HIV This Week

Welcome to the fifty-fifth issue of HIV This Week! In this issue, we cover risk compensation (since it’s all about psychology, we need to think about how to influence risk set points and mindsets; the resurgent HIV-1 epidemic among men who have sex with men in the Netherlands: time to take a step back to the old days), migration (boatmen as a bridging population between Myanmar and Bangladesh), highly exposed persistent seronegative people (some call them HEPS for short: highly fascinating individuals whose immune systems hold secrets we need to know) cost-effectiveness (cotrimoxazole prophylaxis in Zambian children with HIV infection: what more is needed to influence decision-making across sub-Saharan Africa?; one part of the equation in Andhra Pradesh but where does fertility planning fit in?), treatment (township South Africa and Switzerland compare favourably except for early mortality but there are lessons for both; another frontier for dried blood spots: HIV-1 drug resistance genotyping), male circumcision (high acceptability among predominantly Hindu mothers in Mysore, India), transgendered women (high time to address structural barriers to formal employment while reducing health risks), basic science (immune activation causes disease progression; long-lived reservoirs are a safe harbour for HIV), epidemiology (place trumps in the risk stakes in Tanzania; the puzzle of HIV-2 in Bissau; striking disease burden in Nairobi slums), and herpes simplex virus-2 (two trials find HSV-2 suppression in HIV-negative people does not reduce HIV risk).

To find out how you can access a majority of scientific journals free of charge, please click on the Journal access tab above. 

We want to be as helpful to you as we can. Please let us know what your interests are and what you think of HIV This Week by sending a comment to hivthisweek@unaids.org or by posting one on the HIV This Week website.  If you would like to recommend an article for inclusion in HIV This Week, please let us know.

Don’t forget that you can find a wealth of information on the HIV epidemic and responses to it at www.unaids.org

For full PDF access to this issue: HIV This Week Issue #55

Eaton LA, Kalichman S. Risk compensation in HIV prevention: implications for vaccines, microbicides, and other biomedical HIV prevention technologies. Curr HIV/AIDS Rep. 2007;4:165-72.

Photo credit: unaids/fsanchez

Studies investigating the effects of biologic HIV prevention technologies have been reported with promising results for slowing the spread of the disease. Although they can reduce the rate of HIV transmission at varying levels of efficaciousness, it is vital to anticipate their impact on subsequent sexual behaviours. Risk homeostasis theory posits that decreases in perceived risk, which will occur with access to HIV prevention technologies, will correspond with increases in risk-taking behaviour. Here Eaton and colleagues review the literature on risk compensation in response to HIV vaccines, topical microbicides, antiretroviral medications, and male circumcision. Behavioural risk compensation is evident in response to prevention technologies that are used in advance of HIV exposure and at minimal personal cost. The authors conclude that behavioural risk compensation should be addressed by implementing adjunct behavioural risk-reduction interventions to avoid negating the preventive benefits of biomedical HIV prevention technologies.

Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic. Bezemer and colleagues focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs. The authors used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses. They show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000-2004 (95% confidence interval 0.98-1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate. This study provides the first detailed quantitative analysis of the HIV epidemic in a well-defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

Gazi R, Mercer A, Wansom T, Kabir H, Saha NC, Azim T. An assessment of vulnerability to HIV infection of boatmen in Teknaf, Bangladesh. Confl Health. 2008;2(1):5

