Male circumcision and risk of male-to-female HIV-1 transmission: a multinational prospective study in African HIV-1-serodiscordant couples.

Baeten JM, Donnell D, Kapiga SH, Ronald A, John-Stewart G, Inambao M, Manongi R, Vwalika B, Celum C; for the Partners in Prevention HSV/HIV Transmission Study Team. AIDS. 2009. Dec [Epub ahead of print].

Male circumcision reduces female-to-male HIV-1 transmission risk by approximately 60%. Data assessing the effect of circumcision on male-to-female HIV-1 transmission are conflicting, with one observational study among HIV-1-serodiscordant couples showing reduced transmission but a randomized trial suggesting no short-term benefit of circumcision. Data were collected as part of a prospective study among African HIV-1-serodiscordant couples were analyzed for the relationship between circumcision status of HIV-1-seropositive men and risk of HIV-1 acquisition among their female partners. Circumcision status was determined by physical examination. Cox proportional hazards analysis was used. A total of 1096 HIV-1-serodiscordant couples in which the male partner was HIV-1-infected were followed for a median of 18 months; 374 (34%) male partners were circumcised. Sixty-four female partners seroconverted to HIV-1 (incidence 3.8 per 100 person-years). Circumcision of the male partner was associated with a nonstatistically significant approximately 40% lower risk of HIV-1 acquisition by the female partner (hazard ratio 0.62, 95% confidence interval 0.35-1.10, P = 0.10). The magnitude of this effect was similar when restricted to the subset of HIV-1 transmission events confirmed by viral sequencing to have occurred within the partnership (n = 50, hazard ratio 0.57, P = 0.11), after adjustment for male partner plasma HIV-1 concentrations (hazard ratio 0.60, P = 0.13), and when excluding follow-up time for male partners who initiated antiretroviral therapy (hazard ratio 0.53, P = 0.07). Among HIV-1-serodiscordant couples in which the HIV-1-seropositive partner was male, the authors observed no increased risk and potentially decreased risk from circumcision on male-to-female transmission of HIV-1.

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Editors’ note: The trend seen here among 1096 couples toward a protective effect of male circumcision for HIV-negative women in discordant partnerships is intriguing. Sexual behaviours of couples with circumcised men were similar to those in which the man was not circumcised, only genetically-linked transmissions (i.e. transmissions within the couple) were considered (incidence 3.0 per 100 person years), and follow-up time after initiation of antiretroviral treatment (when viral loads presumably fell) was excluded. The result was a borderline statistically significant 47 per cent reduced risk of HIV-1 acquisition in women. Possible mechanisms that might explain lower risk for women are reduced risk of sexually transmitted infections in circumcised men or reduced likelihood of direct HIV transmission that would have otherwise occurred as a result of microtrauma or inflammation of the foreskin.

Price LB, Liu CM, Johnson KE, Aziz M, Lau MK, Bowers J, Ravel J, Keim PS, Serwadda D, Wawer MJ, Gray RH., PLoS One. 2010. 5:e8422.

Circumcision is associated with significant reductions in HIV, HSV-2, and HPV infections among men and significant reductions in bacterial vaginosis among their female partners. The authors assessed the penile (coronal sulci) microbiota in 12 HIV-negative Ugandan men before and after circumcision. Microbiota were characterized using sequence-tagged 16S rRNA gene pyrosequencing targeting the V3-V4 hypervariable regions. Taxonomic classification was performed using the RDP Naïve Bayesian Classifier. Among the 42 unique bacterial families identified, Pseudomonadaceae and Oxalobactericeae were the most abundant irrespective of circumcision status. Circumcision was associated with a significant change in the overall microbiota (PerMANOVA p = 0.007) and with a significantdecrease in putative anaerobic bacterial families (Wilcoxon Signed-Rank test p = 0.014). Specifically, two families-Clostridiales Family XI (p = 0.006) and Prevotellaceae (p = 0.006)-were uniquely abundant before circumcision. Within these families they identified a number of anaerobic genera previously associated with bacterial vaginosis including: Anaerococcus spp., Finegoldia spp., Peptoniphilus spp., and Prevotella spp. The anoxic microenvironment of the subpreputial space may support pro-inflammatory anaerobes that can activate Langerhans cells to present HIV to CD4 cells in draining lymph nodes. Thus, the reduction in putative anaerobic bacteria after circumcision may play a role in protection from HIV and other sexually transmitted diseases.

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Editors’ note: Although molecular analyses have been used to characterise the microbiota or microbial community in the vagina, this is the first molecular assessment of the bacterial diversity found in the male genital mucosa. This pre-post circumcision study of 12 men shows that removing the foreskin removes the oxygen-poor environment of the mucosa under the foreskin that provides a warm, moist home for bacteria, many of which are anaerobic and are associated with bacterial vaginosis in women. This helps explain why the female partners of circumcised men have fewer sexually transmitted infections and less bacterial vaginosis. Getting rid of these bacteria through circumcision reduces mucosal inflammation and may provide part of the explanation for the reduced risk of HIV, herpes simplex-2, and human papilloma virus (HPV) infections in circumcised men.

Rearranging retroviral regimens for HIV-intermittent prophylaxis with oral Truvada protects macaques from rectal SHIV Infection

García-Lerma G, Cong M, Mitchell J, Youngpairoj A, Zheng Q, Masciotra S, Martin A, Kuklenyik Z, Holder A, Lipscomb J, Pau C, Barr J, Hanson D, Otten R, Paxton L, Folks T and Heneine W. Sci Transl Med. 2010. 2: 14ra4.

Antiretroviral drugs have transformed the lives of HIV-infected people by preventing progression to full-blown AIDS. These drugs also dramatically reduce HIV transmission from mothers to infants during pregnancy and breastfeeding, and work in monkeys suggests that daily doses can also reduce transmission from unprotected sex. But prophylactic treatment with antiretroviral drugs is costly and impractical—even if confined to a high-risk population. García-Lerma et al. now show that in monkeys a more realistic medication schedule may work just as well as daily doses. To simulate how people are likely to be infected with HIV, the authors exposed macaque monkeys rectally to 14 weekly doses of simian-human immunodeficiency virus (SHIV) engineered to resemble the human virus. Control macaques treated in this way became infected within the first five exposures to SHIV. Researchers then assessed whether oral, human-equivalent doses of antiretroviral agents could prevent infection in monkeys. The best protection—equivalent to that provided by daily antivirals—occurred when the drug Truvada was given 1, 3, or 7 days before virus exposure followed by a second dose 2 hours after exposure. Less effective, but still better than no treatment at all, was a schedule in which the drug was given 2 hours before or after exposure and then again 24 hours later. Drugs given only 24 or 48 hours after exposure did not safeguard against infection. The results of this study are preliminary, largely because each of the groups had only six macaques, but they are nevertheless promising. If ongoing clinical trials in healthy people show that daily antiretroviral therapy can diminish the chances of acquiring HIV after exposure, a reasonable next step would be to evaluate more practical, less costly drug schedules in humans. For example, a weekly dose followed by a second dose after a possible exposure could prove both effective and tractable. It will also be important to evaluate treatments based solely on exposure, as these would not require ongoing prophylactic drug treatment and would minimize any drug toxicity. If one or more of these therapeutic regimens is successful, antiretroviral drugs may expand the transformation they have already engendered by preventing many more new infections as well as controlling existing ones.

