HIV This Week

Welcome to the 63rd issue of HIV This Week ! In this first issue of 2009, we cover paediatric treatment (early diagnosis and treatment of asymptomatic infants in South Africa reaps benefits; better viral suppression with protease inhibitor-based regimens in infants previously exposed to single dose nevirapine; how universal p neumococcal conjugate vaccine programmes benefit HIV-positive infants ), prevention of mother-to-child transmission (trials in Ethiopia, India, and Uganda assess whether extended nevirapine prophylaxis for breastfeeding infants prevents HIV acquisition; single dose nevirapine suppresses breast milk HIV-1 RNA for 14 days in a Kenya phase II randomized clinical trial ), women’s health (middle-aged women, the menopause, and HIV), HIV testing (home-based HIV testing popular in rural Malawi; promising first year results from a trial in 48 communities in Tanzania, Zimbabwe, South Africa and Thailand), treatment (how does Maraviroc work?; using an insulin-sensitizing agent to treat lipodystrophy; how antiretroviral treatment benefits the gut), risk compensation (safer sexual behaviour with treatment access in Cape Town; no increase in risky behaviour among uninfected household members of adults on antiretroviral therapy in Uganda), HIV prevention: integrating service delivery (family planning and HIV prevention dual-use policies: a case study of Zimbabwe and Mozambique; contraception as HIV prevention: what it will take to integrate), basic science (superinfection in women suggests that vaccines will have to induce more robust responses than natural infection; repeated exposure to a partner’s virus without overt superinfection), economics (global health financing, transparency, and country ownership; cost-effectiveness of CD4 monitoring in southern Africa), injecting drug use (a systematic review of adherence to antiretroviral therapy), and national responses (3.8 million person-years of potential life lost from 2000 to 2005 in South Africa).

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HIV This Week Issue #63

Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA; CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants . N Engl J Med; 2008 20;359(21):2233-44

In countries with a high seroprevalence of human immunodeficiency virus type 1 (HIV-1), HIV infection contributes significantly to infant mortality. Violari and colleagues investigated antiretroviral-treatment strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial. HIV-infected infants 6 to 12 weeks of age with a CD4 lymphocyte percentage (the CD4 percentage) of 25% or more were randomly assigned to receive antiretroviral therapy (lopinavir-ritonavir, zidovudine, and lamivudine) when the CD4 percentage decreased to less than 20% (or 25% if the child was younger than 1 year) or clinical criteria were met (the deferred antiretroviral-therapy group) or to immediate initiation of limited antiretroviral therapy until 1 year of age or 2 years of age (the early antiretroviral-therapy groups). They report the early outcomes for infants who received deferred antiretroviral therapy as compared with early antiretroviral therapy. At a median age of 7.4 weeks (interquartile range, 6.6 to 8.9) and a CD4 percentage of 35.2% (interquartile range, 29.1 to 41.2), 125 infants were randomly assigned to receive deferred therapy, and 252 infants were randomly assigned to receive early therapy. After a median follow-up of 40 weeks (interquartile range, 24 to 58), antiretroviral therapy was initiated in 66% of infants in the deferred-therapy group. Twenty infants in the deferred-therapy group (16%) died versus 10 infants in the early-therapy groups (4%) (hazard ratio for death, 0.24; 95% confidence interval [CI], 0.11 to 0.51; P<0.001). In 32 infants in the deferred-therapy group (26%) versus 16 infants in the early-therapy groups (6%), disease progressed to Centers for Disease Control and Prevention stage C or severe stage B (hazard ratio for disease progression, 0.25; 95% CI, 0.15 to 0.41; P<0.001). Stavudine was substituted for zidovudine in four infants in the early-therapy groups because of neutropenia in three infants and anaemia in one infant; no drugs were permanently discontinued. After a review by the data and safety monitoring board, the deferred-therapy group was modified, and infants in this group were all reassessed for initiation of antiretroviral therapy. Early HIV diagnosis and early antiretroviral therapy reduced early infant mortality by 76% and HIV progression by 75%.