Mobile population groups are at high risk for contracting HIV infection. Many factors contribute to this risk, including high prevalence of risky behaviour and increased risk of violence due to conflict and war. The Naf River serves as the primary border crossing point between Teknaf, Bangladesh, and Mynamar [Burma] for both official and unofficial travel of people and goods. Little is known about the risk behaviour of boatmen who travel back and forth between Teknaf and Myanmar. However, Gazi and colleagues hypothesize that boatmen may act as a bridging population for HIV between the high-prevalence country of Myanmar and the low-prevalence country of Bangladesh. Methods included initial rapport building with community members, mapping of boatmen communities, and in-depth qualitative interviews with key informants and members from other vulnerable groups such as spouses of boatmen, female sex workers, and injecting drug users. Information from the first three stages was used to create a cross-sectional survey that was administered to 433 boatmen. Over 40% of the boatmen had visited Myanmar during the course of their work. 17% of these boatmen had sex with sex workers while abroad. There was a significant correlation found between the number of nights spent in Myanmar and sex with commercial sex workers. In the past year, 19% of all boatmen surveyed had sex with another man. Fourteen per cent of boatmen had participated in group sex, with groups ranging in size from three to fourteen people. Condom use was rare [0 to 4.7% during the last month], irrespective of types of sex partners. Regression analysis showed that boatmen who were 25 years and older were statistically less likely to have sexual intercourse with non- marital female partners in the last year compared to the boatmen aged less than 25 years. Similarly, deep sea fishing boatmen and non-fishing boatmen were statistically less likely to have sexual intercourse with non-marital female partners in the last year compared to the day-longfishing boatmen adjusting for all other variables. Boatmen’s knowledge regarding HIV transmission and personal risk perception for contracting HIV was low. Boatmen in Teknaf are an integral part of a high-risk sexual behaviour network between Myanmar and Bangladesh. They are at risk of obtaining HIV infection due to cross-border mobility and unsafe sexual practices. There is an urgent need for designing interventions targeting boatmen in Teknaf to combat an impending epidemic of HIV among this group. They could be included in the serological surveillance as a vulnerable group. Interventions need to address issues on both sides of the border, other vulnerable groups, and refugees. Strong political will and cross-border collaboration are mandatory for such interventions.

Hirbod T, Kaul R, Reichard C, Kimani J, Ngugi E, Bwayo JJ, Nagelkerke N, Hasselrot K, Li B, Moses S; Kibera HIV Study Group, MacDonald KS, Broliden K. Collaborators: Keli F, Kamunyo G, Wanguru R, Mwakisha R, Waithira G, Nganga D, Nyambogo C, Ombette J, Njeri J, Onyango I, Malonza I, Mwangi F, Fonck K, Temmerman M, Ronald AR, Luscher M. HIV-neutralizing immunoglobulin A and HIV-specific proliferation are independently associated with reduced HIV acquisition in Kenyan sex workers. AIDS. 2008;22(6):727-35.

HIV-neutralizing immunoglobulin A (IgA) and HIV-specific cellular immunity have been described in highly exposed, persistently seronegative individuals, but well controlled studies have not been performed. Hirbod and colleagues performed a prospective, nested case-control study to examine the association of genital IgA and systemic cellular immune responses with subsequent HIV acquisition in high-risk Kenyan female sex workers. A randomized trial of monthly antibiotic prophylaxis to prevent sexually transmitted disease/HIV infection was performed from 1998 to 2002 in HIV-uninfected Kenyan female sex workers. After the completion of trial, female sex workers who had acquired HIV (cases) were matched 1: 4 with persistently uninfected controls based on study arm, duration of HIV-seronegative follow-up, and time of cohort enrolment. Blinded investigators assayed the ability at enrolment of genital IgA to neutralize primary HIV isolates as well as systemic HIV-specific cellular IFN-gamma-modified enzyme-linked immunospot and proliferative responses. The study cohort comprised 113 female sex workers: 24 cases who acquired HIV and 89 matched controls. Genital HIV-neutralizing IgA was associated with reduced HIV acquisition (P = 0.003), as was HIV-specific proliferation (P = 0.002), and these associations were additive.  HIV-specific IFN-gamma production did not differ between case and control groups.  In multivariable analysis, HIV-neutralizing IgA and HIV-specific proliferation each remained independently associated with lack of HIV acquisition. Genital herpes (HSV2) was associated with increased HIV risk and with reduced detection of HIV-neutralizing IgA. Genital HIV-neutralizing IgA and systemic HIV-specific proliferative responses, assayed by blinded investigators, were prospectively associated with HIV nonacquisition. The induction of these immune responses may be an important goal for HIV vaccines.

Editors´note: Much is to be learned from the careful study of the immune responses of high exposed, persistently seronegative individuals, whether they are sex workers or seronegative people in long-term discordant partnerships. In this study, two independent factors were prospectively associated with reduced sexual acquisition: HIV-neutralizing immunoglobulin A (IgA) and HIV-specific proliferation in cervicovaginal lavage specimens. Herpes simplex-2 infection interfered with this partial protection by reducing HIV-neutralizing IgA in the genital tract. How to induce such protective humoral immune responses in the genital tract, whether they are associated with specific host genetics, and how they might combine with strong cellular responses are questions waiting to be answered.