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Editors’ note: Despite several limitations of these non-human primate trials, they nonetheless provide food for thought and for human trial design. All the current oral Pre-Exposure Prophylaxis (PrEP) phase IIb and III trials in humans are studying daily administration of either tenofovir (TDF) or a combination of TDF and emtricitabine (FTC). Good complements to each other, FTC appears to have more rapid absorption and tissue distribution while TDF has a long intracellular persistence. Based on these findings of good protection from rectal challenge in macaques given intermittent oral TDF/FTC treatment (varying times before but topping up 2 hours after exposure in active arms), the results of human trials of intermittent PrEP are needed. Intermittent PrEP regimens would likely be easier to adhere to, while decreasing drug costs and probably reducing drug toxicities. Those animals that did become infected appeared to have lower peak levels of virus in the blood. If lower viral set points are confirmed, this may reduce CD4+ cell count depletion and slow disease progression but may also mean less onward transmission. There are many questions to be answered about PrEP before it can be considered as a candidate to join the biomedical component of combination prevention (biomedical, behavioural, structural) strategies. The first question is whether daily administration will prove effective in the current trials of men who have sex with men, people who inject drugs, and heterosexuals at increased risk. If it does, there will be heightened interest in rapidly testing the safety and efficacy of intermittent PrEP in humans to inform policy and programme design decision-making.

Two Distinct Epidemics: The Rise of HIV-1 and Decline of HIV-2 Infection Between 1990 and 2007 in Rural Guinea-Bissau.

van Tienen C, van der Loeff MS, Zaman SM, Vincent T, Sarge-Njie R, Peterson I, Leligdowicz A, Jaye A, Rowland-Jones S, Aaby P, Whittle H.  J Acquir Immune Defic Syndr. 2009 Oct. [Epub ahead of print]

This study set out to assess changes in HIV incidence and prevalence in Caió, a rural area of Guinea-Bissau, between 1990 and 2007. Three cross-sectional community surveys in 1990, 1997, and 2007, were conducted among adults. The prevalence of HIV-1 and of HIV-2 was estimated for each survey, and incidence rates were calculated for the first (1990-1997) and second period (1997-2007). The HIV-1 incidence was approximately 4.5/1000 person-years in the two periods, whereas the HIV-2 incidence decreased from 4.7 (95% confidence interval 3.6-6.2) in the first to 2.0 (95% confidence interval 1.4-3.0) per 1000 person-years in the second period (P < 0.001). HIV-1 prevalence rose from 0.5% in 1990 to 3.6% in 2007, and HIV-2 prevalence decreased from 8.3% in 1990 to 4.7% in 2007. HIV-1 prevalence was less than 2% in 15 to 24 year olds in all surveys and was highest (7.2%) in 2007 among 45 to 54 year olds. The HIV-2 prevalence was fivefold higher in older subjects (>/=45 yr) compared with those less than 45 years in both sexes in 2007. HIV-1 incidence is stable, and its prevalence is increasing, whereas HIV-2 incidence and prevalence are both declining. In contrast with what has been observed in other sub-Saharan countries, HIV-1 prevalence is lower in younger age groups than older age groups.

Abstract: 1

Editors’ note: HIV-1 has spread globally while HIV-2 remains confined to West Africa where it is thought to have originated and to countries with socio-economic links to Portugal. HIV-2 has lower sexual and vertical transmissibility, likely due to the lower levels of viraemia seen in HIV-2 infection. This study, the largest community-based study monitoring changes in incidence and prevalence of HIV-1 and HIV-2, found a decline in HIV-2 incidence over an 18 year period and lower HIV-1 incidence and prevalence in 15 to 24 year olds compared with other age groups in this rural area of Guinea-Bissau, suggesting that public health HIV prevention programming from 2002 to 2006 could have influenced risk behaviour among young people. It would be useful to conduct behavioural research and qualitative studies with young people to obtain their views on serological and behavioural findings and what they think has been most effective in protecting them from HIV infection.

Baseline characteristics, response to and outcome of antiretroviral therapy among patients with HIV-1, HIV-2 and dual infection in Burkina Faso.

Harries K, Zachariah R, Manzi M, Firmenich P, Mathela R, Drabo J, Onadja G, Arnould L, Harries A. Trans R Soc Trop Med Hyg. 2009. [Epub ahead of print]

In an urban district hospital in Burkina Faso Harries et al investigated the relative proportions of HIV-1, HIV-2 and HIV-1/2 among those tested, the baseline sociodemographic and clinical characteristics, and the response to and outcome of antiretroviral therapy (ART). A total of 7368 individuals (male=32%; median age=34 years) were included in the analysis over a 6 year period (2002-2008). The proportions of HIV-1, HIV-2 and dual infection were 94%, 2.5% and 3.6%, respectively. HIV-1-infected individuals were younger, whereas HIV-2-infected individuals were more likely to be male, have higher CD4 counts and be asymptomatic on presentation. Antiretroviral therapy was started in 4255 adult patients who were followed up for a total of 8679 person-years, during which time 469 deaths occurred. Mortality differences by serotype were not statistically significant, but were generally worse for HIV-2 and HIV-1/2 after controlling for age, CD4 count and WHO stage. Among severely immune-deficient patients, mortality was higher for HIV-2 than HIV-1. CD4 count recovery was poorest for HIV-2. HIV-2 and dually infected patients appeared to do less well on antiretroviral therapy than HIV-1 patients. Reasons may include differences in age at baseline, lower intrinsic immune recovery in HIV-2, use of ineffective ART regimens (inappropriate prescribing) by clinicians, and poor drug adherence.

Full text: 1

Editors’ note : HIV-2 is thought of as being less pathogenic than HIV-1. People with HIV-2 have a much longer asymptomatic stage, slower progression to AIDS, a slower decline in CD4 count, and lower mortality. So why did this Burkina Faso study find poorer immunological responses to antiretroviral treatment and worse treatment outcomes in adults with HIV-2 infection? Several possibilities deserve further attention. Aside from the fact that people with HIV-1 infection tended to initiate treatment at a much earlier age, 25% of HIV-2 infected patients were given non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens when HIV-2 is naturally resistant to NNRTI. About 38% were also placed on a nelfinavir-containing regimen that has limited virological benefit in people with HIV-2. Matching viral type with treatment regimen is clearly important and it requires correct diagnosis, training, and mentoring along with adequate access to effective antiretroviral drug regimens.

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

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

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

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

Foreskin surface area and HIV acquisition in Rakai, Uganda (size matters).

