HIV This Week

 Welcome to the forty-second issue of HIV This Week! In this issue, we cover a variety of subjects, many of which relate to the meeting held this week in Geneva, entitled ‘Making HIV Trials Work for Women and Adolescent Girls’. For more information go to www.unaids.org

Topics in this issue are microbicides (why women in Soweto, South Africa participate in HIV prevention trials; men, is this what you would think about being exposed to a vaginal microbicide?; ethical concerns about trials), vaccines (low negative social impacts of trial participation for men/ no answers for women; great news about HPV vaccine effectiveness in women with HPV infection; vaccines and HIV-related stigma in the Dominican Republic), structural determinants/interventions (structural pathways to HIV risk stemming from poverty and gender inequities; microfinance, women’s empowerment, and the reduction of intimate partner violence in a trial in South Africa; customary norms and women’s civil rights: negotiating gender equality and sexual rights in Caprivi Region, Namibia), adolescents involvement in trials (breaking the age barrier to include adolescents in HIV vaccine trials; informed consent in kids: are they capable?; modelling vaccine delivery strategies for maximum effect in South Africa), treatment (no sex differences found in progression to AIDS and death and in responses to antiretroviral treatment but are they being missed?; is HIV-associated Kaposi sarcoma an issue for women?), basic science (measuring mucosal immunity in women in vaccine trials; microbicide safety: finding biomarkers for vaginal epithelial damage), and epidemiology (Uganda shows that data from voluntary testing in a mother-to-child transmission programme can be used to adjust sentinel surveillance findings; women are the infected partner in 30 to 40 per cent of discordant couples in Burkina Faso, Cameroon, Ghana, Kenya, and Tanzania).

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Stadler JJ, Delany S, Mntambo M. Women’s perceptions and experiences of HIV prevention trials in Soweto, South Africa. Soc Sci Med 2007 Sep 27; [Epub ahead of print]

Photo credit: UNAIDS L. Alyanak

Persistently high rates of HIV infection in sub-Saharan Africa have driven the exploration for additional methods of prevention, such as microbicides.  Multi-site, field-based clinical trials of microbicides are conducted in diverse social and cultural contexts. Local social and cultural perceptions of HIV, AIDS, and sexual risk can have profound implications in shaping community responses to the clinical trials, thereby affecting enrolment and retention. Moreover, clinical trials may have a significant impact on trial participants with regard to their views of AIDS, health, and relationships. Following these issues, this paper explores the subjective experiences of women enrolled in a microbicide feasibility study. Qualitative data were collected in two phases. The first phase took place prior to the inception of the feasibility study. Men and women from Soweto participated in focus group discussions about their perceptions and experiences of the AIDS epidemic and sexual risk. The second phase started once enrolment into the feasibility study had begun. Twenty-one women who were enrolled in the microbicide feasibility study were interviewed and participated in focus groups, and were asked about their experiences of participating in the microbicide feasibility study. Special attention was placed on how they felt their participation had affected their everyday lives. Interviews and discussions were conducted in local languages, recorded, translated and transcribed. Data were analysed thematically. The central finding of this study is the sense of empowerment that feasibility study participants felt in spite of their being embedded in a culture that has come to fear, deny or ignore AIDS. The authors Stadler and colleagues discuss the critical role of repeated, voluntary counselling and testing, knowledge of HIV status, and heightened awareness of sexual and reproductive health in reshaping study participants’ approaches to sexual relationships and AIDS, as well as the benefits that participation entailed.

Editors’ note: This article confirms reports from well-run trials elsewhere about women’s positive perceptions about their trial participation. They cite being treated with respect; access to information; having an opportunity to talk; free HIV testing, condoms, and care; and a sense of belonging and altruism as major benefits.

Carballo-Diéguez A, Balán IC, Morrow K, Rosen R, Mantell JE, Gai F, Hoffman S, Maslankowski L, El-Sadr W, Mayer K. Acceptability of tenofovir gel as a vaginal microbicide by US male participants in a Phase I clinical trial (HPTN 050). AIDS Care 2007;19:1026-31.

The authors Carballo and colleagues studied the acceptability of tenofovir gel among HIV-infected and uninfected men who were exposed to it during vaginal intercourse. The gel was found to be highly acceptable to most men, the large majority indicating they would probably use it in the future if they were concerned about HIV and the product were available. Men liked the gel’s transparency and odourless qualities, although reactions to its viscosity were more varied. Men acknowledged women’s rights to self-determination concerning HIV-prevention, yet considered that women’s covert use of the product was more acceptable in the context of ‘one-night-stands’ than in stable relationships, for which dialogue on protection measures was preferred.  Restrictions to couples’ habitual sexual repertoire and the protocol requirement to use condoms resulted in complaints. Microbicide trials that do not require condom use from men who don’t typically use them may provide a more accurate assessment of acceptability. Consistent microbicide use may be contingent on its ease of incorporation into typical sexual practices, type of sexual partnership, and contextual issues.

