HIV This Week

Buchbinder, SP, Mehrotra, DV, Duerr, A, Fitzgerald, DW, Mogg, R, Li, D, Gilbert, PB, Lama, JR, Marmor, M, del Rio, C, McElrath, MJ, Casimiro, DR, Gottesdiener, KM, Chodakewitz, JA, Corey,L, Robertson, MN, and the Step Study Protocol Team*. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial Lancet 2008 Epub

Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. Buchbinder and colleagues undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. They randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was pre-stratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint ( early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the pre-specified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. In a pre-specified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1·2 [95% CI 0·6–2·2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4·61 vs 4·41 log10 copies per mL, one tailed p value for potential benefit 0·66). The vaccine elicited interferon-γ ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the hazard ratio of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (hazard ratio 2·3 [95% CI 1·2–4·3]) and uncircumcised men (3·8 [1·5–9·3]), but was not increased in Ad5 seronegative (1·0 [0·5–1·9]) or circumcised (1·0 [0·6–1·7]) men.

Editors’ note: This study was stopped for futility, not safety, when the first interim analysis showed that, even if it had gone its full course, the trial would have not been able to prove or disprove the hypothesis that the vaccine could prevent infection and/or lower viral set point in those that did become infected. Further analyses showed that uncircumcised men in the vaccine arm, particularly if they reported unprotected insertive anal sex, were more likely to seroconvert, as were men who had high levels of antibodies to adenovirus 5, a common virus used as a vaccine vector. The vaccine did not infect them but rather seemed to increase their risk of becoming infected when exposed to HIV. Many questions are being asked about mucosal immune responses and pre-existing vector immunity but confounding due to herpes simplex virus 2, host genetic factors, or sexual network clustering has not been ruled out and is under study.

Van Damme L, Govinden R, Mirembe FM, Guédou F, Solomon S, Becker ML, Pradeep BS, Krishnan AK, Alary M, Pande B, Ramjee G, Deese J, Crucitti T, Taylor D; CS Study Group. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med. 2008;359(5):463-72.

Women make up more than 50% of adults living with human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa. Thus, female-initiated HIV prevention methods are urgently needed. Van Damme and colleagues performed a randomized, double-blind, placebo-controlled trial of cellulose sulfate, an HIV-entry inhibitor formulated as a vaginal gel, involving women at high risk for HIV infection at three African and two Indian sites. The primary end point was newly acquired infection with HIV type 1 or 2. The secondary end point was newly acquired gonococcal or chlamydial infection. The primary analysis was based on a log-rank test of no difference in the distribution of time to HIV infection, stratified according to site. A total of 1398 women were enrolled and randomly assigned to receive cellulose sulfate gel (706 participants) or placebo (692 participants) and had follow-up HIV test data. There were 41 newly acquired HIV infections, 25 in the cellulose sulfate group and 16 in the placebo group, with an estimated hazard ratio of infection for the cellulose sulfate group of 1.61 (P=0.13). This result, which is not significant, is in contrast to the interim finding that led to the trial being stopped prematurely (hazard ratio, 2.02 [corrected]; P=0.05 [corrected]) and the suggestive result of a preplanned secondary (adherence-based) analysis (hazard ratio, 2.02; P=0.05). No significant effect of cellulose sulfate as compared with placebo was found on the risk of gonorrheal infection (hazard ratio, 1.10; 95% confidence interval [CI], 0.74 to 1.62) or chlamydial infection (hazard ratio, 0.71; 95% CI, 0.47 to 1.08). The authors concluded that cellulose sulfate did not prevent HIV infection and may have increased the risk of HIV acquisition.

Editors’ note: This trial was stopped prematurely after its independent data safety monitoring board ruled that the cellulose sulfate gel may have increased the risk of HIV infection compared to placebo. A second study of the same product underway in Nigeria was also stopped because of the safety concerns in the first trial. The results were not statistically significant but subsequent study showed that at high concentrations cellulose sulfate does inhibit HIV but at low concentrations it increases HIV infection (Tao et al. AIDS Res Hum Retro 2008; 24:925-9). A polyanionic compound derived from cotton, cellulose sulphate is not safe for mucosal application in humans.