Editors’ note: The findings of this randomised controlled trial of early initiation of antiretroviral therapy confirm results of studies in the global north reporting better outcomes in infants receiving early treatment. Because nevirapine-based regimens may not be as effective in infants who have been exposed to single–dose nevirapine for prevention of mother-to-child transmission, infants in the trial’s intervention arm received a protease inhibitor-based regimen. Increasing the availability of the paediatric formulations of these drugs, as well as that of the polymerase-chain- reaction (PCR) tests for HIV-1 DNA that are needed for early infant diagnosis, is essential if the December 2008 WHO guidelines recommending antiretroviral treatment for all infants with confirmed HIV infection, including those that are asymptomatic, are to be implemented.

Jaspan HB, Berrisford AE, Boulle AM. Two-Year Outcomes of Children on Non-Nucleoside Reverse Transcriptase Inhibitor and Protease Inhibitor Regimens in a South African Pediatric Antiretroviral Program. Pediatr Infect Dis 2008;27(11):993-8

Few data exist on the efficacy of the limited regimens for children with HIV, which are available in sub-Saharan Africa. Jaspan and colleagues conducted a retrospective cohort study to evaluate the clinical and laboratory outcomes of 391 children who received protease inhibitor (PI) or non-nucleoside reverse transcription inhibitor (nNRTI)-containing highly active antiretroviral regimens (HAART) from a Cape Town clinic. Endpoints included CD4% and count, viral loads, weight-for-age Z score, survival, drug changes, and loss to follow-up over 24 months. A generalized estimating equation population-averaged model was used to identify associations with virological suppression, and a log-rank test explored associations with survival. Overall, this cohort achieved a sustained doubling of median CD4% from baseline, steady increase of median weight-for-age Z score, and survival of 91%, despite only 49% virologic suppression at 24 months. However, when analyzed according to regimen, PI-containing regimens had better virologic suppression at all time points. There were no differences in immunologic and growth endpoints between regimens or in survival. In a multivariate model predicting virologic suppression at any duration up to 24 months and adjusting for baseline CD4%, regimen, age, baseline weight-for-age Z score, duration of HAART, and year of HAART initiation, nNRTI-based regimens (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.19-0.77) and length of time on HAART were inversely associated with virologic suppression. Age (OR: 1.23 per year; 95% CI: 1.09-1.39) was positively associated with virologic suppression. The benefits of antiretroviral treatment are substantial in this setting, although PI regimens achieved greater virologic suppression than nNRTIs. Further exploration of regimens and dosing of antiretrovirals for children in these settings is needed.

Editors’ note: This retrospective cohort study was not designed to compare treatment regimens but did find that protease inhibitor-based therapy was strongly associated with a greater probability of viral suppression, likely because of the strong genetic barrier to resistance mutations conferred by boosted lopinavir (LPV/r). The high early mortality seen in this study reinforces the need to initiate antiretroviral therapy in children before severe immune suppression develops.

Zar HJ, Madhi SA. Pneumococcal conjugate vaccine—a health priority. S Afr Med J 2008; 98(6):463-7.