Kigozi G, Wawer M, Ssettuba A, Kagaayi J, Nalugoda F, Watya S, Mangen FW, Kiwanuka N, Bacon MC, Lutalo T, Serwadda D, Gray RH. AIDS. 2009; 23:2209-13.

Male circumcision reduces HIV acquisition in men. The authors assessed whether foreskin surface area was associated with HIV acquisition prior to circumcision. In two randomized trials of male circumcision, the surface area of the foreskin was measured after surgery using standardized procedures. Nine hundred and sixty-five initially HIV-negative men were enrolled in a community cohort who subsequently enrolled in the male circumcision trials, provided 3920.8 person-years of observation prior to circumcision. They estimated HIV incidence per 100 person-years prior to circumcision, associated with foreskin surface area categorized into quartiles. Mean foreskin surface area was significantly higher among men who acquired HIV (43.3 cm2, standard error 2.1) compared with men who remained uninfected (36.8 cm, standard error 0.5, P = 0.01). HIV incidence was 0.80/100 person-years (8/994.9 person-years) for men with foreskin surface areas in the lowest quartile (< or =26.3 cm2), 0.92/100 person-years (9/975.3 person-years) with foreskin areas in the second quartile (26.4-35.0 cm2), 0.90/100 person-years (8/888.5 person-years) with foreskin area in the third quartile (35.2-45.5 cm2) and 2.48/100 person-years (23/926.8 person-years) in men with foreskin surfaces areas in the highest quartile (>45.6 cm2). Compared with men with foreskin surface areas in the lowest quartile, the adjusted incidence rate ratio of HIV acquisition was 2.37 (95% confidence interval 1.05-5.31) in men with the largest quartile of foreskin surface area. The risk of male HIV acquisition is increased among men with larger foreskin surface areas.

For access to abstract click here: 1

Editors’ note: This retrospective cohort study is the first study examining the association between foreskin surface area and risk of HIV acquisition – and its findings are biologically plausible. Removing the foreskin reduces the risk of HIV acquisition by 50 to 60% because the only remaining unkeratinized mucosa on the penis after circumcision is the urethral meatus (opening). Before circumcision, more foreskin means more HIV target cells in the inner mucosa of the prepuce exposed to vaginal fluids during sex, likely more of the traumatic micro lesions that are open doors for HIV, and more genital ulcers that have welcoming mats out for HIV. In this study, risk of HIV acquisition in men with the largest foreskins was more than twice that of those with the smallest, leading to the claim that size matters. The larger your foreskin, the more you should think about getting it removed if you might be exposed to HIV now or later.

Circumcision and risk of HIV infection in Australian homosexual men.

Templeton DJ, Jin F, Mao L, Prestage GP, Donovan B, Imrie J, Kippax S, Kaldor JM, Grulich AE. AIDS. 2009;23:2347-51.

The aim of the study was to assess circumcision status as a risk factor for HIV seroconversion in homosexual men. The Health in Men (HIM) study was a prospective cohort of homosexual men in Sydney, Australia. HIV-negative men (n = 1426) were recruited primarily from community-based sources between 2001 and 2004 and followed to mid-2007. Participants underwent annual HIV testing, and detailed information on sexual risk behaviour was collected every 6 months. The main outcome measure was HIV incidence in circumcised compared with uncircumcised participants, stratified by whether or not men predominantly practised the insertive role in anal intercourse. There were 53 HIV seroconversions during follow-up; an incidence of 0.78 per 100 person-years. On multivariate analysis controlling for behavioural risk factors, being circumcised was associated with a nonsignificant reduction in risk of HIV seroconversion [hazard ratio 0.78, 95% confidence interval (CI) 0.42-1.45, P = 0.424]. Among one-third of study participants who reported a preference for the insertive role in anal intercourse, being circumcised was associated with a significant reduction in HIV incidence after controlling for age and unprotected anal intercourse (UAI) (hazard ratio 0.11, 95% CI 0.03-0.80, P = 0.041). Those who reported a preference for the insertive role overwhelmingly practised insertive rather than receptive UAI. Overall, circumcision did not significantly reduce the risk of HIV infection in the Health in Men cohort. However, it was associated with a significant reduction in HIV incidence among those participants who reported a preference for the insertive role in anal intercourse. Circumcision may have a role as an HIV prevention intervention in this subset of homosexual men.

For access to abstract click here: 1 

Editors’ note: With strategic positioning among gay men on the rise in Australia and the USA (HIV-negative men adopting the insertive role in unprotected anal sex to reduce their risk with HIV-positive partners or those of unknown status), there is increasing interest in the possible protection that male circumcision may provide to primarily insertive men who have sex with men. This first prospective study, following on mixed findings from cross-sectional studies, included systematic validation of circumcision status in a sub-group of participants to assess validity of self-report. Despite lowered study power (only 33% of person-years of exposure were in men with a preference for the insertive role), circumcised men with this preference had significantly reduced HIV incidence. Only randomised controlled trials recruiting uncircumcised men who have sex with men and who predominantly or exclusively practise insertive anal sex in high HIV incidence settings will answer once and for all the question of whether male circumcision reduces the risk of HIV acquisition for primarily insertive men who have sex with men as it does for men who have sex with women.  

Maraviroc Concentrates in the Cervicovaginal Fluid and Vaginal Tissue of HIV-Negative Women.

Dumond JB, Patterson KB, Pecha AL, Werner RE, Andrews E, Damle B, Tressler R, Worsley J, Kashuba AD. J Acquir Immune Defic Syndr. 2009; 51:546-53.

The authors compared single- and multiple-dose maraviroc exposures in cervicovaginal fluid (CVF) and vaginal tissue (VT) with blood plasma (BP) and quantified maraviroc protein binding in cervicovaginal fluid. In this open-label pharmacokinetic study of 12 HIV-negative women, 7 paired CVF and BP samples were collected over 12 hours after 1 maraviroc dose. Subjects then received maraviroc twice daily for 7 days. After the last dose, subjects underwent cervicovaginal fluid and blood plasma sampling as on day 1, with additional sampling during terminal elimination. Vaginal tissue biopsies were obtained at steady state. Day 1 and day 7 median maraviroc cervicovaginal fluid AUCtau were 1.9- and 2.7-fold higher, respectively, than blood plasma. On day 1, 6 of 12 subjects had detectable maraviroc cervicovaginal fluid concentrations within 1 hour; 12 of 12 were detectable within 2 hours, and all exceeded the protein-free IC90. On day 7, maraviroc cervicovaginal fluid protein binding was 7.6% and the VT AUCtau was 1.9-fold higher than blood plasma. Maraviroc cervicovaginal fluid concentrations 72 hours after dose and blood plasma concentrations 12 hours after dose were similar. Higher maraviroc exposure in the female genital tract provides a pharmacologic basis for further evaluation of chemokine receptor 5 antagonists in HIV infection prophylaxis. This is the first study to report antiretroviral vaginal tissue concentrations, cervicovaginal fluid protein binding, and cervicovaginal fluid terminal elimination.