Ryan M, Griffin S, Chitah B, Walker AS, Mulenga V, Kalolo D, Hawkins N, Merry C, Barry MG, Chintu C, Sculpher MJ, Gibb DM. The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia. AIDS. 2008;22(6):749-57.

Ryan and colleagues aimed to assess the cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia, as implementation at the local health centre level has yet to be undertaken in many resource-limited countries despite recommendations in recent updated World Health Organization (WHO) guidelines. A probabilistic decision analytical model of HIV progression in children based on the CD4 cell percentage (CD4%) was populated with data from the placebo-controlled Children with HIV Antibiotic Prophylaxis trial that had reported a 43% reduction in mortality with cotrimoxazole prophylaxis in HIV-infected children aged 1-14 years. Unit costs (US$ in 2006) were measured at University Teaching Hospital, Lusaka. Cost-effectiveness, expressed as cost per life-year saved; cost per quality adjusted life-year saved; and cost per disability adjusted life-year averted, was calculated across a number of different scenarios at tertiary and primary healthcare centres. Cotrimoxazole prophylaxis was associated with incremental cost-effectiveness ratios of US$72 per life-year saved, US$94 per quality adjusted life-year saved, and US$53 per disability adjusted life-year averted, i.e. substantially less than a cost-effectiveness threshold of US$1019 per outcome (gross domestic product per capita, Zambia 2006). Incremental cost-effectiveness ratios of US$5 or less per outcome demonstrate that cotrimoxazole prophylaxis is even more cost-effective at the local healthcare level. The intervention remained cost-effective in all sensitivity analyses including routine haematological and CD4% monitoring, varying starting age, AIDS status, cotrimoxazole formulation, efficacy duration, and discount rates. Cotrimoxazole prophylaxis in HIV-infected children is an inexpensive low technology intervention that is highly cost-effective in Zambia, strongly supporting the adoption of WHO guidelines into essential healthcare packages in low-income countries.

Editors´note: Along with other factors, cost-effectiveness analyses can inform decision-making on competing priorities. In this case, highly cost-effective cotrimoxazole in children with HIV infection is life-saving, simple, well–tolerated and inexpensive. It is a key element of pre-antiretroviral treatment care and part of the HIV chronic care package. The gap between World Health Organisation guidance and actual practice at the country level in sub-Saharan Africa needs to close rapidly for all children with HIV infection.

Dandona L, Kumar SG, Ramesh YK, Rao MC, Marseille E, Kahn JG, Dandona R. BMC Health Serv Res. 2008;8:26. Outputs, cost and efficiency of public sector centres for prevention of mother to child transmission of HIV in Andhra Pradesh, India.

Prevention of mother to child transmission is an important part of the effort to control HIV. PMTCT services are mostly provided at public sector government hospitals in India. Systematic data on the cost and efficiency of providing prevention of mother-to-child transmission services in India are not available readily for further planning. Cost and output data were collected at 16 sampled prevention of mother to child transmission centres in the south Indian state of Andhra Pradesh using standardized methods. The services provided were analysed, and the relation of unit cost of services with scale was assessed. In the 2005-2006 fiscal year, 125,073 pregnant women received prevention of mother to child transmission services at the 16 centres (range 2,939 to 20,896, median 5,679). The overall HIV positive rate among those tested was 1.67%. Of the total economic cost, the major components were personnel (47.3%) and recurrent goods (31.7%). For the 16 prevention of mother-to-child transmission centres, the average economic cost per post-HIV-test counselled pregnant woman was Indian Rupees (INR) 98.9 (US$ 2.23), ranging 2.7-fold from INR 71.4 (US$ 1.61) to INR 189.9 (US$ 4.29). The economic cost per mother-neonate pair who received nevirapine had a higher variation, ranging 41-fold for the 16 centres from INR 4,354 (US$ 98 ) to INR 179,175 (US$ 4,047), average INR 10,210 (US$ 231), with very high unit cost at some centres where HIV prevalence among pregnant women and the total volume of services were both low. Scale had a significant inverse relation with both of the unit costs, per post-HIV-test counselled pregnant woman and per mother-neonate pair who received nevirapine. In addition, HIV prevalence among pregnant women had a significant inverse relation with unit cost per mother-neonate pair who received nevirapine. Although the variation between prevention of mother-to-child transmission centres for unit cost per post-HIV-test counselled pregnant woman was modest that per mother-neonate pair receiving nevirapine was over 40-fold. The extremely high unit cost for each mother-neonate pair receiving nevirapine at some centres suggests that the new approach of combining prevention of mother to child transmission services with voluntary counselling and testing services that has recently been started in India could potentially offer better efficiency.

