Maphoshane Nchabeleng

Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study

Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C.BACKGROUND The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. METHODS We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. FINDINGS 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76-2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20,483 copies per mL (n=33) in the vaccine group and 34,032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. INTERPRETATION The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine. FUNDING The US National Institute of Allergy and Infectious Disease and Merck and Co Inc.

Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study

Background The Phambili study, conducted in South Africa amongst a predominantly heterosexual population, evaluated the efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine. Enrollment and vaccinations were stopped, participants unblinded, and follow-up extended when the Step study evaluating the same vaccine in the Americas, Caribbean and Australia was unblinded for non-efficacy with more HIV infections amongst vaccinee than placebo recipients [ZM1]. Extensive analyses over the complete follow-up period, most of which was unblinded, are reported.BACKGROUND The HVTN 503/Phambili study, which assessed the efficacy of the Merck Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine in South Africa, was stopped when futility criteria in the Step study (assessing the same vaccine in the Americas, Caribbean, and Australia) were met. Here we report long-term follow-up data. METHODS HVTN 503/Phambili was a double-blind, placebo-controlled, randomised trial that recruited HIV-1 uninfected, sexually active adults aged 18-35 years from five sites in South Africa. Eligible participants were randomly assigned (1:1) by computer-generated random numbers to either vaccine or placebo, stratified by site and sex. Cox proportional hazards models were used to estimate HIV-1 infection in the modified intention-to-treat cohort, all of whom were unmasked early in follow-up. The trial is registered with ClinicalTrials.gov, number NCT00413725 and the South African National Health Research Database, number DOH-27-0207-1539. FINDINGS Between Jan 24, 2007, and Sept 19, 2007, 801 participants (26·7%) of a planned 3000 were randomly assigned (400 to vaccine, 401 to placebo); 216 (27%) received only one injection, 529 (66%) received only two injections, and 56 (7%) received three injections. At a median follow-up of 42 months (IQR 31-42), 63 vaccine recipients (16%) had HIV-1 infection compared with 37 placebo recipients (9%; adjusted HR 1·70, 95% CI 1·13-2·55; p=0·01). Risk for HIV-1 infection did not differ according to the number of vaccinations received, sex, circumcision, or adenovirus type 5 (Ad5) serostatus. Differences in risk behaviour at baseline or during the study, or annualised dropout rate (7·7% [95% CI 6·2-9·5] for vaccine recipients vs 8·8% [7·1-10·7] for placebo recipients; p=0·40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccine recipients. INTERPRETATION The increased risk of HIV-1 acquisition in vaccine recipients, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. We caution against further use of the Ad5 vector for HIV vaccines. FUNDING National Institute of Allergy and Infectious Diseases, Merck, and South African Medical Research Council.

Antimicrobial susceptibility patterns of selected bacteraemic isolates from South African public sector hospitals, 2010

We report on antimicrobial susceptibility surveillance data for six key bloodstream pathogens (Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Pseudomonas aeruginosa, Acinetobacter baumannii and Staphylococcus aureus) identified in public sector hospitals in South Africa during 2010. Major findings include the accelerated emergence of carbapenem resistance among K. pneumoniae and Enterobacter species, with overall susceptibility rates of 98% and 96% for ertapenem, and above 99% for meropenem and imipenem. Levels of resistance among P. aeruginosa and A. baumannii remain high in all centres, with few changes since 2009. Large decreases in piperacillin-tazobactam susceptibility rates were noted at three institutions, probably related to methodological issues. S. aureus remains a major pathogen countrywide, with between 30-60% of isolates resistant to cloxacillin [methicillin-resistant S. aureus (MRSA)]. Ongoing surveillance for antimicrobial resistance is vital, and the use of a centralised data ...

Continued Follow-Up of Phambili Phase 2b Randomized HIV-1 Vaccine Trial Participants Supports Increased HIV-1 Acquisition among Vaccinated Men.