Pneumonia is a major cause of childhood mortality and morbidity. Streptococcus pneumoniae is the most important bacterial pathogen causing pneumonia in children. The HIV epidemic has increased the burden and severity of childhood pneumococcal pneumonia and invasive disease fortyfold. Pneumococcal conjugate vaccine is a highly effective intervention to reduce invasive pneumococcal disease and pneumonia. Studies evaluating a 9-valent pneumococcal conjugate vaccine in South Africa and The Gambia reported a 72 – 77% reduction in vaccine-serotype-specific invasive disease in vaccinated children. As many of the pneumococcal serotypes associated with antibiotic resistance are included in pneumococcal conjugate vaccine, vaccination has also been associated with a reduction in antimicrobial-resistant invasive disease. Pneumococcal conjugate vaccine may also reduce childhood mortality, especially in places with limited access to health care, as shown in Gambian study in which pneumococcal conjugate vaccine reduced childhood mortality by 16%. In addition to the direct effects of pneumococcal conjugate vaccine, there is a substantial reduction in disease burden through indirect protection of non-vaccinated populations. Pneumococcal conjugate vaccine is immunogenic in HIV-infected children and provides protection against invasive disease or pneumonia in a substantial number of children. Although the efficacy of pneumococcal conjugate vaccine for prevention of invasive disease or pneumonia is lower in HIV-infected compared to -uninfected children, the overall burden of disease prevented is much greater in HIV-infected children because of the higher burden of pneumococcal disease in these children. Consequently, vaccine-preventable invasive disease is almost 60 times higher in HIV-infected compared to HIV-uninfected children, while the reduction in pneumonia in HIV-infected children is 15 times greater. However, the long-term efficacy of pneumococcal conjugate vaccine wanes in HIV-infected children who are not taking antiretroviral therapy, and booster doses are probably indicated. Although there is concern about the potential for replacement disease due to non-vaccine serotypes, a substantial and sustained reduction in invasive disease has occurred overall in populations with widespread childhood immunisation. Routine childhood immunisation is now the standard of care in most developed countries. However, pneumococcal conjugate vaccine is much less accessible to children in developing countries due to cost and availability. Cost-effectiveness analysis indicates that use of pneumococcal conjugate vaccine is potentially highly cost-effective, at tiered pricing, even in very low-income countries. Widespread availability and vaccination with pneumococcal conjugate vaccine is urgently needed for all children under 2 years of age in South Africa. In addition, the use of pneumococcal conjugate vaccine for all HIV-infected children under 9 years should be prioritised.

Editors’ note: WHO recommends that countries with high HIV prevalence prioritise the introduction of pneumococcal conjugate vaccine. Infants and children living with HIV are protected directly by the vaccine and indirectly by the reduced transmission of pneumococci that results from a universal immunisation programme.

Six Week Extended-Dose Nevirapine (SWEN) Study Team, Bedri A, Gudetta B, Isehak A, Kumbi S, Lulseged S, Mengistu Y, Bhore AV, Bhosale R, Varadhrajan V, Gupte N, Sastry J, Suryavanshi N, Tripathy S, Mmiro F, Mubiru M, Onyango C, Taylor A, Musoke P, Nakabiito C, Abashawl A, Adamu R, Antelman G, Bollinger RC, Bright P, Chaudhary MA, Coberly J, Guay L, Fowler MG, Gupta A, Hassen E, Jackson JB, Moulton LH, Nayak U, Omer SB, Propper L, Ram M, Rexroad V, Ruff AJ, Shankar A, Zwerski S. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet 2008; 26;372(9635):300-13.

UNICEF/WHO recommends that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months. The aim of three trials in Ethiopia, India, and Uganda was to assess whether daily nevirapine given to breastfed infants through 6 weeks of age can decrease HIV transmission via breastfeeding. HIV-infected women breastfeeding their infants were eligible for participation. Participants were randomly assigned to receive either single-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborns after birth) or 6 week extended-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborn babies after birth plus nevirapine 5 mg daily from days 8-42 for the infant). The randomisation sequences were generated by computer at a central data coordinating centre. The primary endpoint was HIV infection at 6 months of age in infants who were HIV PCR-negative at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth. A total of 2024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0.80, 95% CI 0.58-1.10; p=0.16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0.54, 0.34-0.85; p=0.009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p=0.54). Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint-risk of HIV transmission at 6 months-suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high.

Editors’ note: Science moves quickly in this field. Although the co-principal investigator and several colleagues in India disputed the interpretation of the results of this study, the PEPI study in Malawi now has found possibly even better results with 14 weeks of nevirapine prophylaxis started immediately after birth without a one-week delay. There is no doubt that major efforts should intensify to expand basic mother-to-child transmission prevention programmes beyond the current one-third coverage worldwide. Pending normative guidance, programmes that are already up and running need to consider whether to move now to add extended infant nevirapine prophylaxis when breastfeeding is the safest option that mothers have.

Chung MH, Kiarie JN, Richardson BA, Lehman DA, Overbaugh J, Kinuthia J, Njiri F, John-Stewart GC. Highly active antiretroviral therapy versus zidovudine/nevirapine effects on early breast milk HIV type-1 Rna: a phase II randomized clinical trial. Antivir Ther 2008;13(6):799-807.

