HIV This Week

Lockman S, Shapiro RL, Smeaton LM, Wester C, Thior I, Stevens L, Chand F, Makhema J, Moffat C, Asmelash A, Ndase P, Arimi P, van Widenfelt E, Mazhani L, Novitsky V, Lagakos S, Essex M. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007;356:135-47.http://content.nejm.org/cgi/content/full/356/2/135

A single dose of nevirapine during labour reduces perinatal transmission of HIV-1 but often leads to viral nevirapine resistance mutations in mothers and infants. Lockman and colleagues studied the response to nevirapine-based antiretroviral treatment among women and infants who had previously been randomly assigned to a single, peripartum dose of nevirapine or placebo in a trial in Botswana involving the prevention of the transmission of HIV-1 from mother to child. All women were treated with antenatal zidovudine. The primary end point for mothers and infants was virologic failure by the 6-month visit after initiation of antiretroviral treatment, estimated within groups by the Kaplan–Meier method. Of 218 women who started antiretroviral treatment, 112 had received a single dose of nevirapine and 106 had received placebo. By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine (P=0.002). Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure (P<0.001). In contrast, virologic failure rates did not differ significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively; P=0.39). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo (P<0.001). Maternal and infant findings did not change qualitatively by 12 and 24 months after the initiation of antiretroviral treatment. The authors conclude that women who received a single dose of nevirapine to prevent perinatal transmission of HIV-1 had higher rates of virologic failure with subsequent nevirapine-based antiretroviral therapy than did women without previous exposure to nevirapine. However, this applied only when nevirapine-based antiretroviral therapy was initiated within 6 months after receipt of a single, peripartum dose of nevirapine.

Editors’ note: These study results are encouraging because they suggest that the risk that single dose nevirapine will compromise subsequent treatment success for women can be reduced if antiretroviral treatment is started at least 6 months after childbirth. If confirmed by similar studies, these findings could have important implications for decisions about when to treat women post-partum; however, combining drugs for prevention of mother-to-child transmission would also reduce the risk of resistance and keep treatment options open for women.

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Garcia R, Badaro R, Netto EM, Silva M, Amorin FS, Ramos A, Vaida F, Brites C, Schooley RT. Cross-sectional study to evaluate factors associated with adherence to antiretroviral therapy by Brazilian HIV-infected patients. AIDS Res Hum Retroviruses 2006;22:1248-52.

Antiretroviral therapy success is highly dependent on the ability of the patient to fully adhere to the prescribed treatment regimen. Garcia and colleagues present the results of a cross-sectional study that evaluates the predictive value of a self-administered questionnaire on adherence to antiretroviral therapy (ART). Study participants were interviewed using a 36-item Patient Medication Adherence Questionnaire (PMAQ) designed to assess knowledge about ART, motivation to adhere to treatment, and behavioural skills. Plasma HIV-1 RNA levels were correlated with the results obtained from the PMAQ. Of the 182 study participants, 82 (45%) were receiving their initial ART regimen. Of the remaining patients, 39 (21%) and 61 (34%) were on a second or additional ART regimen, respectively. An undetectable viral load was documented in 47/62 (76%) patients on their first regimen who reported missing medication on less than 4 days in the last 3 months. The Patient Medication Adherence Questionnaire had a higher predictive value of plasma viral suppression for patients in the initial regimen than for patients in salvage therapy. The overall predictive value of the Patient Medication Adherence Questionnaire to identify adherence was 74%, and 59% for nonadherence, with an overall efficacy of 64%. Of the 74 patients (45%) who did not understand the concept of ART, 80% were failing or had previously failed the ART. Of 35 patients with doubts about their HIV status or skeptical of the benefits of ART, 29 (84%) were nonadherent. Despite the positive predictive value of PMAQ in identifying adherence, self-reported adherence is not a sufficiently precise predictor of treatment success to substitute for viral load monitoring. On the other hand, the use of such an instrument to identify factors associated with nonadherence provides an excellent opportunity to apply early intervention designed to specifically address factors that might be contributing to the lack of adherence prior to regimen failure.