Pronyk PM, Kim JC, Abramsky T, Phetla G, Hargreaves JR, Morison LA, Watts C, Busza J, Porter JD. A combined microfinance and training intervention can reduce HIV risk behaviour in young female participants. AIDS. 2008 Aug 20;22(13):1659-65.

Pronyk and colleagues aimed to assess effects of a combined microfinance and training intervention on HIV risk behaviour among young female participants in rural South Africa. The study was secondary analyses were conducted using quantitative and qualitative data from a cluster randomized trial, the Intervention with Microfinance for AIDS and Gender Equity study. Eight villages were pair-matched and randomly allocated to receive the intervention. At baseline and after 2 years, HIV risk behaviour was assessed among female participants aged 14-35 years. Their responses were compared with women of the same age and poverty group from control villages. Intervention effects were calculated using adjusted risk ratios employing village level summaries. Qualitative data collected during the study explored participants’ responses to the intervention including HIV risk behaviour. The authors found that after 2 years of follow-up, when compared with controls, young participants had higher levels of HIV-related communication (adjusted risk ratio 1.46, 95% confidence interval 1.01-2.12), were more likely to have accessed voluntary counselling and testing (adjusted risk ratio 1.64, 95% confidence interval 1.06-2.56), and less likely to have had unprotected sex at last intercourse with a nonspousal partner (adjusted risk ratio 0.76, 95% confidence interval 0.60-0.96). Qualitative data suggest a greater acceptance of intrahousehold communication about HIV and sexuality. Although women noted challenges associated with acceptance of condoms by men, increased confidence and skills associated with participation in the intervention supported their introduction in sexual relationships. In addition to affecting impacts on economic well being, women’s empowerment and intimate partner violence, interventions addressing the economic and social vulnerability of women may contribute to reductions in HIV risk behaviour .

Editors´note: The original trial which collected these data, known as the IMAGE trial, suggested that microfinance combined with gender and HIV training lead to improvements in household economic well being, women’s empowerment, and reductions in levels of intimate partner violence. This secondary analysis reveals improvements in risk behaviours, increased communication about sex, and greater uptake of HIV testing, with potential synergies between these. The IMAGE trial has made its mark by highlighting the potential for structural interventions that address the economic and social vulnerability of women to contribute to measurable health gains. These findings underscore the need for further innovation and operational research.

Cowan FM, Pascoe SJ, Langhaug LF, Dirawo J, Chidiya S, Jaffar S, Mbizvo M, Stephenson JM, Johnson AM, Power RM, Woelk G, Hayes RJ. The Regai Dzive Shiri Project: a cluster randomised controlled trial to determine the effectiveness of a multi-component community-based HIV prevention intervention for rural youth in Zimbabwe - study design and baseline results. Trop Med Int Health. Volume 13, Issue 10, Date: October 2008, Pages: 1235-1244

Cowan et all set out to assess the effectiveness of a community-based HIV prevention intervention for adolescents in terms of its impact on (1) HIV and Herpes simplex virus type 2 (HSV-2) incidence and on rates of unintended pregnancy and (2) reported sexual behaviour, knowledge and attitudes. These were assessed through a cluster randomised trial of a multi-component HIV prevention intervention for adolescents based in rural Zimbabwe. Thirty communities were selected and randomised in 2003 to early or deferred intervention implementation. A baseline bio-behavioural survey was conducted among 6791 secondary school pupils (86% of eligibles) prior to intervention implementation. At baseline, prevalences were 0.8% (95% CI: 0.6-1.0) for HIV and 0.2% (95% CI: 0.1-0.3%) for HSV-2. Four girls (0.12%) were pregnant. There was excellent balance between study arms. Orphans who made up 35% of the cohort were at increased risk of HIV [ age-sex adjusted odds ratio 3.4 (95% CI: 1.7-6.5)]. 11.9% of young men and 2.9% of young women reported that they were sexually active (P < 0.001); however, there were inconsistencies in the sexual behaviour data. Girls were less likely to know about reproductive health issues than boys (P < 0.001) and were ). This is one of the first rigorous evaluations of a community-based HIV prevention intervention for young people in southern Africa. The low rates of HIV suggest that the intervention was started before this population became sexually active. Inconsistency and under-reporting of sexual behaviour re-emphasise the importance of using externally validated measures of sexual risk reduction in behavioural intervention studies.