Editors’ note: Not only the acceptability of a vaginal microbicide for male partners but also the safety of the product for them need to be established. They will be exposed to the microbicide vehicle itself (gel, cream, capsule, ring, etc.) and either the experimental product (in this case, a gel containing an antiretroviral) or the placebo when their partner participates in a trial.

Moodley K. Microbicide research in developing countries: have we given the ethical concerns due consideration? BMC Med Ethics 2007;8:10.

HIV prevention research has been fraught with ethical concerns since its inception. These concerns were highlighted during HIV vaccine research and have been elaborated in microbicide research. A host of unique ethical concerns pervade the microbicide research process from trial design to post-trial microbicide availability. Given the urgency of research and development in the face of the devastating HIV pandemic, these ethical concerns represent an enormous challenge for investigators, sponsors, and Research Ethics Committees (RECs) both locally and internationally. Ethical concerns relating to safety in microbicide research are a major international concern.  However, in the urgency to develop a medically efficacious microbicide, some of these concerns may not have been anticipated. In the risk-benefit assessment of research protocols, both medical and psycho-social risk must be considered. In this paper four main areas that have a potential for medical and/or psycho-social harm are examined. Male partner involvement is controversial in the setting of covert use of microbicides. However, given the long-term exposure of men to experimental products, this may be methodologically, ethically, and legally important. Covert use of microbicides may impact negatively on relationship dynamics leading to psychosocial harm to varying extents. The unexpectedly high rates of pregnancy during clinical trials raise important methodological and ethical concerns. Enrolment of adolescents without parental consent generates ethical and legal concerns that must be carefully considered by RECs and trial sites. Finally, paradoxical outcomes in recent trials internationally have advanced the debate on the nature of informed consent and responsibility of researchers to participants who become HIV positive during or after trials.  In summary, Phase III microbicide trials are an undisputed research and ethical priority in developing countries. However, such trials must be conducted with attention to both methodological and ethical detail. It is imperative that guidelines are formulated to ensure that high ethical standards are maintained despite the scientific urgency of microbicide development. Given the controversy raised by emergent ethical issues during the course of microbicide development, it is important that international consensus is reached amongst the various ethics and regulatory agencies in developing and developed countries alike.

Editors’ note: International consensus has been reached and the results detailed in 19 guidance points in the recently published UNAIDS/WHO guidance document “Ethical considerations in biomedical HIV prevention trials”. It addresses each of the concerns raised by this author. It may be found at www.unaids.org.

Fuchs J, Durham M, McLellan-Lemal E, Vittinghoff E, Colfax G, Gurwith M, Buchbinder S. Negative Social Impacts Among Volunteers in an HIV Vaccine Efficacy Trial. J Acquir Immune Defic Syndr 2007 Aug 23; [Epub ahead of print]

The objective of the study was to describe the negative social impacts (NSIs) and their predictors in an HIV vaccine efficacy trial. In methods of the study, volunteers in the North American phase 3 trial of AIDSVAX B/B vaccine were questioned semi-annually about NSIs.  Multivariable logistic models identified independent predictors of NSI reporting.  The results revealed that of 5417 volunteers (94% male), 18% reported at least 1 negative social impact. Most events occurred early during trial participation and involved concerns by family and friends that the volunteer was HIV-infected or at risk for infection. Problems with disability/life insurance and employment occurred less frequently (<1%).  Individuals who became HIV-infected reported negative social impacts similar to HIV-negative volunteers. In multi-predictor analysis of male volunteers, NSI reporters were younger (adjusted odds ratio [ORAdj] = 1.6, 95% confidence interval [CI]: 1.2 to 2.1 and ORAdj = 1.4, 95% CI: 1.1 to 1.8 for ages 18 to 25 years and 26 to 35 years vs. >/=46 years, respectively), enrolled at sites with 50 or fewer volunteers (ORAdj = 2.3, 95% CI: 1.7 to 3.1), or lived in cities with high AIDS case rates (ORAdj = 1.4, 95% CI: 1.1 to 1.8). In conclusion, a modest proportion of vaccine efficacy trial volunteers reported problems in interpersonal relationships from trial participation. Serious harms involving insurance and employment were rare. Strategies to prevent harm from disclosure, particularly for younger volunteers and those from high sero-incidence sites, may reduce NSIs in future trials.

Editors’ note: Women were under represented in this trial. In 1998 when enrolment began, almost 20% of AIDS cases in the USA were among women and adolescent girls whereas 6% of the trial participants were female. Understanding whether fear of negative social impact might be a significant disincentive for women and girls is important to their successful recruitment. Documenting and addressing negative social impacts during trials is essential to retention of a population that must be represented in adequate numbers in trials so that conclusions relevant to them can be drawn.