Editors’ note: The relatively short administration time of this questionnaire which could assist in tailoring adherence counselling, suggests that it should be validated for use as a screening tool in other settings where patients are literate.

Hallett TB, White PJ, Garnett GP. The appropriate evaluation of HIV prevention interventions: from experiment to full scale implementation. Sex Transm Infect 2007 Jan 10[Epub ahead of print]. http://sti.bmj.com/cgi/rapidpdf/sti.2006.023663v1

Preventing HIV infection is an essential goal in tacking the HIV pandemic. Remarkably little is known about how best to reduce HIV incidence because the majority of trials focus on the reduction of risk behaviours and assume an effect on HIV incidence. Hallett and colleagues discuss the evidence for the effectiveness of HIV prevention strategies, exploring the different types of evidence available, including individual and community randomised controlled trials and observational studies. Whilst providing a gold standard for evidence, trials have been limited in their scope and are difficult to interpret and generalise. There have been examples of national level successes in preventing HIV which have been detected in surveillance data and understood through behavioural and modelling studies. These have the advantage of being to scale and indicating effectiveness rather than efficacy. The authors conclude that whilst randomised trials are important because of their scientific rigor, it is also important that evidence from observational epidemiology is not overlooked. Only if good quality and consistent data are available can the history of the HIV epidemic be appropriately analysed.

Editors’ note: There is a long history of debating the value of observational versus randomised controlled trial evidence. Both are valuable, including negative trial results which are often not published. More attention needs to be paid to qualitative methodologies which not only can produce information that helps explain quantitative findings but also can guide policy making and decisions about programming.

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Lyles CM, Kay LS, Crepaz N, Herbst JH, Passin WF, Kim AS, Rama SM, Thadiparthi S, DeLuca JB, Mullins MM; HIV/AIDS Prevention Research Synthesis Team. Best-evidence interventions: findings from a systematic review of HIV behavioral interventions for US populations at high risk, 2000-2004. Am J Public Health 2007;97:133-43.

The Centers for Disease Control and Prevention's HIV/AIDS Prevention Research Synthesis Team conducted a systematic review of US-based HIV behavioural intervention research literature from 2000 through 2004 to identify interventions demonstrating best evidence of efficacy for reducing HIV risk. The authors used standard systematic review methods. Each eligible study was reviewed on the basis of Prevention Research Synthesis Team efficacy criteria that focused on 3 domains: study design, implementation and analysis, and strength of evidence. Eighteen interventions met the criteria for best evidence. Four targeted HIV-positive individuals. Of those targeting populations at risk for HIV, 4 targeted drug users, 6 targeted adults at risk because of heterosexual behaviours only, 2 targeted men who have sex with men, and 2 targeted youths at high risk. Eight interventions focused on women, and 13 had study samples with more than 50% minority participants. Significant intervention effects included increased condom use and reductions in unprotected sexual intercourse, number of sexual partners, injection drug use or needle sharing, and newly acquired sexually transmitted infections. The authors conclude that most of the best-evidence interventions are directly applicable for populations in greatest need of effective prevention programmes; however, important gaps still exist.

 Editors’ note: Scaling up now what is known to be effective and addressing structural determinants, while conducting research to fill remaining knowledge gaps, constitute critical elements in the path to HIV prevention success.

