Safety and Immunogenicity Study of Multiclade HIV-1 Adenoviral Vector Vaccine Alone or as Boost following a Multiclade HIV-1 DNA Vaccine in Africa

We conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replication-defective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIV-uninfected African adults.Volunteers were randomized to 4 groups receiving the rAd5 vaccine intramuscularly at dosage levels of 1×10(10) or 1×10(11) particle units (PU) either alone or as boost following 3 injections of the DNA vaccine given at 4 mg/dose intramuscularly by needle-free injection using Biojector® 2000. Safety and immunogenicity were evaluated for 12 months. Both vaccines were well-tolerated. Overall, 62% and 86% of vaccine recipients in the rAd5 alone and DNA prime - rAd5 boost groups, respectively, responded to the HIV-1 proteins by an interferon-gamma (IFN-γ) ELISPOT. The frequency of immune responses was independent of rAd5 dosage levels. The highest frequency of responses after rAd5 alone was detected at 6 weeks; after DNA prime - rAd5 boost, at 6 months (end of study). At baseline, neutralizing antibodies against Ad5 were present in 81% of volunteers; the distribution was similar across the 4 groups. Pre-existing immunity to Ad5 did not appear to have a significant impact on reactogenicity or immune response rates to HIV antigens by IFN-γ ELISPOT. Binding antibodies against Env were detected in up to 100% recipients of DNA prime - rAd5 boost. One volunteer acquired HIV infection after the study ended, two years after receipt of rAd5 alone.The HIV-1 rAd5 vaccine, either alone or as a boost following HIV-1 DNA vaccine, was well-tolerated and immunogenic in African adults. DNA priming increased the frequency and magnitude of cellular and humoral immune responses, but there was no effect of rAd5 dosage on immunogenicity endpoints.ClinicalTrials.gov NCT00124007

Associations of sexual risk taking among Kenyan female sex workers after enrollment in an HIV-1 prevention trial.

Background: Female sex workers (FSWs) often lack the ability to negotiate safer sex and are at high risk for HIV-1 infection and sexually transmitted infections (STIs). Methods: Seronegative FSWs were enrolled in an STI/HIV-1 prevention trial in Nairobi, Kenya. Demographics and sexual risk taking were assessed every 3 months. Predictors of reduced risk taking were defined using multivariate logistic regression. Results: Four hundred sixty-six FSWs were enrolled and followed for just over 2 years each. A spectrum of sex work was apparent: FSWs working in night clubs were younger, charged more for sex, and used condoms more frequently; FSWs working from home were older, charged less, and used condoms the least; and those working in bars were intermediate. Increases in reported condom use were most significant and sustained for FSWs working from home and charging less for sex and were poorly maintained for bar-based FSWs. Self-reported lower condom use, higher client numbers, and alcohol use were associated with higher STI rates. Conclusions: Home-based FSWs and those charging less for sex used condoms the least at baseline but showed the greatest and most sustained improvements over time. Potential response heterogeneity in FSW subgroups should be considered in the design of HIV-1 prevention programs

Monthly Antibiotic Chemoprophylaxis and Incidence of Sexually Transmitted Infections and HIV-1 Infection in Kenyan Sex Workers