The FUTURE II Study Group. Prophylactic Efficacy of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Women with Virological Evidence of HPV Infection. J Inf Dis 2007;196: 1438-46.

A quadrivalent (types 6, 11, 16, and 18) human papillomavirus (HPV) L1 virus-like-particle (VLP) vaccine has been shown to be 95%–100% effective in preventing cervical and genital disease related to HPV-6, -11, -16, and -18 in 16–26-year-old women naive for HPV vaccine types. Because most women in the general population are sexually active, some will have already been infected with  1 HPV vaccine types at the time vaccination is offered. Here, the FUTURE II Study Group assessed whether such infected women are protected against disease caused by the remaining HPV vaccine types. Two randomized, placebo-controlled trials of the quadrivalent (types 6, 11, 16, and 18) HPV vaccine enrolled 17,622 women without consideration of baseline HPV status. Among women infected with 1–3 HPV vaccine types at enrolment, efficacy against genital disease related to the HPV vaccine type or types for which subjects were naive was assessed. Vaccination was 100% effective (95% confidence interval [CI], 79%–100%) in preventing incident cervical intraepithelial neoplasia 2 or 3 or cervical adenocarcinoma in situ caused by the HPV type or types for which the women were negative at enrolment. Efficacy for preventing vulvar or vaginal HPV-related lesions was 94% (95% CI, 81%–99%). Among women positive for 1–3 HPV vaccine types before vaccination, the quadrivalent HPV vaccine protected against neoplasia caused by the remaining types. These results support vaccination of the general population without pre-screening.

Editors’ note: The results of this study are very encouraging because they show that pre-screening before vaccination is not necessary in women 16-26 years, the so-called “catch-up cohort” who may already have acquired one or more of the four HPV types covered by this vaccine. Current recommendations are for universal vaccination of 11-12 year old girls but these could now be extended to 13-26 years olds based on the high-level protection found here against precancerous cervical vulvar, and vaginal lesions (HPV 16/18) and genital warts (HPV 6/11). Now we need to know how well HPV vaccines work in HIV-positive women.

Barrington C, Moreno L, Kerrigan D. Local understanding of an HIV vaccine and its relationship with HIV-related stigma in the Dominican Republic. AIDS Care 2007;19:871-7.

This study explored local perceptions and experiences regarding vaccines in general and HIV vaccines and vaccine trials in the Dominican Republic. In-depth interviews were carried out with 25 participants representing two study groups: (1) individuals considered at high risk for HIV infection including female sex workers and male STI clinic attendees and (2) individuals considered at low risk of HIV infection including women and men recruited at a general outpatient clinic. Across the groups, participants often characterized vaccines in general as having both preventive and curative properties. In turn, one of the most salient concerns regarding the receipt of an HIV vaccine was the fear that one would be labelled ‘HIV positive’ and stigmatized, as the vaccine may be perceived as a cure for those already infected. These findings suggest the importance of individual and community level education to clarify the nature and mechanisms of the given HIV vaccine being tested. Social support and counselling services should also accompany HIV vaccine trials and distribution plans to assist individuals in determining if and how they communicate their participation and/or receipt of an HIV vaccine to others and manage potential negative social reactions.

Editors’ note: The study population for this qualitative research was comprised of 15 women and 10 men. Concerns about social stigmatisation related to participation in an HIV vaccine trial focused on ‘people talking’ and being labelled ‘HIV positive’. Most study participants perceived an HIV vaccine as a curative treatment for people already infected. Similar studies in the US also reveal ‘talk from other people’ as a concern, but related to being perceived as ‘being at risk’ rather than infected. Concern about vaccine-induced seropositivity, common in the US, was not cited in the Dominican Republic, perhaps reflecting the importance of improved vaccine research literacy as a condition for trial conduct.

Krishnan S, Dunbar MS, Minnis AM, Medlin CA, Gerdts CE, Padian NS. Poverty, Gender Inequities and Women’s risk of HIV/AIDS. Ann N Y Acad Sci 2007 Oct 22; [Epub ahead of print]

Entrenched economic and gender inequities together are driving a globally expanding, increasingly female, AIDS epidemic. To date, significant population-level declines in HIV transmission have not been observed at least in part because most approaches to prevention have presumed a degree of individual control in decision-making that does not speak to the reality of women’s and girls’ circumstances in many parts of the world. Such efforts have paid insufficient attention to critical characteristics of the risk environment, most notably poverty and gender-power inequities. Even fewer interventions have addressed specific mechanisms through which these inequities engender risky sexual practices that result in women’s disproportionately increased vulnerabilities to HIV infection. This paper focuses on identifying those mechanisms, or structural pathways, which stem from the interactions between poverty and entrenched gender inequities and recommending strategies to address and potentially modify those pathways. Krishnan and colleagues highlight four such structural pathways to HIV risk, all of which have the potential to be transformed: 1) lack of access to critical information and health services for HIV and sexually transmitted infection (STI) prevention; 2) limited access to formal education and skills development; 3) intimate partner violence; and 4) the negative consequences of migration prompted by insufficient economic resources. The authors argue for interventions that enhance women’s access to education, training, employment, and HIV and STI prevention information and tools; minimize migration; and by working with men and communities, at the same time reduce women’s poverty and promote gender equitable norms. In conclusion, the authors identify challenges in developing and evaluating strategies to address these structural pathways.