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Lewis JJ, Donnelly CA, Mare P, Mupambireyi Z, Garnett G, Gregson S. Evaluating the proximate determinants framework for HIV infection in rural Zimbabwe. Sex Transm Infect 2007 Jan 10 [Epub ahead of print]. http://sti.bmj.com/cgi/rapidpdf/sti.2006.023671v1

Risk factors for HIV infection can act at one of several causal levels, making interpretation of results problematic. One suggested solution has been a proximate determinants framework, analogous to that used in the study of fertility and child survival. In this framework, risk factors are grouped into "underlying", "proximate" and "biological" determinants. Lewis and colleagues carried out a baseline, cross-sectional survey of HIV serostatus and potential risk factors among 9480 adults in Zimbabwe. Associations were assessed separately for men and women using logistic regression models; data were only included for those who reported sexual debut. The predictive ability of proximate determinants describing both individual and partnership characteristics was assessed along with the predictive ability of the underlying determinants. The significance of the underlying determinants once adjusted for proximate determinants was then evaluated. Finally the relationship between the underlying determinants and some of the key proximate determinants was explored. The two most important proximate determinants for both men and women were lifetime number of sexual partners and symptoms of sexually transmitted infections (p<0.001). After adjustment for all proximate determinants, some underlying determinants were still significant, particularly age group, marital status and community (<0.001). The authors conclude that whilst the proximate determinants could explain the action of many of the underlying determinants, several of the underlying determinants remained significant after adjustment for the proximate determinants. This suggests that the proximate determinants were not measured completely. One of the most important determinants of an individual's risk of HIV infection is the HIV status of their sexual partners. This was not measured in this survey and may be related to the individual's age (as a predictor for the age of the partner), marital status and community prevalence. Hence, partner's HIV status will be measured in a subsequent survey of this cohort.  

Editors’ note: It has often been said that, although they are highly interrelated, the prevalence of HIV in your bed is more important than that of the community in which you live in determining your risk of HIV exposure. Unknown sero-discordance in stable, exclusive partnerships is responsible for a significant amount of HIV transmission in many settings around the world. Effectively assisting couples to learn their HIV status together in a supportive fashion and to implement and maintain safer sex practices to reduce their risk is key to addressing this aspect of the epidemic.

Wilkinson J, Cunningham AL. Mucosal transmission of HIV-1: first stop dendritic cells. Curr Drug Targets 2006;7:1563-69.

Worldwide the heterosexual route is the prevalent mode of transmission of HIV, increasing the demand for measures that block the sexual (penile-vaginal) spread of HIV infection. Vaccines designed to prevent mucosal transmission of HIV should be considered a component of vaccine strategies against HIV (in addition to cytotoxic T cells required for clearance and to prevent viral dissemination) and include antibodies, which are capable of blocking HIV entry at mucosal epithelial barriers, and prevent initial infection of target cells in the mucosa. However, in the interim and in the absence of an effective vaccine, the development of microbicides, topical preparations that block the early steps of HIV infection and transmission, may represent a more viable alternative to condom use in many HIV infected regions of the world, especially by empowering women. To date there has been some success with antiviral antibodies applied as a microbicide capable of preventing SIV infection in macaques and there have been reports of vaccines capable of preventing intravaginal and intrarectal inoculated SIV. However, for such success in humans a much greater understanding of the mechanisms involved in the very early stages of mucosal transmission in HIV infection is required. These may lead to additional strategies to inactivate or inhibit viral uptake and replication before a potentially life threatening acute infection develops. Such measures will lead to the development of effective microbicides and vaccines that will diminish the global spread of HIV.

Editors’ note: The role of dendritic cells in transferring HIV to CD4 and other target cells for HIV needs further study, whether for vaccines or microbicide development.

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Liu J, Roederer M. Differential susceptibility of leukocyte subsets to cytotoxic T cell killing: implications for HIV immunopathogenesis. Cytometry A. 2007 Jan 2 [Epub ahead of print].