Editors´note: This community-based HIV prevention trial targeting young people, their parents, and adults in the community to change individual behaviour, as well as societal and cultural norms about adolescent sexuality to reduce risk more broadly, will report results in Dakar at the ICASA conference next month. These baseline findings from 2003 reveal good balance between the study arms and low levels of HIV and herpes simplex virus 2 infection. A striking finding that emphasises the need to validate self-report of sexual behaviours is the fact that none of the four young women that were pregnant reported having had sexual intercourse.

Loutfy MR, Macdonald S, Myhr T, Husson H, Du Mont J, Balla S, Antoniou T, Rachlis A. Prospective cohort study of HIV post-exposure prophylaxis for sexual assault survivors. Antivir Ther. 2008;13(1):87-95

There is a lack of standardized programs for HIV counselling and post-exposure prophylaxis (PEP) in the setting of sexual assault. Loutfy and associates conducted an 18-month prospective cohort study assessing universal HIV counselling for all sexual assault survivors presenting to 18 Ontario Sexual Assault Treatment Centres. HIV PEP was universally offered to those at risk of HIV infection (high risk or unknown risk) presenting < or =72 h after the assault, using Combivir (Lamivudine/Zidovudine) one pill and Kaletra (Lopinavir/Ritonavir) three capsules twice a day for 28 days. Those who accepted HIV PEP were monitored via a schedule of frequent follow ups. The primary outcomes were acceptance and completion rates, and their predictors were determined using multivariable logistic regression. Adverse events were categorized using a standardized toxicity grading system. Of the 900 evaluable participants eligible for PEP, 798 (69 at high risk and 729 at unknown risk) were offered treatment. Acceptance rates were 66.7% (n=46) and 41.3% (n=301) for participants at high risk and unknown risk, respectively. Participants at high risk were 2.2 times more likely to accept PEP than those at unknown risk (adjusted odds ratio 2.2; 95% confidence interval 1.2-4.0; P=0.01). Overall, 23.9% high-risk (n=11) and 33.2% unknown-risk participants (n=100) completed PEP (P=0.20). Predictors of acceptance and completion included assault by a stranger and participant anxiety. Adverse events were common, with 77.1% of participants reporting grade 2-4 symptoms. A province-wide standardized program of universal HIV counselling and offering of PEP to sexual assault survivors with frequent follow up was successfully implemented and feasible.

Editors´note: Post-exposure prophylaxis for sexual assault survivors requires contact with the health system within 72 hours of the attack, availability of antiretroviral drugs and willingness to take them, and, in most cases, consent for HIV testing and counselling. Both anxiety and perceived risk that the assailant could have been HIV-positive influence uptake and completion, but so do side effects. Only 32% of those who started on post-exposure prophylaxis actually finished the 28-day course.

Morin SF, Morfit S, Maiorana A, Aramrattana A, Goicochea P, Mutsambi JM, Robbins JL, Richards TA. Building community partnerships: case studies of Community Advisory Boards at research sites in Peru, Zimbabwe, and Thailand. Clin Trials. 2008;5(2):147-56.

Differences in resources, knowledge, and infrastructure between countries initiating and countries hosting HIV prevention research trials frequently yield ethical dilemmas. Community Advisory Boards have emerged as one strategy for establishing partnerships between researchers and host communities to promote community consultation in socially sensitive research. Morin and co-authors undertook to understand the evolution of Community Advisory Boards and community partnerships at international research sites conducting HIV prevention trials. Three research sites of the HIV Prevention Trials Network (HPTN) were selected to include geographical representation and diverse populations at risk for HIV exposure - Lima, Peru; Chitungwiza, Zimbabwe; and Chiang Mai, Thailand. Data collection included review of secondary data, including academic publications and site-specific progress reports; observations at the research sites; face-to-face interviews with Community Advisory Boards members, research staff, and other key informants; and focus groups with study participants. Rapid assessment techniques were used for data analysis. The authors found that two of the three Community Advisory Boards developed new strategies for community representation in response to new studies. All three Community Advisory Boards expanded their original function and became advocates for broader community interests beyond HIV prevention. The participation and input of community representatives, in response to critical incidents that occurred at the sites over the past five years, helped to solidify partnerships between researchers and communities. In terms of limitations the authors point out that Rapid Assessment is an exploratory methodology designed to provide an understanding of a situation based on the integration of multiple data sources, collected within a short period of time, without a formal examination of transcribed and coded data. Case studies, as a method, are meant to draw out what can be learned from a single case but are not, in the scientific sense, generalizable. They conclude that in developing countries, Community Advisory Boards can be dynamic entities that enhance the HIV research process, assist in responding to issues involving research ethics, and prepare communities for HIV research.