Editors’ note: Understanding the multiple dimensions of a risk environment that is impinging on individual “choices” is pivotal to addressing the structural pathways that mediate that risk environment’s influence on behaviour. For example, limited access to education and skills can lead to migration for economic opportunity that may increase the likelihood of transactional sex. Programmes addressing the latter will have limited effect without attention to “upstream” determinants.

Kim JC, Watts CH, Hargreaves JR, Ndhlovu LX, Phetla G, Morison LA, Busza J, Porter JD, Pronyk P. Understanding the impact of a microfinance-based intervention on women’s empowerment and the reduction of intimate partner violence in South Africa. Am J Public Health 2007;97:1794-802.

Kim and colleagues sought to obtain evidence about the scope of women’s empowerment and the mechanisms underlying the significant reduction in intimate partner violence documented by the Intervention With Microfinance for AIDS and Gender Equity (IMAGE) cluster-randomized trial in rural South Africa. The IMAGE intervention combined a microfinance program with participatory training on understanding HIV infection, gender norms, domestic violence, and sexuality.  Outcome measures included past year’s experience of intimate partner violence and 9 indicators of women’s empowerment. Qualitative data about changes occurring within intimate relationships, loan groups, and the community were also collected. Results showed that after two years, the risk of past-year physical or sexual violence by an intimate partner was reduced by more than half (adjusted risk ratio=0.45; 95% confidence interval=0.23, 0.91). Improvements in all 9 indicators of empowerment were observed. Reductions in violence resulted from a range of responses enabling women to challenge the acceptability of violence, expect and receive better treatment from partners, leave abusive relationships, and raise public awareness about intimate partner violence. In conclusion, the authors’ findings, both qualitative and quantitative, indicate that economic and social empowerment of women can contribute to reductions in intimate partner violence.

Editors’ note: Stand alone health programmes can encounter difficulties in recruiting and retaining vulnerable women. This study demonstrates the synergy of deliberately integrating public health interventions into development initiatives, such as microfinance. High uptake of the intervention, consistent village level violence reduction and its congruency with changes in structural pathway variables such as economic well-being and empowerment, and plausible mechanisms suggested by qualitative findings converge to support the effectiveness of this intervention. It should be scaled-up in the context of macro-economic and policy initiatives addressing gender inequities.

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Thomas F. Global rights, local realities: Negotiating gender equality and sexual rights in the Caprivi Region, Namibia. Cult Health Sex 2007;9:599-614.

Gender inequalities are frequently cited as a major reason for high HIV-prevalence rates in southern Africa. While steps have been taken to promote and pass legislation that upholds equal rights for women, this paper examines the ways in which discourses of gender equality and ensuing sexual rights can have complex, contradictory, and even adverse implications when they are mobilised, resisted, and reinterpreted at local level. Drawing upon research undertaken in the Caprivi Region of Namibia, this paper examines the ways in which men and women respond to ideas about gender equality, and seeks to place these responses within the wider context of socio-economic change and understandings of morality prevalent within the region. The tendency of many young women to seek out relationships with older men and the increasing costs of bride-wealth payments play a key role in reinforcing patriarchal attitudes and fuelling non respect for women’s rights both before and within marriage. In addition, a failure to adhere to customary norms, which uphold men’s dominant role, continues to threaten the support networks and assets available to women. The consequences of this situation are examined with particular focus on implications for the future transmission of HIV.

Editors’ note: This paper describes a “catch-22” situation in which adherence to the customary norms that can undermine women’s civil rights is necessary for women to access the social and economic entitlements they need for day-to-day subsistence. Promoting sexual rights and gender equality requires looking for openings and creating opportunities for negotiation to change customary norms so that they build on locally accepted core values such as respect, fairness, and justice. Only then will enforcement of national legislation promoting gender equality find fertile ground.