For abstract access click here: 1

Editors’ note: Discordance between antiretroviral concentrations in the blood plasma and genital tract compartments may result in ongoing HIV genital shedding in the presence of undetectable viral load in blood plasma. This has implications for onward HIV transmission and could lead to harbouring of resistant virus which could reseed systemically producing treatment failure. Thus the degree to which antiretroviral drugs concentrate in the genital tract is important both for public health and for individual treatment outcome. Since viruses that use CCR5 chemokine receptors predominate in the early stages of mucosal transmission, this team studied the pharmacokinetics of the CCR5 inhibitor maraviroc in the genital tract. It achieved not only high cervicovaginal fluid concentrations but also high vaginal tissue concentrations – about twice as high as in blood plasma. These results were a surprise because maraviroc has high protein-binding affinity which reduces its activity. Interestingly this study found protein-binding to be 10 times less in the cervicovaginal fluid than in blood plasma, meaning that the drug is active where we need it to be. A number of questions remain unanswered but maraviroc deserves further study for the prevention of heterosexual transmission.

Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women.

Nel A, Smythe S, Young K, Malcolm K, McCoy C, Rosenberg Z, Romano J. J Acquir Immune Defic Syndr. 2009; 51:416-23.

Vaginal microbicides for the prevention of HIV transmission may be an important option for protecting women from infection. Incorporation of dapivirine, a lead candidate nonnucleoside reverse transcriptase inhibitor, into intravaginal rings (IVRs) for sustained mucosal deliverymay increase microbicide product adherence and efficacy compared with conventional vaginal formulations. Twenty-four healthy HIV-negative women 18-35 years of age were randomly assigned (1:1:1) to dapivirine matrix intravaginal ring, dapivirine reservoir intravaginal ring, or placebo intravaginal ring. Dapivirine concentrations were measured in plasma and vaginal fluid samples collected at sequential time points over the 33-day study period (28 days of intravaginal ring use, 5 days of follow-up). Safety was assessed by pelvic/colposcopic examinations, clinical laboratory tests, and adverse events. Both intravaginal ring types were safe and well tolerated with similar adverse events observed in the placebo and dapivirine groups. Dapivirine from both intravaginal ring types was successfully distributed throughout the lower genital tract at concentrations over 4 logs greater than the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) values were significantly higher with the matrix than reservoir intravaginal ring. Mean plasma concentrations of dapivirine were <2 ng/mL. These findings suggest that intravaginal ring delivery of microbicides is a viable option meriting further study.

For abstract access click here: 1

Editors’ note: The idea of an intravaginal ring carrying an antiretroviral for HIV prevention and needing replacement once a month or less is attractive. This study found that such rings, carrying the nonnucleoside reverse transcriptase inhibitor dapivirine, were safe, well-tolerated, and produced high levels of dapirivine in cervicovaginal secretions. The rings tested released drug through different mechanisms but pharmacokinetic studies found that systemic exposure of dapivirine in the blood was low with both of them. Now it’s on to the next stage!  

Effective, low-titre antibody protection against low-dose repeated mucosal SHIV challenge in macaques.

Hessell AJ, Poignard P, Hunter M, Hangartner L, Tehrani DM, Bleeker WK, Parren PW, Marx PA, Burton DR. Nat Med. 2009 15(8):951-4.

Neutralizing antibodies are thought to be crucial for HIV vaccine protection, but studies in animal models suggest that high antibody concentrations are required. This is a major potential hurdle for vaccine design. However, these studies typically apply a large virus inoculum to ensure infection in control animals in single-challenge experiments. In contrast, most human infection via sexual encounter probably involves repeated exposures to much lower doses of virus. Therefore, animal studies may have provided an overestimate of the levels of antibodies required for protection in humans. The authors investigated whether plasma concentrations of antibody corresponding to relatively modest neutralization titres in vitro could protect macaques from repeated intravaginal exposure to low doses of a simian immunodeficiency virus-HIV chimera (SHIV) that uses the CC chemokine receptor 5 (CCR5) co-receptor. An effector function-deficient variant of the neutralizing antibody was also included. The results show that a substantially larger number of challenges is required to infect macaques treated with neutralizing antibody than control antibody-treated macaques, and support the notion that effector function may contribute to antibody protection. Overall, the results imply that lower amounts of antibody than previously considered protective may provide benefit in the context of typical human exposure to HIV-1.

For abstract access click here: 1

Editors’ note: This study, as in virtually all similar studies published to date, used viruses matched to the neutralising antibody tested. Thus, it is unclear whether this strategy would protect against a variety of circulating viruses. Nonetheless, it is tantalising to think that this macaque study using low dose viral challenges that better reflect repeated human mucosal exposure to low numbers of virus particles may in some way help us to understand the results of the RV144 Thai vaccine trial in which low risk participants may have been better protected. We await with anticipation further results of that trial over the coming months.

Manrique M, Kozlowski P, Wang SW, Wilson R, Micewicz E, Montefiori D, Mansfield K, Carville A, Aldovini A. Mucosal Immunol. 2009; 2:536-50.

Preventive human immunodeficiency virus (HIV) vaccination may require induction of virus-specific immune responses at mucosal sites to contain viral infection locally after exposure, as most HIV infections occur through mucosal surfaces. The authors compared the efficacy of an intranasal or intramuscular Simian immunodeficiency virus (SIV)+ interleukin (IL)-2+IL-15 DNA/SIV-MVA (modified vaccinia virus Ankara) vaccination in preventing disease progression in SIVmac251 intrarectally challenged rhesus macaques. SIV-specific rectal IgA responses were more significantly persistent in nasally vaccinated than in intramuscularly vaccinated animals. No significant differences were observed in the magnitude of systemic T-cell responses between the two groups, although the nasal immunization induced more significant anti-SIV T-cell responses in the colorectal mucosa. After challenge, CD4(+) central memory (C(M)) T-cell preservation and significant disease-delay were observed in both vaccination groups. However, nasally vaccinated animals had more significant early preservation of circulating and colorectal CD4(+) C(M) T cells, of circulating CD4(+)/alpha4beta7(+) effector memory (E(M)) T cells, and a longer disease-free interval when compared with the intramuscularly vaccinated or control groups. Regardless of vaccination status, long-term viraemia control and preservation of CD4(+) C(M) T cells was detected in animals with significantly higher systemic CD8(+)/tumour necrosis factor (TNF)-alpha(+) and CD8(+)/interferon (IFN)-gamma(+) T-cell responses and higher SIV-specific CD4(+)/IL-2(+) responses in colorectal T cells.

For Abstract click here: 1

Editors’ note: Can you imagine taking a vaccine nasally? In this study, nasal vaccination provided more significant protection from progression to AIDS than classical intramuscular vaccination. It is possible that different mucosal routes will provide different degrees of protection. One thing to aim for would be lower viral loads in the gut in acute infection so that there would be less antigen driving immune activation, our antibody response to HIV. A vaccine that did not prevent HIV infection but that would delay the onset of disease by limiting viral replication from the start would be a welcome addition.  

Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand.

