HIV This Week

Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study.

Kilewo C, Karlsson K, Ngarina M, Massawe A, Lyamuya E, Swai A, Lipyoga R, Mhalu F, Biberfeld G; Mitra Plus Study Team. J Acquir Immune Defic Syndr. 2009;52:406-16.

The main aim of this study was to reduce breast-milk transmission of HIV-1 by treating HIV-1-infected women with antiretroviral therapy (ART) during breastfeeding. Mitra Plus was an open-label, nonrandomized, prospective cohort study. HIV-1-infected pregnant women in Dar es Salaam were treated with zidovudine (ZDV) + lamivudine (3TC) + nevirapine (NVP). NVP was later replaced by nelfinavir for mothers with CD4 cell counts >200 cells per microlitre or with adverse reaction to NVP. Antiretroviral therapy was initiated at 34 weeks of gestation. For women with symptomatic HIV infection or CD4 cell counts below 200 cells per microlitre, antiretroviral therapy was started earlier if possible. Treatment of the mothers was stopped at 6 months except for those mothers who needed antiretroviral therapy for their own health. The infants received ZDV + 3TC for 1 week after birth. Mothers were advised to exclusively breastfeed and to wean abruptly between 5 and 6 months. Transmission of HIV-1 was analyzed using the Kaplan-Meier survival technique. Cox regression was used for comparison with the breastfeeding population of the Petra trial arm A. There were 441 infants included in the analysis of HIV-1 transmission. The cumulative transmission of HIV-1 was4.1 % [95% confidence interval (CI): 2.2 to 6.0] at 6 weeks, 5.0% (95% CI: 2.9 to 7.1) at 6 months, and 6.0% (95% CI: 3.7 to 8.3) at 18 months after delivery. The cumulative risk of HIV transmission between 6 weeks and 6 months was 1.0% and between 6 months and 18 months 1.1%. The cumulative HIV infection or death rate was 8.6% (95% CI: 6.0 to 11.2) at 6 months and 13.6% (95% CI: 10.3 to 16.9) at 18 months after delivery. Viral load at enrolment and duration of antiretroviral therapy before delivery were significantly associated with transmission but CD4 cell count at enrolment was not. The median time of breastfeeding was 24 weeks. The transmission in the Mitra Plus study was about half of the transmission in the breastfeeding population in the Petra trial arm A at 6 months after delivery (adjusted relative hazard = 0.49, P < 0.001). The combined outcome HIV infection or death was significantly lower in the Mitra Plus study than in the breastfeeding population in the Petra trialarm A at 18 months (adjusted relative hazard = 0.61, P = 0.007). NVP-related mucocutaneous rash was demonstrated in 6.5% of 429 NVP-exposed women. The incidence of NVP-related grade 3 or 4 hepatotoxicity was low (0.5%). Antiretroviral therapy given to HIV-infected mothers in late pregnancy and during breastfeeding resulted in a low postnatal HIV transmission similar to that previously demonstrated in the Mitra study in Dar es Salaam using infant prophylaxis with 3TC during breastfeeding. The extended maternal prophylaxis with antiretroviral therapy for prevention of mother-to-child transmission of HIV-1 for breastfeeding mothers who do not need antiretroviral therapy for their own health should be further evaluated and compared with the use of infant postnatal antiretroviral prophylaxis regarding safety and cost-effectiveness.

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Editors’ note: These Mitra Plus study findings from Tanzania of low HIV transmission through breastfeeding when mothers receive antiretroviral treatment, whether they need it for their own health or not, may well have informed the new WHO ‘rapid advice’ documents released last week. Although the option remains (Option A) to provide AZT only from as early as 14 weeks of pregnancy, followed by AZT and 3TC during labour and delivery and for 7 days postpartum - with breastfeeding babies then receiving nevirapine until one week after all exposure to breast milk has ended – a new option called Option B has emerged. It includes maternal triple antiretroviral prophylaxis from as early as 14 weeks and continuing until 1 week after all exposure of the infant to breast milk ends. Changes such as these will bring us closer to the goal of virtually eliminating mother-to-child transmission of HIV.

Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda.