Jaspan HB, Cunningham CK, Tucker TJ, Wright PF, Self SG, Sheets RL, Rogers AS, Bekker LG, Wilson CM, Duerr A, Wasserheit JN; the HIV Vaccine Adolescent Trials Working Group. Inclusion of Adolescents in Preventive HIV Vaccine Trials: Public Health Policy and Research Design at a Crossroads. J Acquir Immune Defic Syndr 2007 Nov 1; [Epub ahead of print]

The search for a safe effective HIV vaccine has been a centrepiece of HIV research for almost 2 decades. More than 60 clinical HIV vaccine trials have been conducted to date. Several promising candidate HIV vaccines are in advanced clinical development. To date, however, no trial has included adolescents, one of the most important target groups for any preventive HIV vaccine. To license a vaccine for use in this age group, efficacy data or, at a minimum, bridging safety and immunogenicity data in this population are needed. To accomplish this, several critical issues and special challenges in the development and implementation of HIV vaccine trials in adolescents must be addressed, including regulatory considerations, potential differentials in safety and immunogenicity, alternative trial design strategies, recruitment and retention challenges, community involvement models, and approaches to informed consent/ assent. This article examines these issues and proposes specific next steps to facilitate the routine inclusion of this high-priority population in preventive HIV vaccine trials as early and seamlessly as possible.

 Editors’ note: The onset of sexual activity places adolescents at high risk of exposure to HIV in many sub-Saharan African countries and elsewhere. Although protecting young people with an effective safe vaccine would be a cost-effective public health strategy, such a vaccine could not be provided unless it was licensed for use in this age group. Strategies for the inclusion of adolescents in HIV vaccine trials, so that a safe and effective vaccine product can be licensed simultaneously for adult and adolescent use, are described here and in the report of the March 2006 meeting of the WHO/UNAIDS/AAVP International Expert Group on the Inclusion of Adolescents in HIV Vaccine Trials (AIDS 2007, 21:WI-W10)

Chappuy H, Doz F, Blanche S, Gentet JC, Tréluyer JM. Children’s views on their involvement in clinical research. Pediatr Blood Cancer 2007 Oct 25; [Epub ahead of print]

The objective of this study was to examine the level of children’s understanding of informed consent in clinical trials and factors that may influence these processes. The study design involved twenty nine children included in clinical trials for treatment of cancer or HIV who were offered the possibility to complete a semi directive interview, with parental permission. In methods of the study, children’s understanding was measured by a score of 0-9 including items required to obtain a valid consent according to French and European legislations. The children were 8.5-18 years old (13.6 +/- 2.8 years). A higher percentage of understanding was obtained for the study objectives (n = 18, 62%), the risks (n = 17, 58%), the potential self-benefits (n = 18, 62%) and the potential benefits to other children (n = 17, 58%). The lower percentage of understanding was obtained for the procedures (n = 5, 17%), the possibility of alternative treatments (n = 9, 31%), the duration of participation (n = 6, 21%), their right to withdraw (n = 6, 21%), and the voluntary participation (n = 6, 21%). Sixteen children (55%) thought that the given information was adequate. Understanding was significantly correlated with child’s age (r = 0.65; P = 0.0001) and the mean score was higher in patients over 14 years old compared to patients under the age of 14 (4.4 +/- 2.4, n = 14 vs. 2.6 +/- 2.6, n = 15, P < 0.05). The mean score was also higher in children when informed consent was sought some time after the diagnosis (>7 days) rather than at the same time (<7 days) (score: 4.14 +/- 2.59 n = 21 vs. 1.87 +/- 2.03 n = 8; P = 0.03). The clarity of information perceived by children did not influence their understanding (score: 3.6 +/- 2.6 n = 14 vs. 3.5 +/- 2.7 n = 15; P = 0.91). Chappuy and colleagues conclude that children have an incomplete understanding of the elements included in the informed consent forms. Understanding is related to age and timing of informed consent.

Editors’ note: Children who are capable of doing so have the right to be involved and to have a say in the decisions that affect them. Their capacity to appreciate the risks and benefits associated with a treatment or intervention depends on the appropriateness of the language used to counsel them and evolves with age. There is no arbitrary on-off switch for capacity to consent.

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Johnson LF, Bekker LG, Dorrington RE. HIV/AIDS vaccination in adolescents would be efficient and practical when vaccine supplies are limited. Vaccine 2007;25:7502-9.

The first HIV vaccines are likely to be expensive and limited in supply, and developing countries with a generalized AIDS epidemic will need to distribute the limited vaccine stock in a manner that is both efficient and practical. This analysis compares seven strategies for distributing an AIDS vaccine in different South African sub-populations, using a mathematical model. If vaccination is not coupled with HIV screening, vaccination of 16-year olds in school is likely to be the most efficient strategy for averting HIV infections in the short term. If coupled with screening, vaccination of sex workers and patients seeking STD treatment would be more efficient, but these gains in efficiency would have to be weighed against the practical challenges associated with vaccinating ‘high risk’ groups and conducting screening.