Editors’ note: An inverse relationship between unit cost and scale makes common sense. The piece that is missing in the equation is how many pregnancies in these 16 prevention of mother-to-child transmission centres were unplanned and unwanted. Integrating these services with voluntary counselling and testing services makes more than economical sense if fertility counselling is offered to all men and women testing HIV-positive.

Keiser O, Orrell C, Egger M, Wood R, Brinkhof MW, Furrer H, van Cutsem G, Ledergerber B, Boulle A; for the Swiss HIV Cohort Study (SHCS) and the International Epidemiologic Databases to Evaluate AIDS in Southern Africa (IeDEA-SA). Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared. PLoS Med. 2008;5(7):e148.

The provision of highly active antiretroviral therapy in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. Keiser and colleagues compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting highly active antiretroviral therapy in South Africa and Switzerland. The authors analysed data from the Swiss HIV Cohort Study and two highly active antiretroviral therapy programmes in townships of Cape Town, South Africa. They included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded injecting drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4(+) T cell counts were 80 cells/mul in South Africa and 204 cells/mul in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%-97%) in South Africa and 96% (94%-97%) in Switzerland, and 26% (22%-29%) and 27% (24%-31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of highly active antiretroviral therapy: adjusted hazard ratios were 5.90 (95% CI 1.81-19.2) during months 1-3 and 1.77 (0.90-3.50) during months 4-24. Compared to the highly individualised approach in Switzerland, programmatic highly active antiretroviral therapy in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to highly active antiretroviral therapy and improve the prognosis of patients who start highly active antiretroviral therapy with advanced disease.

Editors´note: It is reassuring that the public health treatment approach in South Africa is as effective virologically as is the individualized approach of Switzerland: 96% of patients in both South Africa and Switzerland suppressed viral load to less than 500 copies/ml within a year. Although similar percentages developed viral rebound within two years, there were differences in mortality primarily due to the much lower CD4 count in South Africans (median 80) compared to Swiss (median of 204) at baseline. Know your status campaigns that provide social support for HIV testing and counselling would permit earlier initiation of treatment and reduce early mortality in South Africans on treatment. On the Swiss side, Switzerland could well consider simplifying its 36 first-line regimens.

Youngpairoj AS, Masciotra S, Garrido C, Zahonero N, de Mendoza C, García-Lerma JG. HIV-1 drug resistance genotyping from dried blood spots stored for 1 year at 4 degrees Celsius. J Antimicrob Chemother. 2008 Mar 15 [Epub ahead of print]

Dried blood spots are an attractive alternative to plasma for HIV-1 drug resistance testing in resource-limited settings. Youngpairoj and colleagues recently showed that HIV-1 can be efficiently genotyped from dried blood spots stored at -20 degrees C for prolonged periods (0.5-4 years). Here, the authors evaluated the efficiency of genotyping from dried blood spots stored at 4 degrees C for 1 year. A total of 40 dried blood spots were prepared from residual diagnostic specimens collected from HIV subtype B-infected persons and were stored with desiccant at 4 degrees C. Total nucleic acids were extracted after 1 year using a modification of the Nuclisens assay. Resistance testing was performed using the ViroSeq HIV-1 assay and an in-house nested Reverse Transciptase PCR method validated for HIV-1 subtype B that amplifies a smaller (1 kb) pol fragment. Using the ViroSeq assay, only 23 of the 40 (57.5%) dried blood spot specimens were successfully genotyped; 22 of these specimens had plasma viraemia >10 000 RNA copies/mL. When the specimens were tested using the in-house assay, 38 of the 40 dried blood spots (95%) were successfully genotyped. Overall, resistance genotypes generated from the dried blood spots and plasma were highly concordant. The authors show that drug resistance genotyping from dried blood spots stored at 4 degrees C with desiccant is highly efficient but requires the amplification of small pol fragments and the use of an in-house nested PCR protocol with quality-controlled reagents. These findings suggest that 4 degrees Celsius may represent a suitable temperature for long-term storage of dried blood spots.