Background The Phase 2b double-blinded, randomized Phambili/HVTN 503 trial evaluated safety and efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine vs placebo in sexually active HIV-1 seronegative participants in South Africa. Enrollment and vaccinations stopped and participants were unblinded but continued follow-up when the Step study evaluating the same vaccine in the Americas, Caribbean, and Australia was unblinded for non-efficacy. Final Phambili analyses found more HIV-1 infections amongst vaccine than placebo recipients, impelling the HVTN 503-S recall study. Methods HVTN 503-S sought to enroll all 695 HIV-1 uninfected Phambili participants, provide HIV testing, risk reduction counseling, physical examination, risk behavior assessment and treatment assignment recall. After adding HVTN 503-S data, HIV-1 infection hazard ratios (HR vaccine vs. placebo) were estimated by Cox models. Results Of the 695 eligible, 465 (67%) enrolled with 230 from the vaccine group and 235 from the placebo group. 38% of the 184 Phambili dropouts were enrolled. Enrollment did not differ by treatment group, gender, or baseline HSV-2. With the additional 1286 person years of 503-S follow-up, the estimated HR over Phambili and HVTN 503-S follow-up was 1.52 (95% CI 1.08–2.15, p = 0.02, 82 vaccine/54 placebo infections). The HR was significant for men (HR = 2.75, 95% CI 1.49, 5.06, p = 0.001) but not for women (HR = 1.12, 95% CI 0.73, 1.72, p = 0.62). Conclusion The additional follow-up from HVTN 503-S supported the Phambili finding of increased HIV-1 acquisition among vaccinated men and strengthened the evidence of lack of vaccine effect among women. Trial Registration clinicaltrials.gov NCT00413725 SA National Health Research Database DOH-27-0207-1539

Does participation in an HIV vaccine efficacy trial affect risk behaviour in South Africa

BACKGROUND Increased sexual risk behaviour in participants enrolled in HIV prevention trials has been a concern. The HVTN 503/Phambili study, a phase 2B study of the Merck Ad-5 multiclade HIV vaccine in South Africa, suspended enrollment and vaccinations following the results of the Step study. Participants were notified of their treatment allocation and continue to be followed. We investigated changes in risk behaviour over time and assessed the impact of study unblinding. METHODS 801 participants were enrolled. Risk behaviours were assessed with an interviewer-administered questionnaire at 6-month intervals. We assessed change from enrolment to the first 6-month assessment pre-unblinding and between enrolment and at least 6 months post-unblinding on all participants with comparable data. A one-time unblinding risk perception questionnaire was administered post-unblinding. RESULTS A decrease in participants reporting unprotected sex was observed in both measured time periods for men and women, with no differences by treatment arm. At 6 months (pre-unblinding), 29.6% of men and 35.8% of women reported changing from unprotected to protected sex (p<0.0001 for each). Men (22%) were more likely than women (14%) to report behaviour change after unblinding (p=0.009). Post-enrolment, 142 (45%) of 313 previously uncircumcised men underwent medical circumcision. 663 participants completed the unblinding questionnaire. More vaccine (24.6%) as compared to placebo recipients (12.0%) agreed that they were more likely to get HIV than most people (p<0.0001), and attributed this to receiving the vaccine. CONCLUSION We did not find evidence of risk compensation during this clinical trial. Some risk behaviour reductions including male circumcision were noted irrespective of treatment allocation.

Antimicrobial susceptibility patterns of selected invasive pathogens from public sector hospitals in South Africa, 2007

Retrospective antibiotic surveillance data of selected invasive pathogens isolated from blood and cerebrospinal fluid at public sector hospitals in South Africa in 2007 are presented. Antimicrobial susceptibilities were determined according to the 2007 Clinical and Laboratory Standards Institute criteria. Klebsiella pneumoniae remains a highly resistant pathogen, with approximately half of all strains producing extended-spectrum beta-lactamases. All laboratories reported considerable resistance among Acinetobacter spp. Approximately 50-60% of Staphylococcus aureus isolates from blood were resistant to cloxacillin. Among Streptococcus pneumoniae isolates from blood and cerebrospinal fluid, resistance to penicillin ranged from 0% to 6% at most laboratories and 16-42% of isolates were classified with intermediate resistance to penicillin. Resistance to ceftriaxone in S. pneumoniae was rare.