Peltier CA, Ndayisaba GF, Lepage P, van Griensven J, Leroy V, Pharm CO, Ndimubanzi PC, Courteille O, Arendt V. AIDS. 2009 23:2415-23.

The aim of the study was to assess the 9-month HIV-free survival of children with two strategies to prevent HIV mother-to-child transmission in a nonrandomized interventional cohort study. Four public health centres in Rwanda enrolled participants between May 2005 and January 2007. All consenting HIV-infected pregnant women were included. Women could choose the mode of feeding for their infant: breastfeeding with maternal antiretroviral therapy for 6 months or formula feeding. All received antiretroviral therapy from 28 weeks of gestation. Nine-month cumulative probabilities of HIV transmission and HIV-free survival were determined using the Kaplan-Meier method and compared using the log-rank test. Determinants were analysed using a Cox model analysis. Of the 532 first-liveborn infants, 227 (43%) were breastfeeding and 305 (57%) were formula feeding. Overall, seven (1.3%) children were HIV-infected of whom six were infected in utero. Only one child in the breastfeeding group became infected between months 3 and 7, corresponding to a 9-month cumulative risk of postnatal infection of 0.5% [95% confidence interval (CI) 0.1-3.4%; P = 0.24] with breastfeeding. Nine-month cumulative mortality was 3.3% (95% CI 1.6-6.9%) in the breastfeeding arm group and 5.7% (95% CI 3.6-9.2%) for the formula feeding group (P = 0.20). HIV-free survival by 9 months was 95% (95% CI 91-97%) in the breastfeeding group and 94% (95% CI 91-96%) for the formula feeding group (P = 0.66), with no significant difference in the adjusted analysis (adjusted hazard ratio for breastfeeding: 1.2 (95% CI 0.5-2.9%). Maternal antiretroviral therapy while breastfeeding could be a promising alternative strategy in resource-limited countries.

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Editors’ note: This study enrolled 562 HIV-positive pregnant women who were placed on antiretroviral treatment at 28 weeks of pregnancy regardless of CD4 count. Those who decided to formula feed stopped antiretroviral treatment after their baby’s birth if they were not eligible in Rwanda (less than 350 CD4 count) and those who decided to breastfeed continued antiretroviral treatment until 1 month after weaning their babies at 6 months of age and then stopped taking antiretroviral drugs if they were not eligible for treatment. All babies received a backbone of AZT and 3TC for seven days after they stopped being exposed to maternal antiretroviral drugs through the placenta or through breast milk to reduce the risk of resistance to the third drug (nevirapine or efavirenz). There was no difference in HIV-free survival and, amazingly, there was no significant difference in the mortality by infant feeding mode (3.3% versus 5.7%) although virtually all studies in low- and middle-income countries have shown higher mortality with formula feeding. This may be because mothers received education and good follow-up and care, regardless of the feeding option they chose. The bottom line is that the risk of HIV transmission during breastfeeding is minimal when mothers are on antiretroviral treatment, regardless of CD4 count.

Community Involvement in HIV and Tuberculosis Research.

Harrington M. J Acquir. Immune Defic Syndr. 2009; Nov:52(S2)

Since advent of the HIV pandemic in the 1980s, affected communities and individuals living with HIV have played key roles in leading the response to the crisis. Achievements of the HIV treatment activist movement include persuading the US Food and Drug Administration to allow expanded access to experimental treatments for those unable to enter controlled clinical trials; accelerated approval of anti-HIV drugs based on surrogate markers such as CD4 cell and HIV RNA changes; and the involvement ofpeople with HIV and their advocates throughout the research system, including in the design, conduct, and evaluation of clinical trials. HIV treatment activists have adapted these skills to tackle tuberculosis (TB) research and programs. Considering the dearth of adequate diagnostic, treatment, and preventive interventions to control TB among people with HIV, the experiences and efforts of HIV activists are vital to accelerate research and development of new diagnostics, drugs, and vaccines to identify, cure, and prevent TB, especially among people living with HIV. Advocacy to implement World Health Organization collaborative HIV/TB activities and to reduce TB's toll among people with HIV provides a case study of how scale-up of HIV and TB programs contributes to health system strengthening.