Editors´note: Dried blood spots are easy to transport, can be stored for long periods, and can be used now for a variety of micro-level diagnostic tests. The HIV drug resistance genotyping test described here would require product development to move it from an “in-house” modified test to a standardized procedure that could be used in national resistance surveillance.

Msisha WM, Kapiga SH, Earls FJ, Subramanian SV. Place matters: multilevel investigation of HIV distribution in Tanzania. AIDS. 2008;22(6):741-8.

Msisha and colleagues aimed to examine the extent to which the regional and neighborhood distribution of HIV in Tanzania is caused by the differential distribution of individual correlates and risk factors, using nationally representative, cross-sectional data on 12,522 women and men aged 15-49 years from the 2003-2004 Tanzanian AIDS Indicator Survey. Three-level multilevel binary logistic regression models were specified to estimate the relative contribution of regions and neighborhoods to the variation in HIV seroprevalence. Spatial distribution of individual correlates (and risk factors) of HIV do not explain the neighborhood and regional variation in HIV seroprevalence. Neighborhoods and regions accounted for approximately 14 and 6% of the total variation in HIV. HIV prevalence ranged from 1.8% (Kigoma) to 6.7% (Iringa) even after adjusting for the compositional make-up of these regions. An inverse association was observed between log odds of being HIV positive and neighborhood poverty [odds ratio (OR) 0.24, 95% confidence interval (CI) 0.09-0.61] and regional poverty (OR 0.97, 95% CI 0.95-0.99). The study provides evidence for independent contextual variations in HIV, above and beyond that which can be ascribed to geographical variations in individual-level correlates and risk factors. The authors emphasize the need to adopt both a group-based and a place-based approach, as opposed to the dominant high-risk group approach, for understanding the epidemiology of HIV as well as for developing HIV intervention activities.

da Silva ZJ, Oliveira I, Andersen A, Dias F, Rodrigues A, Holmgren B, Andersson S, Aaby P. Changes in prevalence and incidence of HIV-1, HIV-2 and dual infections in urban areas of Bissau, Guinea-Bissau: is HIV-2 disappearing? AIDS. 2008;22(10):1195-202.

Da Silva and colleagues aimed to assess the changes in HIV prevalence and incidence between 1996 and 2006 in urban areas of Bissau, using a cross-sectional survey of 384 randomly selected houses within a community-based follow-up study of HIV-1 and HIV-2. A total of 3242 individuals aged at least 15 years were eligible for inclusion. Participants were interviewed about behavioural and socio-economic factors and had a blood sample drawn. A total of 2548 individuals were tested for antibodies to HIV-1 and HIV-2, of whom 649 had taken part in a similar survey in 1996. With 0.5% HIV dual reactions included, the overall HIV-1 prevalence was 4.6% (118 out of 2548 ) and the HIV-2 prevalence was 4.4% (112 out of 2548). The prevalence of HIV-1 increased more for women than men especially in the 25-34-year age group. HIV-2 prevalence decreased below 45 years of age but not for individuals more than 45 years old. The incidence rate between 1996 and 2006 was 0.5 per 100 person-years for HIV-1 and 0.24 per 100 person-years for HIV-2. Compared with a previous period from 1987 to 1996, the incidence of HIV-2 is declining whereas no significant increase in the incidence of HIV-1 was observed. The present study shows an increasing prevalence of HIV-1 and a decreasing prevalence of HIV-2 in Guinea-Bissau. HIV is generally a bigger problem for women. Despite the general decline in prevalence, HIV-2 may continue as an infection in older people, especially women.