Editors´note: This assessment of changes in community advisory board conduct and roles over a five year period found that at each site a conflict or challenge arose in which the views and assistance of community advisory board members became not only valuable to the research team but also important for the future success of the research. These conflicts or challenges generated substantial interactions of mutual benefit as issues were debated which led to a more genuine partnership. Community advisory boards clearly can be dynamic entities striving to better represent and advocate for the communities.

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Djomand G, Metch B, Zorrilla CD, Donastorg Y, Casapia M, Villafana T, Pape J, Figueroa P, Hansen M, Buchbinder S, Beyrer C; for the 903 Protocol Team. The HVTN Protocol 903 Vaccine Preparedness Study: Lessons Learned in Preparation for HIV Vaccine Efficacy Trials. J Acquir Immune Defic Syndr. 2008;48(1):82-9 2008

Successful recruitment and retention of HIV-uninfected at-risk participants are essential for HIV vaccine efficacy trials. A multicountry vaccine preparedness study was started in 2003 to assess enrolment and retention of HIV-negative high-risk participants, and to assess their willingness to participate in future vaccine efficacy trials. HIV-negative high-risk adults were recruited in the Caribbean, in Southern Africa, and in Latin America, and were followed for 1 year. Participants included men who have sex with men, heterosexual men and women, and female sex workers. History of sexually transmitted infections and sexual risk behaviours were recorded with HIV testing at 0, 6, and 12 months, and willingness to participate in future vaccine trials was recorded at 0 and 12 months. Recruitment, retention, and willingness to participate in future trials were excellent at 3 of the 6 sites, with consistent declines in risk behaviours across cohorts over time. Although not powered to measure seroincidence, HIV seroincidence rates per 100 person-years (95% confidence interval [CI]) were as follows: 2.3 (95% CI: 0.3 to 8.2) in Botswana, 0.5 (95% CI: 0 to 2.9) in the Dominican Republic, and 3.1 (95% CI: 1.1 to 6.8 ) in Peru. The HIV Vaccine Trials Network 903 study helped to develop clinical trial site capacity, with a focus on recruitment and retention of high-risk women in the Americas, and improved network and site expertise about large-scale HIV vaccine efficacy trials.

Editors´note: Finding populations with sufficient risk for HIV infection to support the seroincidence demands of trials is a start but they must also have high rates of retention for there to be adequate power to confirm or refute the study’s hypothesis. Even participating in a study to assess enrolment, retention, and HIV incidence can lead to declines in risk behaviour and HIV incidence, above those already happening in the overall general population. Such a positive effect of being studied is sometimes called the Hawthorne Effect.

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Hughes S, L Cuffe R, Lieftucht A, Garrett Nichols W. Informing the selection of futility stopping thresholds: case study from a late-phase clinical trial. Pharm Stat. 2008 Mar 27 [Epub ahead of print]

In an environment where (i) potential risks to subjects participating in clinical studies need to be managed carefully, (ii) trial costs are increasing, and (iii) there are limited research resources available, it is necessary to prioritize research projects and sometimes re-prioritize if early indications suggest that a trial has low probability of success. Futility designs allow this reprioritization to take place. This paper reviews a number of possible futility methods available and presents a case study from a late-phase study of an HIV therapeutic, which utilized conditional power-based stopping thresholds. The two most challenging aspects of incorporating a futility interim analysis into a trial design are the selection of optimal stopping thresholds and the timing of the analysis, both of which require the balancing of various risks. The paper outlines a number of graphical aids that proved useful in explaining the statistical risks involved to the study team. Further, the paper outlines a decision analysis undertaken which combined expectations of drug performance with conditional power calculations in order to produce probabilities of different interim and final outcomes, and which ultimately led to the selection of the final stopping thresholds.

Editors´note: Early indications that a trial has low probability of success - with success defined as confirming or refuting the trial hypothesis - can lead to the stopping of a trial for futility. Although this saves resources, stopping a trial prior to its conclusion because its key endpoints will not be met makes it impossible to determine whether results for secondary endpoints would have generated useful hypotheses for future investigation. It is important to decide up front what the stopping rules will be with respect to all endpoints and understand the consequences and anticipate them.

