ethical guidelines in conducting research within oppressed populations. The authors review existing legislature in the United States and United Kingdom that may be used if trial hardships exist. They conclude by making considerations for any research conducted within oppressed populations.

Editors’ note: The arguments in favour of conducting research in any population must not only outweigh the negatives of not conducting the research, but they must be made by those who will be most affected by the research and their representatives. Participatory decision-making throughout the research life-cycle is described in the UNAIDS/AVAC Good participatory practice guidelines while the UNAIDS/WHO Ethical Considerations in biomedical HIV prevention trials lays out guidance on the specific circumstances in which trials should not be conducted.

Hurwitz JL, Zhan X, Brown SA, Bonsignori M, Stambas J, Lockey TD, Sealy R, Surman S, Freiden P, Jones B, Martin L, Blanchard J, Slobod KS. HIV-1 vaccine development: tackling virus diversity with a multi-envelope cocktail. Front Biosci 2008; 13:609-20.

A major obstacle to the design of a global HIV-1 vaccine is viral diversity. At present, data suggest that a vaccine comprising a single antigen will fail to generate broadly reactive B-cell and T-cell responses able to confer protection against the diverse isolates of HIV-1. While some B-cell and T-cell epitopes lie within the more conserved regions of HIV-1 proteins, many are localized to variable regions and differ from one virus to the next. Neutralizing B-cell responses may vary toward viruses with different i) antibody contact residues and/or ii) protein conformations while T-cell responses may vary toward viruses with different (i) T-cell receptor contact residues and/or (ii) amino acid sequences pertinent to antigen processing. Here Hurwitz and colleagues review previous and current strategies for HIV-1 vaccine development. The authors focus on studies at St. Jude Children’s Research Hospital dedicated to the development of an HIV-1 vaccine cocktail strategy. The St. Jude Children’s Research Hospital multi-vectored, multi-envelope vaccine has now been shown to elicit HIV-1-specific B- and T-cell functions with a diversity and durability that may be required to prevent HIV-1 infections in humans.

Editors’ note: The large number of circulating variants, with vulnerability present both within and between subtypes and within virtually all HIV-1 proteins, poses a challenge to vaccine development unique to HIV. Even the five designated ‘conserved’ regions as opposed to the ‘hypervariable’ regions are heterogeneous. Whether the positive finding of the cocktail approach of a multi-envelope vaccine in macaques challenged with artificial virus can be replicated in humans remains to be seen.