Defining the effect of antiretroviral regimens on breast milk HIV type-1 (HIV-1) levels is useful to inform the rational design of strategies to decrease perinatal HIV-1 transmission. Pregnant HIV-1 seropositive women (CD4+ T-cell count >250 and <500 cells/mm3) electing to breastfeed in Nairobi, Kenya were randomized to highly active antiretroviral therapy (HAART; zidovudine [ZDV], lamivudine and nevirapine [NVP]) during pregnancy and 6 months post-partum or to short-course ZDV plus single-dose NVP (ZDV/NVP). Breast milk samples were collected two to three times per week in the first month post-partum. Between November 2003 and April 2006, 444 breast milk samples were collected from 58 randomized women during the first month after delivery. Between 3 and 14 days post-partum, women in the HAART and ZDV/NVP arms had a similar prevalence of undetectable breast milk HIV-1 RNA. From 15 to 28 days post-partum, women in the HAART arm had significantly lower levels of breast milk HIV-1 RNA than women randomized to ZDV/NVP (1.7 log10 copies/ml [limit of detection] versus >2.10 log10 copies/ml, P<0.001). In contrast to breast milk HIV-1 RNA, suppression of plasma HIV-1 RNA during the neonatal period was consistently several log10 greater in the HAART arm compared with the ZDV/NVP arm. HAART resulted in lower breast milk HIV-1 RNA than ZDV/NVP; however, ZDV/NVP yielded comparable breast milk HIV-1 RNA levels in the first 2 weeks post-partum. Breast milk HIV-1 RNA remained suppressed in the ZDV/NVP arm despite increased plasma HIV-1 levels, which might reflect local drug effects or compartmentalization.

Editors’ note: This study revealed the surprising durability of single-dose nevirapine in suppressing early breast milk HIV-1 RNA compared with combination antiretroviral treatment. A larger trial is needed to determine whether 6-month antiretroviral treatment of breastfeeding mothers, who would not be otherwise eligible for treatment under current guidelines, is incrementally effective in reducing breast milk transmission between 3 weeks and 6 months post-partum.

Conde DM, Silva ET, Amaral WN, Finotti MF, Ferreira RG, Costa-Paiva L, Pinto-Neto AM. HIV, reproductive aging, and health implications in women: a literature review. Menopause 2009; 16(1) [Epub ahead of print]

Infection by the human immunodeficiency virus (HIV) is increasing among women. After the advent of highly active antiretroviral therapy (HAART), a decrease occurred in the mortality rate, which now seems to have stabilized. One of the consequences of this current situation is that more and more HIV-infected women are now reaching menopause. Therefore, factors often investigated in seronegative women need to be evaluated in middle-aged, HIV-positive women. In midlife, HIV-positive women will experience the onset of menopause, while concomitantly they may also be affected by metabolic complications related to the HIV infection and to HAART. This literature review was therefore carried out to identify studies dealing with conditions related to middle-aged women with HIV with the aim of providing data on age at menopause, menopausal symptoms, reproductive hormones, cognitive function, bone mineral density, cardiovascular disease, and lipid and glucose metabolism in middle-aged women with HIV and discussing these issues. Some of these factors may be aggravated by the HIV infection and by HAART. The prevention and treatment of these conditions in middle-aged, HIV-positive women are discussed in the light of current knowledge.

Editors’ note: This excellent review from Brazil is timely because the number of middle-aged women living with HIV is increasing. This is in part the result of improved access to life-prolonging antiretroviral treatment and in part due to biological and social vulnerability to HIV acquisition during this phase of women’s lives. The review highlights the preventive and therapeutic measures needed to minimise the long-term complications of HIV and its treatment as the ovaries fail, as well as the importance of further studies to determine optimal therapies for the conditions experienced by middle-aged HIV-positive women.