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.

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.

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Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth TD, Prins M, Geskus RB, Gras L, Coutinho RA, Fraser C. A resurgent HIV-1 epidemic among men who have sex with men in the era of potent antiretroviral therapy. AIDS. 2008;22(9):1071-7.

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.

García-Lerma JG, Otten RA, Qari SH, Jackson E, Cong ME, Masciotra S, Luo W, Kim C, Adams DR, Monsour M, Lipscomb J, Johnson JA, Delinsky D, Schinazi RF, Janssen R, Folks TM, Heneine W. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. 2008; 5(2):e28.

In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. García-Lerma and colleagues evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. The authors used a repeat-exposure macaque model with 14 weekly rectal simian HIV challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this simian HIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.

Editors’ note: None of the macaques receiving a combination of emtricitabine (FTC) and high dose tenofovir (TDF) either daily or only around the time of exposure to a weekly rectal challenge with SIV became infected. The six macaques that did become infected in the other two active (drug-exposed) arms had a lower viral set point suggesting that the risk of onward transmission during primary infection could be less. These are promising findings in an animal model, however drug resistance in two animals suggest that transmission of resistant virus would be a concern. Furthermore, whether people would be willing to inject themselves subcutaneously either on a daily basis or before a likely exposure remains to be seen. There are six trials in the field now using oral TDF or TDF/FTC with results of the first trial expected in 2008.

Hallett TB, Singh K, Smith JA, White RG, Abu-Raddad LJ, Garnett GP. Understanding the impact of male circumcision interventions on the spread of HIV in Southern Africa. PLoS ONE. 2008; 3(5):e2212. Three randomised controlled trials have clearly shown that circumcision of adult men reduces the chance that they acquire HIV infection. However, the potential impact of circumcision programmes–either alone or in combination with other established approaches–is not known and no further field trials are planned. Hallett and colleagues have used a mathematical model, parameterised using existing trial findings, to understand and predict the impact of circumcision programmes at the population level. The results indicate that circumcision will lead to reductions in incidence for women and uncircumcised men, as well as those circumcised, but that even the most effective intervention is unlikely to completely stem the spread of the virus. Without additional interventions, HIV incidence could eventually be reduced by 25-35%, depending on the level of coverage achieved and whether onward transmission from circumcised men is also reduced. However, circumcision interventions can act synergistically with other types of prevention programmes, and if efforts to change behaviour are increased in parallel with the scale-up of circumcision services, then dramatic reductions in HIV incidence could be achieved. In the long-term, this could lead to reduced AIDS deaths and less need for anti-retroviral therapy. Any increases in risk behaviours following circumcision, i.e. ‘risk compensation’, could offset some of the potential benefit of the intervention, especially for women, but only very large increases would lead to more infections overall. Circumcision will not be the silver bullet to prevent HIV transmission, but interventions could help to substantially protect men and women from infection, especially in combination with other approaches.

Editors’ note: As this modelling study confirms, male circumcision can not and should not be a standalone HIV prevention strategy but rather part of a combination prevention strategy that increases choices for people. Since all methods, other than sexual abstinence, are partially protective, people should aim to combine methods for increased protection. This modelling study also estimates the potential impact for women, the subject of an important consultation being convened by WHO, UNAIDS, UNICEF, and UNFPA in Mombasa, Kenya, June 24-25 2008.

Bernstein A. AIDS and the next 25 years. Science. 2008 ; 320(5877):717.

Since HIV was discovered as the cause of AIDS a quarter century ago, over 60 million people have been infected with the virus and over 25 million people have died. These numbers make the result of two “proof of concept” vaccine efficacy trials—the STEP and Phambili trials—extremely disappointing. These results reflect our still-limited knowledge of HIV, its interactions with the human immune system, and the formidable, unprecedented challenges that it poses. But evidence of immunological protection in certain experimental models of HIV in nonhuman primates, and the intriguing observation that a small proportion of HIV-infected individuals (“elite controllers”) can completely suppress the virus for years, suggest that a vaccine may be achievable. More, not less, basic and early-stage clinical research is needed. We need to understand the role of both the innate and adaptive immune responses during HIV infection. We need to make it much more attractive for young researchers, including those from other fields, to enter the HIV vaccine field. And the continued engagement of industry is essential if we are ever to have a vaccine. We know from experience with other pathogens that a vaccine is the best way to stop a virus. The only end for a journey that began 25 years ago should be the development of a safe and effective HIV vaccine.