Genotypic diversity of Mycobacterium tuberculosis in Pretoria

Tuberculosis is a global health problem. Continuous efforts are needed to understand the genetic diversity and geographical distribution of Mycobacterium tuberculosis. The objective of this study was to determine the genetic diversity of M. tuberculosis strains in Soshanguve, Pretoria. Eighty-nine isolates that were sputum culture-positive in Mycobacterium Growth Indicator Tube 960®, and positively identifed by Accuprobe Probe assay as M. tuberculosis complex, were used in the study. The samples were sub-cultured on Lowenstein-Jensen (L-J) slants to ensure purity. Spoligotyping was performed, with slight modifcations according to the manufacturer’s specifcations. Genotypic data were compared to the international spoligotyping database 4 (SpolDB4) and that suggested by Streicher et al. Spoligotyping identifed 12 genotypes. Of the 89 isolates studied, 75 could be grouped into 11 clusters. The Beijing genotype family formed the largest group, with 21 isolates (28%). The remaining isolates were distributed am...

The HVTN503/Phambili HIV vaccine trial: a comparison of younger and older participants.

By comparing younger to older participants enrolled in a HIV vaccine efficacy trial, we aimed to gain insights into the inclusion of adolescents in future trials. This was a sub-analysis of a multisite HIV vaccine randomized clinical trial in South Africa, conducted January–September 2007. Motivations for trial enrolment, social harms, adverse events and loss to follow-up were compared between younger (18–20 years old) and older participants (21–35 years old). Both younger (n = 238) and older participants (n = 563) were equally likely to report enrolling for altruistic reasons. Younger females were less likely than older participants to join for trial reimbursement (p = 0.005), while younger males were more likely to enrol because the vaccine may provide protection from HIV-acquisition (p < 0.001). There were no significant differences in the number of social harms reported. Compared to males over 20 years old, 18–20-year-old females were less likely to experience adverse events (OR = 0.1, CI 0.01–0.80) and no more likely to be lost to follow-up (OR = 0.7, CI 0.39–1.25), while 18–20-year-old males were no more likely to experience adverse events (OR = 1.3, CI 0.58–2.83) or loss to follow-up (OR = 0.8, CI 0.51–1.41). Our data support the inclusion of younger participants who are at risk for HIV in future HIV vaccine efficacy trials.

P15-08. Did unblinding affect HIV risk behaviour and risk perception in the HVTN503/Phambili study?

Address: 1Perinatal HIV Research Unit, Soweto, South Africa, 2Desmond Tutu HIV Foundation, Cape Town, South Africa, 3Aurum Institute for Health Research, Cape Town, South Africa, 4Medunsa HIV Clinical Research Unit (MeCRU), Tswane, South Africa, 5Centre for the AIDS Programme for Research in South Africa (CAPRISA), Durban, South Africa, 6Statistical Center for HIV/AIDS Research and Prevention, FHCRC, Seattle, WA, USA, 7National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD USA and 8HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA * Corresponding author

Molecular characterisation of resistant Mycobacterium tuberculosis isolates from Dr George Mukhari Hospital, Pretoria, South Africa

.Control of the TB epidemic depends on adequate treatment. Although chemotherapy has been an effective tool in the management and control of TB previously, development of drug resistance poses a serious challenge in the control of the disease. Potential factors contributing to development of drug resistance include inadequate treatment regimens prescribed by health staff, poor case holding of TB patients, poor drug supply, poor drug quality, patient error in following prescribed regimens and misuse of TB drugs including non-compliance.5 TB is treated using three front line agents, isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA), and one of the second line anti-TB drugs, streptomycin (SM) and ethambutol (EMB).6 Multidrug-resistant TB (MDR-TB), defined as resistance to at least INH and RIF with or without resistance to other drugs, has been reported in different parts of the world.7 However, the