Obare F, Fleming P, Anglewicz P, Thornton R, Martinson F, Kapatuka A, Poulin M, Watkins S, Kohler HP. Acceptance of repeat population-based voluntary counseling and testing for HIV in rural Malawi. Sex Transm Infect 2008 Oct 16. [Epub ahead of print]

Obare and colleagues set out to examine the acceptance of repeat population-based voluntary counselling and testing for HIV in rural Malawi. Behavioural and biomarker data were collected in 2004 and 2006 from approximately 3,000 adult respondents. In 2004, oral swab specimens were collected and analyzed using enzyme-linked immunosorbent assay (ELISA) and confirmatory Western blot tests while finger-prick rapid testing was done in 2006. The authors use cross-tabulations with chi-square tests and significance tests of proportions to determine the statistical significance of differences in acceptance of voluntary counselling and testing by year, individual characteristics, and HIV risk. First, over 90% of respondents in each round accepted HIV test, despite variations in testing protocols. Second, the percentage of individuals who obtained their test results significantly increased from 67% in 2004 when the results were provided in randomly selected locations several weeks after the specimens were collected, to 98% in 2006 when they were made available immediately within the home. Third, whereas there were significant variations in the socio-demographic and behavioural profiles of those who were successfully contacted for a second HIV test, this was not the case for those who accepted repeat voluntary counselling and testing. This suggests that variations in the success of repeat testing might come from contacting the individuals rather than from accepting the test or knowing the results. Repeat HIV testing at home by trained health care workers from outside the local area, and with either saliva or blood, is almost universally acceptable in rural Malawi, and thus likely to be acceptable in similar contexts.

Editors’ note: Both the distance people must travel to receive their HIV results and the delay between the time of testing and availability of results can reduce the numbers of people who receive their test results. This study reveals persistently high HIV testing acceptance levels when people are offered at-home testing and immediate test results. Reasons for this may include both reduced transport costs and the perception that at-home testing is more confidential than clinic-based testing.

Khumalo-Sakutukwa G, Morin SF, Fritz K, Charlebois ED, Rooyen HV, Chingono A, Modiba P, Mrumbi K, Visrutaratna S, Singh B, Sweat M, Celentano DD, Coates TJ; for the NIMH Project Accept Study Team. Project Accept (HPTN 043): A Community-Based Intervention to Reduce HIV Incidence in Populations at Risk for HIV in Sub-Saharan Africa and Thailand. J Acquir Immune Defic Syndr 2008 Oct 16. [Epub ahead of print]

Changing community norms to increase awareness of HIV status and reduce HIV-related stigma has the potential to reduce the incidence of HIV-1 infection in the developing world. Khumalo-Sakutukwa and colleagues developed and implemented a multilevel intervention providing community-based HIV mobile voluntary counselling and testing, community mobilization, and post test support services. Forty-eight communities in Tanzania, Zimbabwe, South Africa, and Thailand were randomized to receive the intervention or clinic-based standard voluntary counselling and testing, the comparison condition. The authors monitored utilization of community-based HIV mobile voluntary counselling and testing and clinic-based standard voluntary counselling and testing by community of residence at 3 sites, which was used to assess differential uptake. They also developed quality assurance procedures to evaluate staff fidelity to the intervention. In the first year of the study, a 4-fold increase in testing was observed in the intervention versus comparison communities. The authors also found an overall 95% adherence to intervention components. Study outcomes, including prevalence of recent HIV infection and community-level HIV stigma, will be assessed after 3 years of intervention. The provision of mobile services, combined with appropriate support activities, may have significant effects on utilization of voluntary counselling and testing. These findings also provide early support for community mobilisation as a strategy for increasing testing rates.

Editors’ note: Project Accept is the first international community-randomised controlled phase III trial (48 communities in 4 countries) to determine the effects of a multi-level structural intervention with HIV incidence and stigma reduction as primary end points. Its theoretical foundations are diffusion of innovation, tipping point theory, and social action theory. This first report of process data for the first year of the trial shows a significant difference in HIV testing uptake, providing early validation of the intervention’s theoretical model.

Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, Nadler J, Clotet B, Karlsson A, Wohlfeiler M, Montana JB, McHale M, Sullivan J, Ridgway C, Felstead S, Dunne MW, van der Ryst E, Mayer H; MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008; 2;359(14):1429-41.

CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. Gulick and colleagues conducted two double-blind, placebo-controlled, phase 3 studies—Maraviroc versus Optimized Therapy in Viraemic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2–with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per millilitre. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per millilitre, and the median CD4 cell count was 169 per cubic millimetre. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per millilitre with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per millilitre, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per millilitre (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimetre, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimetre, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving optimized background therapy.

Editors’ note: Current antiretroviral treatment targets one or more of three HIV-1 proteins: reverse transcriptase, protease, and glycoprotein envelope subunit gp41. People with a delta-32 deletion of the CCR5 gene are relatively resistant to HIV infection (if both gene copies have the deletion) or have slower disease progression (if one gene copy has the deletion, resulting in fewer CD4 cells expressing chemokine receptor 5 [CCR5] on their surface). When the predominant virus population is R5 tropic, the virus is looking to dock on the CCR5 receptor. It cannot bind if Maraviroc blocks the site. Inhibiting a host cellular immune function rather than a viral function, Maraviroc is a welcome addition to the treatment chest. More study is needed of its interactions with other new antiretroviral drugs and to determine the optimal timing of its introduction into a regimen. The logistical and financial burden of having to test the tropism (R5 or X4) of the virus that a patient has is an important impediment to its use for treatment but would not affect its use in a preventive product such as a microbicide.

Diehl LA, Fabris BA, Barbosa DS, De Faria EC, Wiechmann SL, Carrilho AJ. Metformin Increases HDL3-Cholesterol and Decreases Subcutaneous Truncal Fat in Nondiabetic Patients with HIV-Associated Lipodystrophy. AIDS Patient Care STDS 2008;22(10):779-86.

The purpose of this study was to assess metformin effects on high-density lipoprotein (HDL) composition of patients with HIV-associated lipodystrophy (LDHIV). Twenty-four adult outpatients were enrolled to receive metformin (1700 mg/d) during 6 months, but 2 were lost to follow-up and 6 stopped the drug due to adverse events (gastrointestinal in 5, and excessive weight loss in 1). From the 16 subjects who completed the study, 69% were female. At baseline, 3 and 6 months, Diehl and colleagues assessed: weight, waist and hip circumferences, blood pressure, fasting glucose and insulin, homeostasis model assessment of insulin resistance (HOMA2-IR), lipids, and HDL subfractions by microultracentrifugation. At 0 and 6 months, body fat distribution was assessed by computed tomography scan (L4 and middle femur). Metformin use was associated with reduction of mean weight (-2.4Kg at 6 months; p < 0.001), body mass index, waist, waist-to-hip ratio and a marked decrease in blood pressure (p < 0.001). Subcutaneous (p = 0.01) and total abdominal fat (p = 0.002) were reduced, but no change was found in visceral or thigh fat. No difference was detected on plasma glucose, insulin, HOMA2-IR, cholesterol or triglycerides, except for an increase in HDL3-cholesterol (from 21 mg/dL to 24 mg/dL, p = 0.002) and a reduction of nascent HDL (the fraction of plasma HDL-cholesterol not associated to subfractions HDL2 or HDL3) (p = 0.008). Adverse effects were very common, but most were gastrointestinal and mild. Thus, metformin use in HIV-associated lipodystrophy increases HDL3-cholesterol (probably due to improved maturation of HDL) and decreases blood pressure, weight, waist, and subcutaneous truncal fat, making this an attractive option for preventing cardiovascular disease in this population.

Editors´note: In HIV-infected patients, high density cholesterol (the good kind) is reduced even before antiretroviral therapy is started and falls further with protease inhibitors. This study had a small sample size and lacked controls but it shows enough promise to proceed to long-term prospective studies to determine whether or not metformin can decrease cardiovascular death and/or heart attacks in people living with HIV who have lipodystrophy.