Supachai Rerks-Ngarm, M.D., Punnee Pitisuttithum, M.D., D.T.M.H., Sorachai Nitayaphan, M.D., Ph.D., Jaranit Kaewkungwal, Ph.D., Joseph Chiu, M.D., Robert Paris, M.D., Nakorn Premsri, M.D., Chawetsan Namwat, M.D., Mark de Souza, Ph.D., Elizabeth Adams, M.D., Michael Benenson, M.D., Sanjay Gurunathan, M.D., Jim Tartaglia, Ph.D., John G. McNeil, M.D., Donald P. Francis, M.D., D.Sc., Donald Stablein, Ph.D., Deborah L. Birx, M.D., Supamit Chunsuttiwat, M.D., Chirasak Khamboonruang, M.D., Prasert Thongcharoen, M.D., Ph.D., Merlin L. Robb, M.D., Nelson L. Michael, M.D., Ph.D., Prayura Kunasol, M.D., Jerome H. Kim, M.D., for the MOPH–TAVEG Investigators. 2009 New England Journal of Medicine. Epub Ahead of print October 20, 2009 (10.1056/NEJMoa0908492)

The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, the authors evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viraemia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], –4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,452 subjects, the vaccine efficacy was 26.2% (95% CI, –13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 51.2; P=0.04). Vaccination did not affect the degree of viraemia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research.

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Editors’ note: These encouraging results are sparking HIV vaccine scientists to explore how this prime-boost strategy using vaccines that were adapted to circulating Thai subtypes (B and E) provided modest levels of protection. This paper was published on line October 20 th simultaneously with the plenary presentation of the results at the AIDS Vaccine 2009 conference in Paris. Webcasting of the conference sessions and media conferences, including the RV144 media conference, is available to viewers until January 21, 2010 at 12:00 PM Central European Time at: http://www.hivvaccineenterprise.org/conference/2009/webcasting.html The mITT or modified intent-to-treat analysis is the gold standard analysis that was followed by the trial’s Data Safety Monitoring Board throughout this test-of-concept trial. It includes all trial participants randomised in the trial with the exception of 7 who were already HIV infected at their first post-screening study visit before the first shot. How exactly did this strategy work (what are the immune correlates of protection?), how high did vaccine efficacy go in the first year and how much did it decrease after the first year post-vaccination (would booster doses be needed?), does the vaccine work better in those at lower risk of infection (why and what would that mean for future vaccine trial design?), was it a single vaccine or the prime-boost combination that produced protective immune responses, was matching the vaccines to Thai virus subtypes important to vaccine efficacy in this study population, and are there different immune system responses to prevent HIV infection compared to those that attempt to control it after infection is established? These and many other intriguing questions are opening up avenues for exploration and invigorating us all. An HIV vaccine is many years away but now we know that it will come.

Potential population health outcomes and expenditures of HIV vaccination strategies in the United States.

Long EF, Brandeau ML, Owens DK. Vaccine. 2009; 27(5402-5010).

Estimating the potential health benefits and expenditures of a partially effective HIV vaccine is an important consideration in the debate about whether HIV vaccine research should continue. We developed an epidemic model to estimate HIV prevalence, new infections, and the cost-effectiveness of vaccination strategies in the U.S. Vaccines with modest efficacy could prevent 300,000-700,000 HIV infections and save $30 billion in healthcare expenditures over 20 years. Targeted vaccination of high-risk individuals is economically efficient, but difficulty in reaching these groups may mitigate these benefits. Universal vaccination is cost-effective for vaccines with 50% efficacy and price similar to other infectious disease vaccines.

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Editors’ note: This is the first analysis to estimate quantitatively the potential health and economic outcomes of a targeted or a universal HIV vaccination programme in the USA, where its estimated that 1.3 million new infections will occur over the next 20 years. Under a variety of scenarios and assumptions about vaccine efficacy and epidemic dynamics in the late-stage US epidemic, investment in vaccines results in positive health and economic outcomes, being ‘good value for money’. These models can be further refined, as we learn more about vaccine efficacy by mode of transmission and intensity of HIV exposure, and then applied to low- and middle-income countries where 40 million new infections are expected to occur over the next 20 years.  

Foreskin inflammation is associated with HIV and herpes simplex virus type-2 infections in Rakai, Uganda.

Johnson KE, Sherman ME, Ssempiija V, Tobian AA, Zenilman JM, Duggan MA, Kigozi G, Serwadda D, Wawer MJ, Quinn TC, Rabkin CS, Gray RH. AIDS. 2009; 23:1807-15

Johnson and colleagues assessed foreskin inflammation associated with HIV and herpes simplex virus type 2 (HSV-2) in circumcised men. Foreskin tissues were assessed in 97 HIV-infected and 135 HIV-uninfected men enrolled in randomized trials of circumcision in Rakai, Uganda. Inflammation was quantified using an ordinal score evaluating extent, intensity, and cellular composition of infiltrates in the epithelium and stroma. Prevalence rate ratios of inflammation were estimated by multivariate Poisson regression. Foreskin inflammation was primarily focal. Epithelial inflammation was present in 4.2% of men with neither HIV nor HSV-2 infection; 7.8% of men with only HSV-2; 19.0% with HIV alone (P = 0.04); and 31.6% in HIV/HSV-2 coinfected men [prevalence rate ratio (PRR) 7.5, 95% confidence interval (CI) 2.3-23.8, P < 0.001]. Stromal inflammation was present in 14.1% of HIV/HSV-2 uninfected men, compared with 29.7% in men with HSV-2 alone (P = 0.03), 33.3% in men with HIV alone (P = 0.04), and 61.0% in men with HIV/HSV-2 coinfection (PRR 4.3, 95% CI 2.3-7.9, P < 0.001). In HIV-infected men, epithelial inflammation was associated with higher HIV viral load. Epithelial inflammation was more frequent among men reporting recent genital ulceration. Both epithelial and stromal inflammation were more common among men with smegma on physical examination. Foreskin inflammation is increased with HIV and HSV-2 infections, higher HIV viral load and presence of smegma. Foreskin inflammation may have implications for HIV transmission and acquisition in uncircumcised men.

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Editors’ note: This analysis of foreskins removed at medical circumcision supports the idea that local mucosal inflammation and ulcerative lesions, as well as recruitment of lymphocytes that target HIV to genital tissues, can influence HIV susceptibility and infectivity. Causative links cannot be made because this is a cross-sectional study but the highest prevalence of foreskin inflammation (in the epithelium and in the layer below it), was found in men with HIV/HSV-2 co-infection. Inflammation was also associated with smegma, a possible surrogate marker of poor genital hygiene. Since smegma could be the result of local inflammation or it be contributing to it, further research is warranted. 

Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target. Walker LM, Phoga SK, Chan-Hui P-Y, Wagner D, Phung P, Goss JL, Wrin T, Simek MD, Fling S, Mitcham JL, Lehrman JK, Priddy FH, Olsen OA, Frey SM, Hammond PW, Protocol G Principal Investigators, Kaminsky S, Zamb T, Moyle M, Koff WC, Poignard P, Burton DL. Science. Published online September 3, 2009. Science DOI: 10.1126/science.1178746

Broadly neutralizing antibodies, which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, Walker and colleagues examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and selected donors for monoclonal antibody generation. They used a high-throughput neutralization screen of antibody-containing culture supernatants from approximately 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent monoclonal antibodies that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of broadly neutralizing antibody responses.

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Editors’ note: The two novel broadly neutralising antibodies described here are the first to be discovered in more than a decade and the first to be isolated from a donor in sub-Saharan Africa. They not only target multiple strains of HIV, i.e. they are broadly neutralising, but they are very potent, binding tightly to the virus and working at minute levels compared to previously discovered neutralising antibodies. As well, they reveal a new vulnerable easier-to-reach spot on the virus that no previously known antibody targets. The unusual features of these two monoclonal antibodies provide exciting new leads for the design of HIV vaccines that would stimulate the body to make potent antibodies that would be active against a broad range of strains of the virus when a person is exposed to the virus.

 Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component. O’Keefe BR, Vojdani F, Buffa V, Shattock RJ, Montefiori DC, Bakke J, Mirsalis J, d’Andrea AL, Hume SD, Bratcher B, Saucedo CJ, McMahon JB, Pogue GP, Palmer KE. Proc Natl Acad Sci U S A. 2009; 14;106:6099-104.

To prevent sexually transmitted HIV, the most desirable active ingredients of microbicides are antiretrovirals that directly target viral entry and avert infection at mucosal surfaces. However, most promising antiretroviral entry inhibitors are biologicals, which are costly to manufacture and deliver to resource-poor areas where effective microbicides are urgently needed. Here, O’Keefe and colleagues report a manufacturing breakthrough for griffithsin, one of the most potent HIV entry inhibitors. This red algal protein was produced in multigram quantities after extraction from Nicotiana benthamiana plants transduced with a tobacco mosaic virus vector expressing griffithsin (GRFT). Plant-produced GRFT (GRFT-P) was shown as active against HIV at picomolar concentrations, directly virucidal via binding to HIV envelope glycoproteins, and capable of blocking cell-to-cell HIV transmission. GRFT-P has broad-spectrum activity against HIV clades A, B, and C, with utility as a microbicide component for HIV prevention in established epidemics in sub-Saharan Africa, South Asia, China, and the industrialized West. Cognizant of the imperative that microbicides not induce epithelial damage or inflammatory responses, the authors also show that GRFT-P is nonirritating and noninflammatory in human cervical explants and in vivo in the rabbit vaginal irritation model. Moreover, GRFT-P is potently active in preventing infection of cervical explants by HIV-1 and has no mitogenic activity on cultured human lymphocytes.

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Editors’ note: This study reports an exciting new development on the microbicide front – using Nicotiana benthamiana, a close relative of Nicotiana tobaccum (tobacco), and a tobacco mosaic virus vector to produce large quantities of a red algal protein, griffithsin, that is both directly virucidal to HIV and blocks cell-to-cell HIV transmission. This HIV entry inhibitor is unlikely to be absorbed systemically when applied topically and the vector used to produce it here is already manufacturing proteins used in clinical trials. Critically, griffithsin does not induce any of the proinflammatory cytokines known to recruit HIV target cells and promote HIV replication. These findings provide support in favour of griffithsin now advancing to human trials.

Disruption of Tight Junctions by Cellulose Sulfate Facilitates HIV Infection: Model of Microbicide Safety. Mesquita, P. Cheshenko N, Wilson S, Mhatre M, Guzman E, Fakioglu E, Keller M, and Herold B. J Infect Dis. 2009;200:599-608.

The lack of biomarkers that are predictive of safety is a critical gap in the development of microbicides. The present experiments were designed to evaluate the predictive value of in vitro models of microbicide safety. Changes in the epithelial barrier were evaluated by measuring transepithelial electrical resistance (TER) after exposure of human epithelial cells to candidate microbicides in a dual-chamber system. The significance of observed changes was addressed by challenging cultures with HIV and measuring the ability of virus to cross the epithelium and infect target T cells cultured in the lower chamber. Exposure to nonoxynol-9 (N-9) or cellulose sulfate (CS), but not 9-[2-(phosphonomethoxy)propyl] adenine (also referred to as tenofovir) or PRO2000, resulted in a rapid and sustained reduction in TER and a marked increase in HIV infection of T cells cultured in the lower chamber. Moreover, cellulose sulfate triggered nuclear factor kB activation in peripheral blood mononuclear cells and increased HIV replication in chronically infected U1 cells. Epithelial barrier disruption and enhanced viral replication may have contributed to the increased risk of HIV acquisition observed in phase 3 trials of nonoxynol-9 and cellulose sulfate. Expansion of in vitro safety testing to include these models would provide a more stringent preclinical assessment of microbicide safety and may prove to be more predictive of clinical outcomes.

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Editors’ note: The microbicide field had faced setbacks in clinical trials, including the unanticipated finding of increased HIV acquisition in one of two recent phase III clinical trials of cellulose sulphate. To date, preclinical safety studies have included in vitro (outside the human body) measurements of cell viability and effects on lactobacilli, rabbit vaginal irritation, and a few macaque studies, while phase I safety studies in humans have looked for signs of irritation, assessed colposcopic abnormalities, measured inflammatory cytokines, or cultured specific bacteria. This innovative study assessed changes in electrical resistance and effects on junctional proteins in the vaginal epithelium when each of four microbicides was applied. The authors found that polarized cells provide a relatively impervious barrier to HIV migration through the epithelium. It is encouraging that neither PMPA (tenofovir) nor PRO 2000 0.5% disrupted epithelial tight junctions or activated inflammatory pathways. Both of these candidates are currently in trials: CAPRISA 004 and MDP 301, respectively. The results of these trials will help better determine the place of this methodology in the safety evaluation of future microbicide candidates but based on this report it does warrant serious consideration.

Lemiale F, Korokhov N. Lentiviral vectors for HIV disease prevention and treatment. Vaccine. 2009; 27:3443-3449.

HIV has posed major challenges to the scientific community, both in terms of treatment and prevention. Current drug regimens, while efficacious, are expensive, inaccessible to major parts of the world, induce major side effects, and cannot prevent escape mutants due to lack of compliance and drug fatigue. In the vaccine field, recent setbacks related to the interruption and cancellation of major advanced clinical trials using adenoviral vectors have highlighted the need for new and innovative strategies. Unique features of HIV-based lentiviral vectors (LVs) and the current progress in the LV-based platform development make them an attractive alternative for the further LV-based HIV vaccine development. In preclinical studies, they have demonstrated a high degree of immunogenicity, while overcoming pitfalls faced by other viral vectors. These findings, combined with recent progress in large scale lentiviral vectors production/purification, make this strategy worth considering for further vaccine development.