Editors’ note: The solution may not be an “either-or” but rather a “more”. Combining a general immunization programme for all 16 year-olds (without initial HIV testing) with an offer of testing for populations at higher risk of HIV exposure, followed by voluntary immunization for those who test HIV-negative, would be most effective. Each of these programmes has different scale-up/roll-out strategies and timelines but choosing to implement only one in hyperendemic situations such as South Africa would be shortsighted.

Nicastri E, Leone S, Angeletti C, Palmisano L, Sarmati L, Chiesi A, Geraci A, Vella S, Narciso P, Corpolongo A, Andreoni M. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review. J Antimicrob Chemother 2007;60:724-732.

Since the introduction of highly active antiretroviral therapy (HAART), morbidity and mortality rates have sharply decreased among HIV-infected patients. Studies of possible differences between men and women in the course of HIV infection give conflicting results. The objective of this study was to assess sex differences during HAART. In methods of the study, a literature search by using the MEDLINE database between March 2002 and February 2007 was performed to identify all published studies on the sex-specific differences on the impact of HAART. All articles with measures of effect (preferably adjusted odds ratio, relative risk or hazard ratio with 95% CI) of sex on viro-immunological and clinical parameters during HAART were included. Five different topics of interest in our research were selected: time of initiation of HAART, adherence, viro-immunological response, clinical response and adverse reactions during HAART. Results showed that United States data report an initiation of HAART at an earlier disease stage in men compared with women. After initiation of HAART, most authors do not report any viro-immunological difference, although a few clinical studies showed a significantly better virological response in women compared with men.  Nevertheless, women were more likely to be less adherent to antiretrovirals and to have non-structured treatment interruptions than men. This is likely to be related to the higher number of adverse reactions they experience during HAART.  Finally, discordant opinions with regard to clinical benefits during HAART exist, but recent clinical and observational trials suggest a better clinical outcome for women. In conclusion, the authors, Nicastri and colleagues, found little evidence of sex differences during antiretroviral treatment. Nevertheless, most of these studies were underpowered to detect sex differences and had limited follow-up at 6 or 12 months. Design of new gender-sensitive clinical trials with both prolonged follow-up and sample size representative of the current HIV prevalence among women are strongly needed to detect the likely sex differences of antiretroviral agents during HIV infection.

Editors’ note: This week UNAIDS convened a consultation in partnership with the Global Coalition on Women and AIDS, the International Center for Research on Women, and Tibotec which focused on the under-representation of women in HIV trials. Entitled ‘Making HIV trials work for women and adolescent girls’, the meeting examined sex differences in biomarkers, pharmacokinetics, and drug interactions; gender differences influencing recruitment and retention; and a number of related topics. More information may be found at www.unaids.org.

Perez-Hoyos S, Rodríguez-Arenas MA, García de la Hera M, Iribarren JA, Moreno S, Viciana P, Peña A, Gómez Sirvent JL, Saumoy M, Lacruz J, Padilla S, Oteo JA, Asencio R, Del Amo J; CoRIS-MD. Progression to AIDS and death and response to HAART in men and women from a multi-centre hospital-based cohort. J Womens Health (Larchmt) 2007;16:1052-61.

The objective of this research by Perez-Hoyos and colleagues was to study if progression to AIDS and death, as well as clinical and virological response to highly active antiretroviral therapy (HAART), differs between men and women. In methods, the authors studied a multi-centre, hospital-based cohort of HIV-infected patients attending 10 hospitals in Spain from January 1997 to December 2003. Kaplan-Meier and Cox regression were used to assess the effect of sex on time to AIDS, survival from AIDS, onset of a new AIDS event or death, and viral suppression from HAART. Of 4643 patients, 27% were women. Women had statistically significant lower viral loads (VL) of 3.9 vs. 4.1 log10/mL (p = 0.02) and higher median CD4 counts of 339 vs. 288 cells/mm3 (p < 0.001) at entry and were more likely to be AIDS free at entry. In univariate analysis, women seemed to show a non-significant lower progression to AIDS (HR 0.88) (95 CI% 0.73-1.07), which disappeared in multivariate analyses (HR 1.03) (95% CI 0.82-1.29). Survival from AIDS seemed to be higher in women (HR 0.65) (95% CI 0.40-1.05), but differences became clearly non-significant after adjustments (HR 0.71) (95% CI 0.42-1.23). No differences were seen in time to new AIDS condition or death after HAART (HR 1.08) (95% CI 0.80-1.46) in multivariate analyses. No differences were seen for time to VL suppression after initiation of HAART (HR 1.07) (95% CI 0.92-1.24). In conclusion, the authors found no differences in HIV progression and response to HAART attributable to gender among patients accessing the Spanish hospital network.