Epple HJ, Schneider T, Troeger H, Kunkel D, Allers K, Moos V, Amasheh M, Loddenkemper C, Fromm M, Zeitz M, Schulzke JD. Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients. Gut. 2008 Oct 20. [Epub ahead of print]

Impairment of the gastrointestinal mucosal barrier contributes to progression of HIV infection. Epple and colleagues aimed to investigate the effect of highly active antiretroviral therapy (HAART) on the HIV-induced intestinal barrier defect and to identify underlying mechanisms. Epithelial barrier function was characterized by impedance spectroscopy and 3H-mannitol fluxes in duodenal biopsies from 11 untreated and 8 suppressively treated HIV-infected patients and 9 HIV-seronegative controls. Villus/crypt ratio was determined microscopically. Epithelial apoptoses were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling and caspase-3 staining. Tight junction protein expression was quantified by densitometric analysis of immunoblots. Mucosal cytokine production was determined by cytometric bead array. Only in untreated but not in treated HIV-infected patients, epithelial resistance was reduced (13(1) versus 23(2)Omegacm2, p<0.01) and mannitol permeability was increased compared to HIV-negative controls (19(3) versus 9(1)nm/s, p<0.05). As structural correlates, epithelial apoptoses and expression of the pore-forming claudin-2 were increased while expression of the sealing claudin-1 was reduced in untreated compared to treated patients and HIV-negative controls. Furthermore, villous atrophy was evident and mucosal production of interleukin (IL)-2, IL-4, and tumour necrosis factor (TNF)-alpha was increased in untreated but not in treated HIV-infected patients. Incubation with IL-2, IL4, TNF-alpha, and IL-13 reduced the transepithelial resistance of rat jejunal mucosa. Suppressive HAART abrogates HIV-induced intestinal barrier defect and villous atrophy. The HIV-induced barrier defect is due to altered tight junction protein composition and elevated epithelial apoptoses. Mucosal cytokines are mediators of the HIV-induced mucosal barrier defect and villous atrophy.

Editors’ note: Chronic immune activation is the main driving force for progressive immune failure in chronic HIV infection. This small study supports the hypothesis that active HIV replication increases inflammatory cytokines in the gut. These impair the epithelial barrier, which then allows gut bacteria and antigens to activate mucosal immunity. Antiretroviral therapy appears to interrupt this self-perpetuating cycle of immune activation and barrier impairment, allowing reconstitution of the gut’s epithelial barrier protective functions.

Eisele TP, Mathews C, Chopra M, Lurie MN, Brown L, Dewing S, Kendall C. Changes in Risk Behavior Among HIV-Positive Patients During Their First Year of Antiretroviral Therapy in Cape Town South Africa. AIDS Behav. 2008 Oct 10. [Epub ahead of print]

Eisele and colleagues explored explore changes in sexual risk behaviour over the first year of antiretroviral therapy among a cohort of patients in Cape Town South Africa initiating treatment in five public facilities in 2006 and again 1 year later (Time 1 and Time 2). Contemporaneous measures of unprotected sex were also obtained from 2 cross-sectional samples of HIV-positive patients waiting to start antiretroviral therapy attending the same facilities. Unprotected sex at last sex among patients on antiretroviral therapy decreased significantly from a baseline of 44.7-23.2% one year later, regardless of partner status. After controlling for confounding factors, the observed decrease in unprotected sex among the ART cohort was highly significant in relation to the 2 cross-sectional samples of patients at Time 1 and Time 2 waiting to initiate antiretroviral therapy. Findings suggest it is critical to start positive prevention to decrease risky sexual behaviour prior to the start of antiretroviral therapy within this setting.

Editors’ note: This is the first study to assess prospectively a causal relationship between antiretroviral treatment and sexual risk compensation, using community controls to compare findings with prevailing or secular changes in sexual behaviour. The striking decrease in unprotected sex reported by patients on antiretroviral treatment in this study is consistent with the results of previous cross-sectional studies in sub-Saharan Africa. Although experiencing significant increases in libido, nearly three-quarters (72.7%) of patients reported disclosing their HIV status which likely facilitated intimate discussions with sex partners, including condom negotiation.