Editors’ note: In making the case for further study of lentiviral vectors, this article provides a description of the evolution of HIV vaccine strategies. These aim to overcome the challenges of HIV-1 sequence diversity, latency, high rates of mutation and recombination, and infection by HIV of critical immune cells. Among the current approaches are strategies using protein-based formulations to induce neutralising antibodies and vector systems to induce cellular immunity – we will likely need both for an effective HIV vaccine.

Wang L, Cheng C, Ko SY, Kong WP, Kanekiyo M, Einfeld D, Schwartz RM, King CR, Gall JG, Nabel GJ. Delivery of adenovirus HIV vaccine vectors to the intestine induces enhanced mucosal cellular immunity. J Virol. 2009;83:7166-75.

Effective vaccines for human immunodeficiency virus-1 (HIV-1) will likely need to stimulate protective immunity in the intestinal mucosa, where HIV-1 infection causes severe CD4(+) T cell depletion . While replication-competent adenoviral vectors (rAd) can stimulate Ad-specific mucosal immunity after replication, oral delivery of replication-defective rAd vectors encoding specific immunogens has proven challenging. In this study, Wang and colleagues have systematically identified barriers to effective gut delivery of rAd vectors and identify sites and strategies to induce potent cellular and humoral immunity. Vector-mediated gene transfer by rAd5 was susceptible to low pH buffer, gastric and pancreatic proteases, and extracellular mucins. Using ex vivo organ explants, they found that transduction with rAd5 was highest in the ileum and colon compared to other intestinal segments. Transgene expression was 100-fold higher after direct surgical introduction into the ileum than observed with oral gavage, with rAd5 showing greater potency than rAd35 or rAd41 vectors. A single immunization of rAd5 encoding HIV-1 gp140B to the ileum stimulated potent CD8(+) T cell responses in the intestinal and systemic compartments, and these responses were further enhanced by intramuscular rAd5 boosting. These studies suggest that induction of primary immune responses by rAd5 gut immunization elicits potent antigen-specific mucosal responses after subsequent systemic boosting.

Editors’ note: This study is one of a series of studies aimed at determining whether different adenovirus vectors with alternative routes of administration can enhance mucosal immunity. Because the gastrointestinal tract is the predominant site of CD4 T-cell loss during the first weeks of HIV infection, these researchers hypothesized that targeted delivery of vaccines to the gut could stimulate mucosal responses that would inhibit uncontrolled viral replication and protect gut-associated lymphoid tissue (GALT). Immune responses induced by a single injection into the small bowel of a recombinant adenovirus encoding gp140B, followed by an intramuscular boost, produced strong cellular immune responses in mice. Whether this will have clinical utility in the future is anyone’s guess (a small bowel injection to prevent HIV seems quite a stretch), but it is a good model for learning more about how mucosal immune responses contribute to protection against HIV.

Wawer MJ, Makumbi F, Kigozi G, Serwadda D, Watya S, Nalugoda F, Buwembo D, Ssempijja V, Kiwanuka N, Moulton LH, Sewankambo NK, Reynolds SJ, Quinn TC, Opendi P, Iga B, Ridzon R, Laeyendecker O, Gray RH. Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial. Lancet. 2009 Jul 18;374(9685):229-37.

Observational studies have reported an association between male circumcision and reduced risk of HIV infection in female partners. Wawer and colleagues set out to assess whether circumcision in HIV-infected men would reduce transmission of the virus to female sexual partners. 922 uncircumcised, HIV-infected, asymptomatic men aged 15-49 years with CD4-cell counts 350 cells per microL or more were enrolled in this unblinded, randomised controlled trial in Rakai District, Uganda. Men were randomly assigned by computer-generated randomisation sequence to receive immediate circumcision (intervention; n=474) or circumcision delayed for 24 months (control; n=448). HIV-uninfected female partners of the randomised men were concurrently enrolled (intervention, n=93; control, n=70) and followed up at 6, 12, and 24 months, to assess HIV acquisition by male treatment assignment (primary outcome). A modified intention-to-treat (ITT) analysis, which included all concurrently enrolled couples in which the female partner had at least one follow-up visit over 24 months, assessed female HIV acquisition by use of survival analysis and Cox proportional hazards modelling. This trial is registered with ClinicalTrials.gov, number NCT00124878. The trial was stopped early because of futility . 92 couples in the intervention group and 67 couples in the control group were included in the modified ITT analysis. 17 (18%) women in the intervention group and eight (12%) women in the control group acquired HIV during follow-up (p=0.36). Cumulative probabilities of female HIV infection at 24 months were 21.7% (95% CI 12.7-33.4) in the intervention group and 13.4% (6.7-25.8) in the control group (adjusted hazard ratio 1.49, 95% CI 0.62-3.57; p=0.368). Circumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months; longer-term effects could not be assessed. Condom use after male circumcision is essential for HIV prevention.

Editors’ note: When this trial was stopped for futility because it lacked the power to answer the question of whether or not HIV-positive men who get circumcised are less likely to transmit HIV, it became clear that we would likely never know the definitive answer to this question. However, a key insight gained from the trial is the importance of sexual abstinence until complete wound healing. Premature resumption of sex may delay wound healing, increase the risk that a man may acquire a new HIV infection, and increase the risk of HIV transmission to sexual partners. These researchers previously found that 93% of HIV-positive men circumcised at CD4 › 350 cells were healed by 6 weeks post-circumcision. However, in this trial, 22% of couples resumed sex early and 25% of the men had not disclosed their HIV status, underscoring the importance of joint couple counselling and testing to learn serostatus and plan abstinence strategies for the healing period.

Mehta et al set out to evaluate whether sexual intercourse soon after adult male circumcision affected HIV risk by conducting a combined analysis of data from African trials of men who were randomized to and underwent circumcision. The authors examined two associations: early sex (intercourse <42 days after circumcision) and HIV acquisition at 3 months for the Orange Farm and Kisumu trials and at 6 months for the Rakai and Kisumu trials and incomplete wound healing at 1 month and seroconversion at 3 and 6 months for the Kisumu trial and at 6 months for the Rakai trial. Early sex was reported by 3.9% of participants in Kisumu, 5.4% in Rakai, and 22.5% in Orange Farm. HIV seroprevalence was 0.0% at 3 months and 1.9% at 6 months among 18-24-year-olds reporting early sex and 0.2% at 3 months and 0.6% at 6 months among those who did not report early sex. In pooled analyses, men reporting early sex did not have higher HIV infection risk at 3 or 6 months. In Kisumu, 16 (1.3%) men had incomplete wound healing at the 30-day visit. One (6.3%) of these seroconverted at 3 months compared with 2 (0.2%) of 1246 men with complete wound healing (P = 0.075). No association was observed between incomplete wound healing and seroconversion for Rakai participants. The authors conclude that most men delayed intercourse after circumcision. Early sex after circumcision was not associated with HIV risk, although the study power was limited. Nevertheless, men should delay intercourse to limit the potential for increased HIV risk until complete wound healing.