Kyobutungi C, Ziraba AK, Ezeh A, Ye Y. The burden of disease profile of residents of Nairobi’s slums: Results from a Demographic Surveillance System. Popul Health Metr. 2008;6(1):1 [Epub ahead of print]

With increasing urbanization in sub-Saharan Africa and poor economic performance, the growth of slums is unavoidable. About 71% of urban residents in Kenya live in slums. Slums are characteristically unplanned, underserved by social services, and their residents are largely underemployed and poor. Recent research shows that the urban poor fare worse than their rural counterparts on most health indicators, yet much about the health of the urban poor remains unknown. This study aims to quantify the burden of mortality of the residents in two Nairobi slums, using a Burden of Disease approach and data generated from a Demographic Surveillance System. Data from the Nairobi Urban Health and Demographic Surveillance System collected between January 2003 and December 2005 were analysed. Core demographic events in the Nairobi Urban Health and Demographic Surveillance System including deaths are updated three times a year; cause of death is ascertained by verbal autopsy and cause of death is assigned according to the ICD 10 classification. Years of Life Lost due to premature mortality were calculated by multiplying deaths in each subcategory of sex, age group, and cause of death, by the Global Burden of Disease standard life expectancy at that age. The overall mortality burden per capita was 205 years of life lost /1,000 person years. Children under the age of five years had more than four times the mortality burden of the rest of the population, mostly due to pneumonia and diarrhoeal diseases. Among the population aged five years and above, HIV and tuberculosis accounted for about 50% of the mortality burden. Slum residents in Nairobi have a high mortality burden from preventable and treatable conditions. It is necessary to focus on these vulnerable populations since their health outcomes are comparable to or even worse than the health outcomes of rural dwellers who are often the focus of most interventions.

Celum C, Wald A, Hughes J, Sanchez J, Reid S, Delany-Moretlwe S, Cowan F, Casapia M, Ortiz A, Fuchs J, Buchbinder S, Koblin B, Zwerski S, Rose S, Wang J, Corey L; HPTN 039 Protocol Team. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371(9630):2109-19.

Across many observational studies, herpes simplex virus type 2 (HSV-2) infection is associated with two-fold to three-fold increased risk for HIV-1 infection. Celum and colleagues investigated whether HSV-2 suppression with aciclovir would reduce the risk of HIV-1 acquisition. The authors undertook a double-blind, randomised, placebo-controlled phase III trial in HIV-negative, HSV-2 seropositive women in Africa and men who have sex with men from sites in Peru and the USA. Participants were randomly assigned by block randomisation to twice daily aciclovir 400 mg (n=1637) or matching placebo (n=1640) for 12-18 months, and were seen monthly for dispensation of study drug, adherence counselling and measurement by pill count and self-reporting, and risk reduction counselling, and every 3 months for genital examination and HIV testing. The primary outcome was HIV-1 acquisition and secondary was incidence of genital ulcers. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00076232. 3172 participants (1358 women, 1814 men who have sex with men) were included in the primary dataset (1581 in aciclovir group, 1591 in control group). The incidence of HIV-1 was 3.9 per 100 person-years in the aciclovir group (75 events in 1935 person-years of follow-up) and 3.3 per 100 person-years in the placebo group (64 events in 1969 person-years of follow-up; hazard ratio 1.16 [95% CI 0.83-1.62]). Incidence of genital ulcers on examination was reduced by 47% (relative risk 0.53 [0.46-0.62]) and HSV-2 positive genital ulcers by 63% (0.37 [0.31-0.45]) in the aciclovir group. Adherence to dispensed study drug was 94% in the aciclovir group and 94% in the placebo group, and 85% of expected doses in the aciclovir group and 86% in the placebo group. Retention was 85% at 18 months in both groups (1028 of 1212 in aciclovir group, 1030 of 1208 in placebo group). The authors recorded no serious events related to the study drug. Their results show that suppressive therapy with standard doses of aciclovir is not effective in reduction of HIV-1 acquisition in HSV-2 seropositive women and men who have sex with men. Novel strategies are needed to interrupt interactions between HSV-2 and HIV-1.

Editors´note: Despite well-founded epidemiological observations, biological plausibility, and mathematical modelling, a protective effect of herpes suppression was not found in this large trial nor in a smaller, similar study in Tanzania (Watson-Jones, Weiss, Rusizoka et al. N Engl J Med. 2008;358(15):1560-71). Studies are ongoing to assess whether co-infected (HIV-1, HSV-2) individuals in serodiscordant couples are less likely to transmit HIV if they achieve HSV-2 suppression and have slower HIV disease progression. Nevertheless, an effective herpes simplex virus vaccine is urgently needed.