Cytotoxic T lymphocytes (CTL) are crucial for the host defence against viral infection. In many cases, this anti-viral immune response contributes to host pathogenesis, through inflammation and tissue destruction. Few studies have explored the relative susceptibility of infected cells to CTL killing, and the range of cell types that may be effectively killed by CTLs in vivo, both of which are key to understanding both immune control of infection and immune-related pathogenesis. Liu and Roederer developed and optimized a highly sensitive method to quantify the relative susceptibility of leukocyte subsets to CTL-mediated killing. Maximal sensitivity was achieved by uniquely measuring cell death occurring during the assay culture. The authors found that leukocyte subsets have a wide range of susceptibility to antigen-specific CTL-mediated lysis. Generally, T cells were more susceptible than B or natural killer (NK) cells, with CD4-T cells being more susceptible than CD8-T cells. In all lymphocyte lineages, susceptibility was greater for more differentiated subsets compared with their naive counterparts; however, for dendritic cells, immature cells are more susceptible than mature cells. Liu and Roederer focused on the susceptibility of T cell subsets, and found that naive cells are far more resistant than memory cells, and in particular, CCR5+ or HLA-DR+ memory cells are highly susceptible to CTL-mediated killing. The authors conclude that the results provide an explanation for the observation that certain subsets of CD4-T cells are ablated during chronic HIV infection, and indicate which subsets are most likely to contain the persistent viral reservoir.

Airhihenbuwa CO. On being comfortable with being uncomfortable: centering an Africanist vision in our gateway to global health. Health Educ Behav 2006 Dec 15 [Epub ahead of print].

African identity must be central to research on African health and development. Airhihenbuwa reflects on three primary themes for advancing a different vision for understanding health issues in Africa. The first is the need to deconstruct conventional assumptions and theories that have been used to frame public health problems and solutions in Africa. The second is to insist that identity be central to how we frame issues of health and behaviour in general and in Africa in particular. The third is the importance of the notion of "social cultural infrastructure" in defining African ways of knowing to guide public health research and intervention in Africa. Finally, the author uses the metaphor of the "African gate" to illuminate these themes while drawing on examples from an HIV- and AIDS-related stigma research in South Africa and its implications for addressing the critical global public health issues of today.

Editors’ note: These are thought-provoking ideas for all of us supporting the response to AIDS in sub-Saharan Africa.

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Falagas ME, Bliziotis IA, Kondilis B, Soteriades ES. Eighteen years of research on AIDS: contribution of and collaborations between different world regions. AIDS Res Hum Retroviruses 2006;22:1199-205.

The scientific community invests significant resources on HIV research to confront the current epidemic. Falagas and colleagues reviewed the medical literature in order to evaluate the contribution of different world regions on HIV research during the past 18 years. The authors retrieved articles, using an elaborate methodology, from three journals focusing on HIV between 1986 and 2003, indexed in the Journal Citation Reports and the Web of Science databases of the Institute for Scientific Information (ISI). Comparisons were made by dividing the world into nine geographic regions, and by using the human development index categorization. A total of 9502 articles on HIV were retrieved from three AIDS journals over an 18-year study period. The United States and Western Europe together made up a striking 83% of the world's research production on HIV. Scientists from the developing world participated in 10.4% of the articles published during 1986-1991, 14.7% during 1992-1997, and 21.3% during 1998-2003. Researchers from countries included in the high, medium, and low human development index category produced 2240, 9, and 15 articles per billion population, respectively. About half of articles originating in Latin America and the Caribbean and half in Asia were produced in collaboration with the United States. However, 40% of articles from Africa and 58% from Eastern Europe were produced in cooperation with Western Europe. Collaboration between researchers within developing regions was negligible. The vast majority of the world's research on AIDS is produced in the developed world. Although research production was minimal in the developing world, regions included in the low and medium human development index categories showed a higher proportion of increase in research productivity than the developed countries. The authors conclude that international collaborations should significantly increase and expand beyond the traditional, cultural and political lines of international relationships.  

Editors’ note: This analysis highlights the need for capacity building in regional networks of researchers and creation of new ones to facilitate within region researcher collaboration. The UNAIDS Technical Support Facilities and the CRIS Research Module will help pave the way for stronger south-south collaboration.