Editors’ note: Women have higher CD4 counts and lower viral loads than men but this does not translate into a benefit in disease progression. Is there a sex difference in the threshold viral load that predicts progression to AIDS in women? Although conclusive evidence is lacking, CDC guidelines suggest that clinicians may consider initiating antiretroviral therapy in women with CD4 counts above 350 at lower viral load thresholds. Understanding the nature and implications of sex differences is important.

Wang J, Stebbing J, Bower M. HIV-associated Kaposi sarcoma and gender. Gend Med 2007;4:266-73.

Cancer in individuals living with HIV is a common source of morbidity and mortality, especially in the underdeveloped world. As antiretrovirals are distributed with greater equity across the globe, individuals with HIV are living longer and developing malignancies, as opposed to other opportunistic infections. The objective of this article was to review the gender differences in studies of AIDS-associated cancers, examining factors related to transmission, treatment, and outcome. MEDLINE, PubMed, Ovid, conference proceedings, and abstract books were searched from 1983 onward for English-language publications and data on gender differences related to AIDS-associated cancers. Relevant trials were similarly reviewed. The search terms used were women or gender, cancer or tumour or malignancy, lymphoma or Kaposi, and HIV or AIDS. From the results of their search, Wang and colleagues, found that studies in established market economies have focused predominantly on men, although a wider view suggests that the rapidly growing rates of HIV infection among women should prompt specific oncologic challenges. In conclusion, immunosuppression-induced malignancies in women, Kaposi sarcoma in particular, are likely to represent a global issue in the future.

Editors’ note: Few studies have examined sex differences in cancer in the context of HIV infection. Human papilloma virus induced cervical cancer in women is likely to be the predominant cancer among women living with HIV for a long time to come. The effectiveness of the two new HPV vaccines (Gardasil and Cervarix) has not been reported in women living with HIV infection. Studying this is worthwhile because cervical cancer is an AIDS-defining condition and a major killer of women living with HIV infection.

Schneider JA, Alam SA, Ackers M, Parekh B, Chen HY, Graham P, Gurwith M, Mayer K, Novak RM. Mucosal HIV-Binding Antibody and Neutralizing Activity in High-Risk HIV-Uninfected Female Participants in a Trial of HIV-Vaccine Efficacy. J Infect Dis 2007;196:1637-44.

This study investigated gp120-binding antibody and neutralizing activity, at the gingival- and cervical-mucosal levels, in response to a bivalent gp120 candidate vaccine. Women who met the study’s inclusion criteria for documented high-risk behaviours participated in a nested sub study of the multi-centre phase 3 trial of human immunodeficiency virus (HIV)-vaccine efficacy, VAX004. Gingival, cervicovaginal lavage, and plasma specimens were collected at 6-month intervals for 3 years. Binding-antibody and neutralizing-activity assays quantified the presence of anti-HIV activity in mucosal specimens. Results revealed that vaccine recipients were more likely than placebo recipients to have IgG binding antibodies in all 3 compartments tested and to have only IgA binding antibody in plasma (P<.0001). The relationship between vaccine and cervicovaginal IgG achieved significance (odds ratio [OR], 6.6 [P=.01]) but was weakened by the presence of cervicovaginal leukocytes. There was no relationship between immunization and the presence of neutralizing activity, in either bivariate or multivariate modelling (OR, 6.0 [P=.29]). Schneider and colleagues conclude that vaccination is associated with the presence of both gp120-binding IgG in all compartments and plasma IgA but not with neutralizing activity. There is a role for the measurement of mucosal immunity in response to candidate vaccines and, in particular, for a determination of HIV-specific neutralizing antibodies.

Editors’ note: This vaccine candidate did not induce the neutralizing activity in the vaginal mucosal that will be key to preventing women from becoming infected through vaginal sexual intercourse. In the future, measurement of mucosal immune responses should be systematically included as a standard component in the evaluation of vaccine candidate efficacy.

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Trifonova RT, Bajpai M, Pasicznyk JM, Chandra N, Doncel GF, Fichorova RN. Biomarkers of leukocyte traffic and activation in the vaginal mucosa. Biomarkers 2007 Aug 22;1-15 [Epub ahead of print]

Development of novel vaginal spermicides and anti-human immunodeficiency virus (HIV) microbicides requires careful assessment of their potential to recruit and activate CD4+ HIV-1 host cells in the female genital tract mucosa, two events that facilitate HIV-1 infection. Leukocyte traffic and activation are mediated by pro-inflammatory cytokines and chemokines, e.g. interleukin (IL)-1, IL-6 and IL-8, which have been detected in vaginal secretions in association with epithelial damage and infections. These pro-inflammatory mediators, however, have bi-directional, destructive as well as beneficial, effects on the mucosal barrier, and may be counterbalanced by endogenous inhibitors. Here Trifinova and colleagues propose additional biomarkers for the evaluation of compound-induced cervicovaginal mucosal inflammation. Displaying different temporal patterns of detection, the levels of soluble E-selecting, vascular adhesion molecule-1, CD14 and myeloperoxidase in vaginal secretions reflected the mucosal leukocyte reaction to pro-inflammatory compounds being evaluated for safety in an improved rabbit vaginal irritation model. These biomarkers, which were also detected in human vaginal secretions, may be used to enhance the characterization of mucosal safety of vaginally applied compounds, both in animal as well as clinical studies.