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Editors’ note: This ‘must read’ article presents a succinct history of the HIV treatment activist movement, underscoring the informed and relentless pressure that accelerated the pace of research and development for novel antiretroviral drugs. Community activists used mass media and the internet, political lawsuits and legislation, public demonstrations and civil disobedience, and coalition-building and other strategies to influence both the speed and conduct of treatment research. The article describes the gains made and the challenges ahead, particularly for tuberculosis research. TB urgently requires new diagnostic methods (the ones in common use today date from the 19 th century), improved treatment drugs and programmes, and a new vaccine (Bacille Calmette-Guérin, the TB vaccine, was developed between 1908 and 1921). Among people living with HIV, TB is the commonest cause of death and over 1.4 million people living with HIV develop TB each year. Activists from among all stakeholders (community, scientists, government, funders, and others) need to join in concerted action to ensure rapid development of diagnostics, drugs, vaccines, and delivery systems to prevent people dying from tuberculosis .

Peersman G, Ferguson L, Torres M, Smith S, Gruskin S. J Acquir Immune Defic Syndr. 2009 52(S2)

The 2001 Declaration of Commitment on HIV/AIDS provided impetus for strengthening collaboration between government and civil society partners in the HIV response. The biennial UNGASS reporting process is an opportunity for civil society to engage in a review of the implementation of commitments. The article is reporting on the descriptive analyses of the National Composite Policy Index from 135 countries; a debriefing on UNGASS reporting with civil society in 40 countries; and 3 country case studies on the UNGASS process. In the latest UNGASS reporting round, engagement of civil society occurred in the vast majority of countries. The utility of UNGASS reporting seemed to be better understood by both government and civil society, compared with previous reporting rounds. Civil society participation was strongest when civil society groupings took the initiative and organized themselves. An important barrier was their lack of experience with national level processes. Civil society involvement in national HIV planning and strategic processes was perceived to be good, but better access to funding and technical support is needed. Instances remain where there are fundamental differences between government and civil society perceptions of the HIV policy and program environment. How or whether differences were resolved is not always clear, but both government and civil society seemed to appreciate the opportunity for discussion. Collaborative reporting by government and civil society on UNGASS indicators is a small but potentially valuable step in what should be an ongoing and fully institutionalized process of collaborative planning, implementation, monitoring, assessment and correction of HIV responses. The momentum achieved through the UNGASS process should be maintained with follow-up actions to address data gaps, formalize partnerships and enhance active and meaningful engagement.

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Editors’ note: Civil society is defined in this article as voluntary associations of citizens that undertake actions in support of people living with or affected by HIV; it does not include the private (profit-making) or public (government) sectors. Civil society involvement in national HIV responses has increased since 2005 but there is room for improvement in virtually all countries if civil society participation is to be truly active and meaningful. One indicator is the number of ‘shadow reports’ from civil society groups dissatisfied with the government reporting on progress. This number has declined from 33 countries in 2006 to 15 countries in 2008, and some of the latter reports were simply providing additional information, as opposed to expressing dissenting views. Although UNGASS reporting is an international accountability tool based on the 2001 Declaration of Commitment, the reporting process itself can be a mechanism to increase civil society engagement in the national HIV response and enhance government accountability to its own citizens.

Anal Sexually Transmitted Infections and Risk of HIV Infection in Homosexual Men.

Jin F, Prestage GP, Imrie J, Kippax SC, Donovan B, Templeton DJ, Cunningham A, Mindel A, Cunningham PH, Kaldor JM, Grulich AE. J Acquir Immune Defic Syndr. 2009 Sep. [Epub ahead of print]

Jin et al examined a range of common bacterial and viral sexually transmitted infections as risk factors for HIV seroconversion in a community-based cohort of HIV-negative homosexual men in Sydney, Australia. Detailed information about HIV risk behaviours was collected by interview twice yearly. Participants were tested annually for HIV, anal and urethral gonorrhoea and chlamydia, herpes simplex virus types 1 and 2, and syphilis. In addition, they reported annual diagnoses of these conditions and of genital and anal warts. Among 1427 enrolled participants, 53 HIV seroconverters were identified, giving an incidence of 0.78 per 100 person-years. After controlling for number of episodes of insertive and receptive nonseroconcordant unprotected anal intercourse, there were independent associations with anal gonorrhoea (adjusted hazard ratio = 7.12, 95% confidence interval: 2.05 to 24.79) and anal warts (hazard ratio = 3.63, 95% confidence interval: 1.62 to 8.14). Anal gonorrhoea and anal warts were independently associated with HIV acquisition. The added HIV prevention value of more frequent screening of the anus to allow early detection and treatment of anal sexually transmitted infections in homosexual men should be considered.