Editors’ note: In an excellent move, these three trials pooled their data to assess the risk to HIV-negative men of early resumption of sex after circumcision. Slightly different definitions of wound healing (e.g. Rakai: healthy scar formation, no scab or open wound; Kisumu: no scab, open wound, swelling or redness), different follow-up periods, and the low number of seroconversions observed in the 6 months after circumcision limited the power to detect meaningful associations. In all 3 trials, early sex was reported more often among men who were married or living as married. For such men, involving women in decision-making about circumcision would facilitate couple counselling about avoiding sexual intercourse during the healing period and practising safer sex thereafter.

Van de Vijver DA, Derdelinckx I, Boucher CA. Department of Virology, Erasmus MC, University Medical Centre Rotterdam, and 2Department of Medical Microbiology, University Medical Centre Utrecht, the Netherlands. Circulating HIV type 1 drug resistance will have limited impact on the effectiveness of preexposure prophylaxis among young women in Zimbabwe. J Infect Dis. 2009;199(9):1310-7.

Preexposure prophylaxis (PrEP) with antiretroviral drugs may prevent transmission of human immunodeficiency virus (HIV). The objective of van de Vijver and colleagues was to predict whether PrEP, in the presence of circulating drug resistance, will reduce the risk of infection with HIV. They used risk equations to calculate the monthly risk of infection with HIV before and after the introduction of PrEP.  Uncertainty and sensitivity analyses were performed for 2 ranges of PrEP effectiveness (40%-60% and 60%-80%). Circulating drug resistance was assumed to reduce the effectiveness of PrEP by 50%-90% and the transmissibility of HIV by 0%-30%. Parameter ranges were chosen for women 17-29 years of age from publications on HIV in Manicaland in Zimbabwe. PrEP would decrease the median risk of HIV transmission by 21%-33% (effectiveness of PrEP, 40%-60% and 60%-80%). If 50% of HIV strains are drug resistant, then the median risk reduction would be 19%-26% if drug-resistant strains were less transmissible than wild-type HIV and 12%-19% if they were equally transmissible. The risk would increase if condoms were frequently replaced with PrEP. Use of PrEP for sexual acts for which no protection is currently used would be beneficial. The public health impact of PrEP will depend on its effectiveness and on risk behaviour. Circulating drug resistance will have only a small impact on the effectiveness of PrEP.

Editors’ note: As this mathematical modelling shows, the precise impact of PrEP will depend on many factors such as its effectiveness (which remains to be determined by clinical trials in humans), the prevalence of condom use, the frequency with which condom use is replaced by PrEP when it becomes available, the number of sex acts performed, and the level of PrEP use among individuals currently not using condoms. Most discussion of drug resistance in relation to PrEP has focused on the extent to which PrEP use might create drug resistance. Interestingly, this model looked at the impact on PrEP of various levels of circulating M184V, the mutation resistant to emtricitabine or FTC. The model predicts limited impact of population-level drug resistance on PrEP’s contribution to HIV prevention, assuming that resistant virus is less fit.

Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, Bennet and colleagues outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 reverse transcriptor and protease mutations meeting these criteria (surveillance drug resistance mutations). Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, the authors follow the same procedures described previously to develop an updated list of surveillance drug resistance mutations that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated surveillance drug resistance mutation list has 93 mutations including 34 non-nucleoside reverse transcriptase protease inhibitor-resistance mutations at 15 reverse transcriptor positions, 19 non-nucleoside reverse transcriptase protease inhibitor-resistance mutations at 10 reverse transcriptor positions, and 40 protease inhibitor-resistance mutations at 18 protease positions.

Editors’ note: Population-based surveillance of transmitted drug resistance in recently infected individuals is a cornerstone of optimal treatment programmes. This WHO updated list of surveillance drug mutations is not designed to be used for individual patient management. Rather, its value lies in the fact that it permits accurate estimation of transmitted resistance as well as comparison of estimates of transmitted resistance from different regions and times.

Saxena BB, Han YA, Fu D, Rathnam P, Singh M, Laurence J, Lerner S. Sustained release of microbicides by newly engineered vaginal rings. AIDS. 2009 May;23(8):917-22.

An effective vaginal microbicide against sexual HIV transmission remains elusive, with requirements for adherence to appropriate application of effective, nontoxic products being a major deterrent. Saxena and colleagues explored methods to enable sustained release of combinations of antiretroviral microbicides, utilizing intravaginal rings composed of biosoluble Acacia gum or non-biodegradable hydrogel of 2-hydroxyethyl methacrylate and sodium methacrylate, materials approved for use by the United States Food and Drug Administration. The reverse transcriptase inhibitors TMC120, PMPA, 3’-azido-3’-deoxythymidine, and a newly characterized anti-HIV agent, Boc-lysinated betulonic acid, were incorporated into vaginal rings with different combinations. Daily and cumulative release rates of these inhibitors in ring eluates were determined by high-performance liquid chromatography, gas chromatography, or immunoassay. Anti-HIV effects were measured by assessment of p24 Gag antigen in T-cell cultures exposed to HIV-1 isolates. Drug release rates were sustained at concentrations higher than the minimum effective dose for HIV inhibition. The release was maintained for no less than 15 and 28 days from the Acacia gum and 2-hydroxyethyl methacrylate and sodium methacrylate rings, respectively. Boc-lysinated betulonic acid showed more than 90% inhibition of HIV-1 infection in H9 cells, with little toxicity to normal cells. The intravaginal rings described here are capable of efficacious drug delivery. Incorporation of several antiretroviral agents, including betulinol derivatives, which act at multiple levels of the HIV life cycle, may provide a synergistic effect to achieve higher efficacy on the inhibition of HIV infection.

Editors’ note: Although many participants in microbicide gel trials report the unexpected benefit of improved sexual satisfaction with gel use, work is proceeding with alternate microbicide delivery systems that have other potential advantages. Those include sustained delivery through a ring that could be put into position monthly, for example. Not having to insert a microbicide before each sex act would likely appeal to many women, particularly if the vaginal ring releases locally active, effective, and safe antiretroviral drugs for prevention.

Legal barriers to conducting public health research on methods of protection for anal intercourse were lifted in the United States in 2003 when the US Supreme Court invalidated all state antisodomy laws. Although research funding has been available for the development of rectal microbicides, the female condom, which has already been approved for vaginal use, has not been evaluated for anal use. Although there is no evidence that the female condom is safe for anal intercourse, it has already been taken up for off-label use by some men who have sex with men. This demonstrates the urgent need for more protection options for anal intercourse and, more immediately, the need to evaluate the safety and efficacy of the female condom for anal intercourse.

Editors’ note: Among men aged 25 to 44 years in the USA, 3.9% report having had anal sex with another man and 40% report having had anal sex with a woman. It is estimated that four times as many women in the USA practice anal sex than do men who have sex with men. Although the ‘female condom’ is recommended by some health providers and health promoters for anal sex, it has not been assessed for safety, ease of insertion (for example, should the inner ring be removed?), or efficacy. With the development and testing of rectal microbicides lagging behind vaginal products, quick studies to determine the optimal method for using the female condom during anal intercourse are needed now.