Editors’ Notes: Disappointment can lead to sober reflection and taking stock of what should remain a firm foundation and what can and should be challenged and changed. HIV has a high degree of sequence diversity and is a phenomenal foe, striking the very cells needed for an effective immune response. The stakes are high- this is not the time to walk away.

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Walker BD, Burton DR. Toward an AIDS vaccine. Science. 2008; 320(5877):760-4.

A quarter century of scientific discovery has been applied to developing an AIDS vaccine, yet this goal remains elusive. Specific characteristics of the virus, including the extreme genetic variability in circulating viral isolates worldwide, biological properties of HIV that impede immune attack, and a high mutation rate that allows for rapid escape from adaptive immune responses, render this a huge challenge. However, evidence of protection against AIDS viruses in animal models and control of HIV in humans under certain circumstances, together with scientific advances in understanding disease pathogenesis, provide a strong rationale and objective paths to continue the pursuit of an effective AIDS vaccine to stem the global epidemic.

Editors’ Notes: This review explains how the vaccines that work do so, before address ing the unique challenges for the development of an HIV vaccine. These include failure thus far to generate an immunogen to elicit effective neutralising antibodies and to identify the nature of T cell responses that could best contribute to vaccine protection against HIV. Nine critical issues and recommendations for immediate attention are laid out along with a call to pursue an HIV vaccine with greater passion than ever.

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Rossi JJ, June CH, Kohn DB. Genetic therapies against HIV. Nat Biotechnol. 2007; 25(12):1444-54.

Highly active antiretroviral therapy prolongs the life of HIV-infected individuals, but it requires lifelong treatment and results in cumulative toxicities and viral-escape mutants. Gene therapy offers the promise of preventing progressive HIV infection by sustained interference with viral replication in the absence of chronic chemotherapy. Gene-targeting strategies are being developed with RNA-based agents, such as ribozymes, antisense, RNA aptamers and small interfering RNA, and protein-based agents, such as the mutant HIV Rev protein M10, fusion inhibitors and zinc-finger nucleases. Recent advances in T-cell-based strategies include gene-modified HIV-resistant T cells, lentiviral gene delivery, CD8(+) T cells, T bodies and engineered T-cell receptors. HIV-resistant hematopoietic stem cells have the potential to protect all cell types susceptible to HIV infection. The emergence of viral resistance can be addressed by therapies that use combinations of genetic agents and that inhibit both viral and host targets. Many of these strategies are being tested in ongoing and planned clinical trials.

Editors’ note: The plot thickens! Gene therapy could be a stand-alone approach or an adjuvant to drug regimens. However, most people living with HIV today are in settings with insufficient infrastructure to support such technology and viral escape will confound even gene therapy approaches. Several clinical trials testing gene transfer strategies are underway, but don’t hold your breath- this will take some time.

Sylla L, Bruce RD, Kamarulzaman A, Altice FL. Integration and co-location of HIV/AIDS, tuberculosis and drug treatment services. Int J Drug Policy 2007; 18:306-12.

Injection drug use plays a critical role in the HIV epidemic in several countries throughout the world. In these countries, injection drug users are at significant risk for both HIV and tuberculosis, and active injection drug use negatively impacts treatment access, adherence, and retention. Comprehensive strategies are therefore needed to effectively deliver preventive, diagnostic, and curative services to these complex patient populations. Sylla and colleagues propose that developing co-located integrated care delivery systems should become the focus of national programmes as they continue to scale-up access to antiretroviral medications for drug users. Existing data suggest that such a programme will expand services for each of these diseases; increase detection of tuberculosis and HIV; improve medication adherence; increase entry into substance use treatment; decrease the likelihood of adverse drug events; and improve the effectiveness of prevention interventions. Key aspects of integration programmes include: co-location of services convenient to the patient; provision of effective substance use treatment, including pharmacotherapies; cross-training of generalist and specialist care providers; and provision of enhanced monitoring of drug-drug interactions and adverse side effects. Central to implementing this agenda will be fostering the political will to fund infrastructure and service delivery, expanding street-level outreach to injection drug users, and training community health workers capable of cost effectively delivering these services.