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Editor’s note: For the most part, the anal gonorrhoea diagnosed in this study of men who have sex with men was asymptomatic, suggesting that it was of relatively long standing. It may have caused a low-grade inflammation that would attract HIV target cells. Likewise, anal warts themselves and/or their treatment can disrupt natural defences, allowing HIV easier access to its prey. Given that these two infections were independently associated with HIV acquisition, it is important to assess the potential impact on HIV incidence in men who have sex with men of frequent sexual health screening and treatment of anal gonorrhoea and anal warts.

Microbicides Development Programme: Engaging the community in the standard of care debate in a vaginal microbicide trial in Mwanza, Tanzania.

Vallely A, Shagi C, Lees S, Shapiro K, Masanja J, Nikolau L, Kazimoto J, Soteli S, Moffat C, Changalucha J, McCormack S, Hayes RJ. BMC Med Ethics 2009;10:17

HIV prevention research in resource-limited countries is associated with a variety of ethical dilemmas. Key amongst these is the question of what constitutes an appropriate standard of health care for participants in HIV prevention trials. This paper describes a community-focused approach to develop a locally-appropriate standard of health care in the context of a phase III vaginal microbicide trial in Mwanza City, northwest Tanzania. A mobile community-based sexual and reproductive health service for women working as informal food vendors or in traditional and modern bars, restaurants, hotels and guesthouses has been established in 10 city wards. Wards were divided into geographical clusters and community representatives elected at cluster and ward level. A city-level Community Advisory Committee with representatives from each ward has been established. Workshops and community meetings at ward and city-level have explored project-related concerns using tools adapted from participatory learning and action techniques e.g. chapati diagrams, pair-wise ranking. Secondary stakeholders representing local public-sector and non-governmental health and social care providers have formed a trial Stakeholders’ Advisory Group, which includes two Community Advisory Committee representatives. Key recommendations from participatory community workshops, Community Advisory Committee and Stakeholders’ Advisory Group meetings conducted in the first year of the trial relate to the quality and range of clinic services provided at study clinics as well as broader standard of care issues. Recommendations have included streamlining clinic services to reduce waiting times, expanding services to include the children and spouses of participants, and providing care for common local conditions such as malaria. Participants, community representatives and stakeholders felt there was an ethical obligation to ensure effective access to antiretroviral drugs and to provide supportive community-based care for women identified as HIV positive during the trial. This obligation includes ensuring sustainable, post-trial access to these services. Post-trial access to an effective vaginal microbicide was also felt to be a moral imperative. Participatory methodologies enabled effective partnerships between researchers, participant representatives and community stakeholders to be developed and facilitated local dialogue and consensus on what constitutes a locally-appropriate standard of care in the context of a vaginal microbicide trial in this setting.

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Editors’ note: HIV prevention trials present a number of ethical dilemmas, including that of determining what is the most appropriate standard of care for people found to be ineligible during initial screening for recruitment and for those who develop illnesses during a trial. Is providing the best standard of care coercive and unethical if only research participants can benefit and parallel services cannot be sustained following trial cessation? Should researchers strive to ‘ratchet up’ local standards of care in the communities hosting clinical trials? Effective, participatory community engagement in trial design and ongoing management, as is described here in this microbicide trial, can help stakeholders decide together where researcher obligations to trial participants end and can help ensure that health service delivery is locally-appropriate, acceptable, and effective. Guidance on ethical dilemmas may be found in the UNAIDS/WHO Ethical considerations in biomedical HIV prevention trials. For more on the principles and practice of community engagement consult the UNAIDS/AVAC Good Participatory Practice (GPP) guidelines for biomedical HIV prevention trials. Sharing experiences in resolving ethical dilemmas through meaningful participatory processes helps advance both knowledge and practice.