Context Sexually transmitted infections (STIs) are common in female sex workers (FSWs) and may enhance susceptibility to infection with human immunodeficiency virus type 1 (HIV-1). Objective To examine regular antibiotic prophylaxis in FSWs as a strategy for reducing the incidence of bacterial STIs and HIV-1. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted between 1998-2002 among FSWs in an urban slum area of Nairobi, Kenya. Of 890 FSWs screened, 466 who were seronegative for HIV-1 infection were enrolled and randomly assigned to receive azithromycin (n = 230) or placebo (n = 236). Groups were well matched at baseline for sexual risk taking and STI rates. Intervention Monthly oral administration of 1 g of azithromycin or identical placebo, as directly observed therapy. All participants were provided with free condoms, risk-reduction counseling, and STI case management. Main Outcome Measures The primary study end point was incidence of HIV-1 infection. Secondary end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus ducreyi, as well as bacterial vaginosis. Analysis of herpes simplex virus type 2 (HSV-2) infection was performed post hoc. Results Seventy-three percent of participants (n = 341) were followed up for 2 or more years or until they reached an administrative trial end point. Incidence of HIV-1 did not differ between treatment and placebo groups (4% [19 cases per 473 person-years of follow-up] vs 3.2% [16 cases per 495 person-years of follow-up] rate ratio [RR], 1.2; 95% CI, 0.6-2.5). Incident HIV-1 infection was associated with preceding infection with N gonorrhoeae (rate ratio [RR], 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9). There was a reduced incidence in the treatment group of infection with N gonorrhoeae (RR, 0.46; 95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95% CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI, 0.40-0.78). The seroprevalence of HSV-2 infection at enrollment was 72.7%, and HSV-2 infection at baseline was independently associated with HIV-1 acquisition (RR, 6.3; 95% CI, 1.5-27.1). Conclusions Despite an association between bacterial STIs and acquisition of HIV-1 infection, the addition of monthly azithromycin prophylaxis to established HIV-1 risk reduction strategies substantially reduced the incidence of STIs but did not reduce the incidence of HIV-1. Prevalent HSV-2 infection may have been an important cofactor in acquisition of HIV-1. Sexually transmitted infections (STIs) are important cofactors in the human immunodeficiency virus type 1 (HIV-1)/AIDS pandemic. In HIV-infected individuals, not only may symptomatic and asymptomatic STIs enhance sexual transmission of HIV-1 by increasing virus shedding from the genital tract,1-3 but at the same time HIV-1 infection itself increases susceptibility to STIs.4 There is also considerable evidence that STIs may increase HIV-1 susceptibility in uninfected individuals,5,6 although differentiating cause from effect is more difficult in this situation.7 Prevention or control of STIs as a strategy for preventing HIV-1 transmission has met with mixed success. Improved syndromic management of STIs reduced HIV-1 incidence in communities in Mwanza, Tanzania,8 but in Uganda neither a similar strategy nor antibiotic mass-treatment of whole communities had an impact on HIV-1 incidence.9,10 Factors contributing to the lack of efficacy in the Uganda trials may have included the greater effectiveness of continuously available STI treatment services11 and the reduction in spread of HIV-1 during primary infection due to counseling given at the time of STI therapy.12 Another important factor may be that the Tanzanian study was performed early in the epidemic, when community prevalence of HIV-1 was below 5%. The Ugandan studies, by contrast, were performed later, in communities with much higher prevalences of HIV-1 (range, 10%-16%).11,13 Curable STIs may play a lesser role in HIV-1 transmission in the context of a mature epidemic, because most transmission occurs in the context of stable partnerships, reducing the potential impact of STI prevention and treatment.14 Interventions based on prevention or control of STIs may therefore be more effective in communities in the early stages of an epidemic13 or in subgroups at high risk of STIs.3 Female sex workers (FSWs) constitute an important vulnerable group in the acquisition and transmission of both HIV-1 infection and STIs15 but may be excluded from household-based community studies of STI control.16 It has therefore been suggested that interventions for control of STIs should target these women specifically.17 Studies in Kenya have shown that certain FSW cohorts have an annual HIV incidence of 16% to 50%18,19 and a high incidence of cervicitis due to infection with Neisseria gonorrhoeae and Chlamydia trachomatis.18 This may be partly attributed to low levels of condom use and poor access to STI counseling and treatment services.20 We hypothesized that these high rates of bacterial STI and HIV-1 infection would make FSWs an ideal population in which to test antibiotic prophylaxis of common genital tract infections as an HIV-1 prevention strategy. Since the use of prophylactic antibiotics by FSWs has been associated with increased sexual risk taking,21 we elected to test this intervention in a blinded fashion

Brief report: Reduced HIV risk-taking and low HIV incidence after enrolment and risk-reduction counselling in a sexually transmitted disease prevention trial in Nairobi, Kenya

There is an urgent need in sub-Saharan Africa to develop more effective methods of HIV prevention, including improved strategies of sexually transmitted infection (STI) prevention or an HIV vaccine. The efficacy of these strategies may be tested through clinical trials within cohorts at high risk for STI and HIV, such as female commercial sex workers. For ethical reasons, standard HIV prevention services, including access to free condoms, risk-reduction counseling, and STI therapy, will generally be offered to all study subjects. Because study subjects would often not otherwise have access to these prevention services, it is possible that enrollment in such clinical trials will itself reduce incidence rates of STI and HIV below expected levels, reducing the power to test the efficacy of the randomized intervention. We show that the provision of standard HIV prevention services as part of a randomized STI/HIV prevention trial is temporally associated with a dramatic reduction in sexual risk-taking, and that this reduction is directly associated with reduced STI incidence. This finding should be considered in the design of clinical trials with an endpoint of HIV incidence, in particular HIV preventive vaccine trials