Editors’ note: The case for co-location of HIV, TB, and drug treatment services is strong. The “two diseases-one life” nomenclature for TB/HIV puts the focus on the patient, adding drug treatment services and reproductive health services recognises the need for integrated care for this complex and vulnerable patient population.

Ickovics JR. « Bundling » HIV prevention: Integrating services to promote synergistic gain. Prev Med 2007; 46 (3):222-5.

Bundling is defined as the aggregation of services to increase effectiveness (i.e., creating synergy of effort). Ickovics and colleagues aimed to review the utilization and potential benefits of bundling in its application to HIV prevention. A review of the literature was conducted to provide a broad perspective on the concept of bundling and specific examples of bundling in HIV prevention. Benefits, challenges, and directions were considered. To be effective, bundling must offer strategic advantage: greater value, less cost. It provides an opportunity to target multiple risk behaviours simultaneously for synergistic gain. Technological advances including rapid HIV tests permit non-invasive sampling in clinical and non-clinical settings. Bundling of HIV prevention provides an opportunity to reach high-risk persons who are asymptomatic and/or may not otherwise seek care by eliminating barriers to prevention. In conclusion, programmes that work must be implemented and innovative approaches considered to stem the AIDS epidemic; bundling provides one such opportunity to create an efficient paradigm targeting multiple risk behaviours simultaneously.

Editors’ note: Bundling goods or services in business is done to increase profitability with customers benefiting from integrated value-added services, one-stop shopping, and lower prices. In HIV prevention, what gets bundled together, how and how much are important to programme effectiveness-it is high time to create synergy and secondary gain through thoughtful bundling.

Allen M, Lau CY. Social impact of preventive HIV vaccine clinical trial participation: A model of prevention, assessment and intervention. Soc Sci Med. 2008;66(4):945-51

Preventive HIV vaccine trial participants may experience problems related to trial participation, including difficulties with personal relationships, employment, education, health care, housing, health insurance, disability insurance, life insurance, travel or immigration. During the 19 years that the U.S.-based National Institute of Allergy and Infectious Diseases (NIAID) has conducted preventive HIV vaccine trials, Allen and colleagues have developed a model to prevent and resolve social impact related to study participation and assist study participants who report such events. Key elements of the model include: informing potential volunteers of risks prior to enrollment; standardizing data collection methods on social impact events; reviewing and following-up on reported social impact events; assisting participants, including provision of free HIV testing to differentiate HIV infection from vaccine-induced HIV antibody; implementing broad-based and targeted community education programs for achieving community support; communicating with scientific and health care communities; and working with government agencies, non-government agencies and industry on mechanisms to address social impact. This approach, established in collaboration with NIAID-funded clinical trial groups, serves as a model for prevention, assessment, monitoring, and intervention for social impact related to preventive HIV vaccine clinical trial participation. Although further research is necessary, this model could be adapted for use in different clinical trials.

Editors’ note: All clinical trials have the potential to cause social harms and these can be anticipated. Plans should be drawn up, in consultation with community and other research stakeholders prior to trial onset, to monitor, minimize, and mitigate them.

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Mills EJ, Singh S. Health, human rights, and the conduct of clinical research within oppressed populations. Global Health 2007; 3:10.

Clinical trials evaluating interventions for infectious diseases require enrolling participants that are vulnerable to infection. As clinical trials are conducted in increasingly vulnerable populations, issues of protection of these populations become challenging. In settings where populations are forseeably oppressed, the conduct of research requires considerations that go beyond common ethical concerns and into issues of international human rights law. Using examples of HIV prevention trials in Thailand, hepatitis-E prevention trials in Nepal and malaria therapeutic trials in Burma ( Myanmar), Mills and Singh address the inadequacies of ethical guidelines in conducting research within oppressed populations. The authors review existing legislature in the United States and United Kingdom that may be used if trial hardships exist. They conclude by making considerations for any research conducted within oppressed populations.

Editors’ note: The arguments in favour of conducting research in any population must not only outweigh the negatives of not conducting the research, but they must be made by those who will be most affected by the research and their representatives. Participatory decision-making throughout the research life-cycle is described in the UNAIDS/AVAC Good participatory practice guidelines while the UNAIDS/WHO Ethical Considerations in biomedical HIV prevention trials lays out guidance on the specific circumstances in which trials should not be conducted.