Bechange S, Bunnell R, Awor A, Moore D, King R, Mermin J, Tappero J, Khana K, Bartholow B. Two-Year Follow-Up of Sexual Behavior Among HIV-Uninfected Household Members of Adults Taking Antiretroviral Therapy in Uganda: No Evidence of Disinhibition. AIDS Behav. 2008 Oct 24. [Epub ahead of print]

This paper examines HIV risk behaviour among HIV-uninfected adults living with people taking antiretroviral therapy (ART) in Uganda. A prospective cohort of 455 HIV-uninfected non-spousal household members of ART patients receiving home-based AIDS care was enrolled. Sexual behaviour, HIV risk perceptions, AIDS-related anxiety, and the perception that AIDS is curable were assessed at baseline, 6, 12 and 24 months. Generalized linear mixture models were used to model risk behaviour over time and to identify behavioural correlates. Overall, risky sex decreased from 29% at baseline to 15% at 24-months. Among women, risky sex decreased from 31% at baseline to 10% at 6 months and 15% at 24 months. Among men, risky sex decreased from 30% at baseline to 8% at 6 months and 13% at 24 months. Perceiving HIV as curable and lower AIDS-related anxiety were independently associated with risky sex. No evidence of increased risk compensation was observed. Concerns regarding increased risk compensation should not slow down efforts to increase ART access in Africa.

Editors’ note: Directly observing the positive impact that antiretroviral treatment has on one’s sexual partner may result in risk compensation (increases in risky behaviour) related to treatment optimism. This study of uninfected adult household members of people starting on antiretroviral treatment in rural Uganda showed the opposite. Decreases in sexual risk behaviours occur when treatment and prevention programmes are integrated and delivered at household level.

Prata N, Sreenivas A, Bellows B. Potential of dual-use policies to meet family planning and HIV prevention needs: a case study of Zimbabwe and Mozambique. J Fam Plann Reprod Health Care 2008; 34(4):219-26.

The fight against the HIV epidemic in many high-prevalence countries is a struggle to motivate culturally relevant risk reduction in general populations that have been educated to associate HIV risk with commercial sex, injection drug use, and other stigmatised behaviours. Common concurrent partnerships, which facilitate transmission of HIV in many high-prevalence countries, are only beginning to receive the attention they deserve. This has made the promotion of dual-use methods, such as condoms, for individuals who require both HIV protection and contraception very difficult. Recent research on concurrent partnerships and the implications for high HIV risk in sexually networked but sexually modest general populations is forcing another assessment of the response to HIV. In the light of the epidemic, it is important to better understand which policies will better meet HIV prevention and family planning needs. This article explores the potential of dual-use policies by examining Zimbabwe and Mozambique. Zimbabwe, with a vertically driven, stronger family planning programme predating the HIV epidemic, has not yet seen an increase in condom use to the level desired by their moderately strong HIV prevention programme – one that has adopted a primarily single-use condom policy. Mozambique, however, continues to have a much weaker family planning programme, but is witnessing a significant increase in condom use driven by their strong HIV programme – one that is further integrated with family planning content. Integration of HIV and family planning programmes has the potential to meet the need for HIV and pregnancy prevention more efficiently. By themselves, these programmes are unable to meet the need for condoms. The poorest of the poor are feeling the brunt of this inadequacy. Countries such as Zimbabwe and Mozambique have the potential to tremendously improve their efforts in increasing condom use. Prata and colleagues suggest that thoughtful and detailed integration of HIV and family planning programmes will work synergistically to reach common goals. Until a more promising method besides condoms is commercially available for protection against unintended pregnancy and sexually transmitted infections such as HIV, effective strategies must include dual-use policies as well as counselling on all available contraceptive methods so that women can maximise the benefits of mixing methods.

Editors’ note: This case study of Zimbabwe and Mozambique underscores the need for high HIV prevalence countries to move rapidly to promote dual protection to provide the most protection possible for all women from unwanted pregnancy and to address the unmet need for family planning among HIV-positive women. Positioning condoms as primarily contraceptive tools rather than disease protection devices may make condom negotiations in couples easier. Integration of family planning and HIV programmes requires national action supported by alignment of the donors that currently fund family planning and HIV programmes in parallel streams. Essential synergies will not be realised without integration.