Editors’ note: Vaginal microbicide candidates need to be evaluated by a variety of biomarkers and assays that can predict vaginal irritation before these candidates enter into large scale efficacy trials. The additional biomarkers in vaginal secretions described here (soluble E-selecting, VCAM-1, and others) may prove to be useful indicators of mucosal tissue signs of leucocyte activation suggesting a promising avenue for continued research.

Fabiani M, Yoti Z, Nattabi B, Ayella EO, Opio AA, Musinguzi J, García Calleja JM, Declich S. Adjusting HIV Prevalence Data From a Program for the Prevention of Mother-to-Child Transmission for Surveillance Purposes in Uganda. J Acquir Immune Defic Syndr 2007 Aug 30; [Epub ahead of print]

The objectives of the study were to evaluate a method for adjusting estimates of HIV prevalence based on data from a program for the prevention of mother-to-child transmission (PMTCT) of HIV infection for the potential bias attributable to refusal of PMTCT-related testing. Age-specific logistic regression models were used to estimate the HIV risk coefficients for 10 predictor variables among women who accepted the PMTCT-related testing (n = 1874) at an antenatal clinic in northern Uganda. These risk coefficients were used to predict the prevalence among women who were not tested (n = 1719) and to adjust the PMTCT-based prevalence for non-participation bias. Crude and adjusted PMTCT-based prevalence estimates were compared with the prevalence among women who were anonymously tested as part of routine sentinel surveillance (n = 2225). The results showed that the PMTCT-based prevalence represented an underestimate compared with that based on anonymous surveillance in 2004 (9.0% vs. 10.5%); in 2005, it constituted an overestimate (11.8% vs. 10.9%). Adjusting the PMTCT-based prevalence reduced the difference attributable to non-participation bias by approximately 70% in both years, so that the adjusted prevalence (10.1% in 2004 and 11.2% in 2005) was similar to the surveillance-based prevalence. In conclusion, the adjustment method was effective in reducing the non-participation bias. Further studies are needed to assess the utility of PMTCT program data for HIV surveillance. 

Editors’ note: Triangulating data from antenatal anonymous testing with anonymous routine sentinel surveillance is standard practice in many countries. Trying to do the same thing when HIV testing is nominal and participation rates are lower is a challenge. This study demonstrates that it can be done and that adjustment of national estimates of the number of people living with HIV can go up or down.

De Walque D. Sero-Discordant Couples in Five African Countries: Implications for Prevention Strategies. Population and Development Review Sep 2007;33(3):501-523.

This study of sero-discordant couples uses data from Demographic and Health Surveys which allow comparison of the HIV status of cohabiting couples (formally married or not) and sexual behaviour reported by the man and the woman. Data are examined from five countries Burkina Faso, Cameroon, Ghana, Kenya, and Tanzania. A couple is described as concordant negative when both partners are HIV negative and concordant positive when both are HIV positive. A discordant couple is one in which one partner is HIV positive and the other is HIV negative. A “discordant male couple” is one in which the male is HIV positive and the female is HIV negative and a “discordant female couple” is one in which the man is negative and the woman positive. Concordance proportions range from 14.8 per cent in Burkina Faso to 33.3 per cent in Ghana. Across the five countries, at least two-thirds of the infected couples are discordant couples in which only one of the two partners is HIV positive, meaning that there is scope for prevention of transmission from one partner to another. Between 30 and 40 percent of the infected couples are discordant female, a finding that is at odds with common assumptions about unfaithful males and HIV transmission in generalized epidemic settings. De Walque explores possible explanations for the driving force behind the sizable fraction of discordant female couples and finds that infection prior to marriage is not the main contributing factor. He concludes that either extramarital sex among women is more common than reported, or, even if it is infrequent, women are highly vulnerable to infection during extramarital sex. He recommends prevention efforts directed toward the partners of individuals who have been identified as HIV positive, encouraging joint voluntary counselling and testing to detect infected couples.

Editors’ note: These findings are similar to those from home-based testing and counselling programmes in Uganda. Although 60 to 70 percent of discordant couples are ones in which the man is infected, the remainder are the reverse. This may help explain why some women found to be HIV-positive in PMCTC programmes are unwilling to disclose to their partners. Clearly qualitative research is needed to help understand these findings. Concerted efforts to combat stigma and promote acceptance of people living with HIV are needed to help break the silence that is contributing to serodiscordant couples becoming concordant.