Hurwitz JL, Zhan X, Brown SA, Bonsignori M, Stambas J, Lockey TD, Sealy R, Surman S, Freiden P, Jones B, Martin L, Blanchard J, Slobod KS. HIV-1 vaccine development: tackling virus diversity with a multi-envelope cocktail. Front Biosci 2008; 13:609-20.

A major obstacle to the design of a global HIV-1 vaccine is viral diversity. At present, data suggest that a vaccine comprising a single antigen will fail to generate broadly reactive B-cell and T-cell responses able to confer protection against the diverse isolates of HIV-1. While some B-cell and T-cell epitopes lie within the more conserved regions of HIV-1 proteins, many are localized to variable regions and differ from one virus to the next. Neutralizing B-cell responses may vary toward viruses with different i) antibody contact residues and/or ii) protein conformations while T-cell responses may vary toward viruses with different (i) T-cell receptor contact residues and/or (ii) amino acid sequences pertinent to antigen processing. Here Hurwitz and colleagues review previous and current strategies for HIV-1 vaccine development. The authors focus on studies at St. Jude Children’s Research Hospital dedicated to the development of an HIV-1 vaccine cocktail strategy. The St. Jude Children’s Research Hospital multi-vectored, multi-envelope vaccine has now been shown to elicit HIV-1-specific B- and T-cell functions with a diversity and durability that may be required to prevent HIV-1 infections in humans.

Editors’ note: The large number of circulating variants, with vulnerability present both within and between subtypes and within virtually all HIV-1 proteins, poses a challenge to vaccine development unique to HIV. Even the five designated ‘conserved’ regions as opposed to the ‘hypervariable’ regions are heterogeneous. Whether the positive finding of the cocktail approach of a multi-envelope vaccine in macaques challenged with artificial virus can be replicated in humans remains to be seen.

Weiss HA, Halperin D, Bailey RC, Hayes RJ, Schmid G, Hankins CA. Male circumcision for HIV prevention: from evidence to action? AIDS. 2008 Mar 12; 22( 5): 567-74.

The conclusive results of three randomized controlled trials (RCT) showing that male circumcision reduces the risk of HIV acquisition by 58% (95% CI 43–69%) are both promising and challenging. To guide the translation of these research findings into public health policy, Weiss and colleagues estimate the global prevalence and distribution of male circumcision, summarize the evidence of an impact on HIV incidence, and highlight the major public health opportunities and challenges raised by these findings. The authors estimate that 30–34% of adult men are circumcised worldwide. Overall, an estimated 68% of circumcised men are Muslim and 1% are Jewish, with coverage almost universal in the Middle East, north Africa, Pakistan, Bangladesh, and Indonesia. The results of the RCTs confirmed the findings of a previous meta-analysis of 15 observational studies that circumcised men had a large, highly statistically significant reduced risk of HIV acquisition (risk reduction 58%, 95% CI 46–66%). Further, the high density of HIV target cells that are relatively accessible to HIV infection in the inner foreskin provides a plausible biological mechanism that could explain the increased risk of HIV in uncircumcised men. Several countries are planning to introduce or expand safe male circumcision programmes, including Kenya, Zambia, Swaziland and Rwanda, and international funding agencies are backing this strategy. National policies, however, are needed to maximize the safety, efficiency, and availability of male circumcision service provision. Challenges include potential behaviour change following male circumcision (risk compensation), predicting the potential population-level epidemic impact and cost-effectiveness of male circumcision, knowing the impact on female partners, and knowing the impact for men who have sex with men. In summary, male circumcision provides a much needed addition to the current HIV prevention armamentarium. It is not a new, untested or unknown technology, but possibly the oldest, and certainly the most common, surgical procedure known. The evidence from the trials is conclusive, and the challenges to implementation must now be faced.

Editors’ note:This editorial review constitutes an overview of why male circumcision is currently on the policy agenda of a number of countries, particularly those in southern and eastern Africa with a high HIV prevalence overall or among sub-populations. The WHO/UNAIDS position on male circumcision for HIV prevention may be found at http://data.unaids.org/pub/Report/2007/mc_recommendations_en.pdf.