The fourth generation AlereTM HIV Combo rapid test improves detection of acute infection in MTN-003 (VOICE) samples.

BACKGROUND: Early and accurate detection of HIV is crucial when using pre-exposure prophylaxis (PrEP) for HIV prevention to avoid PrEP initiation in acutely infected individuals and to minimize the risk of drug resistance in individuals with breakthrough infection. OBJECTIVE: To determine if fourth-generation antigen/antibody (Ag/Ab) rapid diagnostic tests (RDT) would have detected HIV infection earlier than the third-generation RDT used in MTN-003 (VOICE). STUDY DESIGN: 5029 VOICE participants were evaluated with third-generation Alere Determine™ HIV-1/2, OraQuick ADVANCE® Rapid HIV-1/2, Uni-Gold™ Recombigen® HIV-1/2 and Bio-Rad GS HIV-1/2+O EIA; and fourth-generation Alere Determine™ HIV-1/2 Ag/Ab Combo, Conformité Européene (CE)-Marked Alere™ HIV Combo and Bio-Rad HIV Combo Ag/Ab EIA. Multispot®, GS HIV-1 Western Blot (WB) and Geenius™ (Bio-Rad) were also evaluated. RESULTS: Of 57 antibody-negative pre-seroconversion plasma samples with HIV RNA >20 copies/mL identified, 16 (28%) were reactive by CE-Marked Alere™ HIV Combo (1 Ab; 9 Ag; 6 Ag/Ab reactive) and 4 (7%) by Alere Determine™ HIV-1/2 Ag/Ab Combo (2 Ab; 2 Ag; 0 Ag/Ab reactive) (p=0.0005). Multispot® confirmed only 1 of 16 acute infections while WB and Geenius™ confirmed none. GS HIV Combo Ag/Ab EIA identified 27 of 57 (47%) pre-seroconversion RNA-positive samples. CONCLUSION: In VOICE, 28% of infections missed by current third-generation RDT would have been identified with the use of CE-Marked Alere™ HIV Combo. Geenius™, Multispot® and WB were all insensitive (<10%) in confirming infections detected by fourth-generation assays. An improved diagnostic algorithm that includes a fourth-generation RDT with HIV RNA testing will be essential for efficiently identifying seroconverters on PrEP.

Obtaining valid laboratory data in clinical trials conducted in resource diverse settings: lessons learned from a microbicide phase III clinical trial.

BACKGROUND: Over the last decade several phase III microbicides trials have been conducted in developing countries. However, laboratories in resource constrained settings do not always have the experience, infrastructure, and the capacity to deliver laboratory data meeting the high standards of clinical trials. This paper describes the design and outcomes of a laboratory quality assurance program which was implemented during a phase III clinical trial evaluating the efficacy of the candidate microbicide Cellulose Sulfate 6% (CS) [1]. METHODOLOGY: In order to assess the effectiveness of CS for HIV and STI prevention, a phase III clinical trial was conducted in 5 sites: 3 in Africa and 2 in India. The trial sponsor identified an International Central Reference Laboratory (ICRL), responsible for the design and management of a quality assurance program, which would guarantee the reliability of laboratory data. The ICRL provided advice on the tests, assessed local laboratories, organized trainings, conducted supervision visits, performed re-tests, and prepared control panels. Local laboratories were provided with control panels for HIV rapid tests and Chlamydia trachomatis/Neisseria gonorrhoeae (CT/NG) amplification technique. Aliquots from respective control panels were tested by local laboratories and were compared with results obtained at the ICRL. RESULTS: Overall, good results were observed. However, discordances between the ICRL and site laboratories were identified for HIV and CT/NG results. One particular site experienced difficulties with HIV rapid testing shortly after study initiation. At all sites, DNA contamination was identified as a cause of invalid CT/NG results. Both problems were timely detected and solved. Through immediate feedback, guidance and repeated training of laboratory staff, additional inaccuracies were prevented. CONCLUSIONS: Quality control guidelines when applied in field laboratories ensured the reliability and validity of final study data. It is essential that sponsors provide adequate resources for implementation of such comprehensive technical assessment and monitoring systems. TRIAL REGISTRATION: ClinicalTrials.gov NCT00153777 and Current Controlled Trials ISRCTN95638385.

Validation of rapid HIV antibody tests in 5 African countries.

The sensitivity and specificity of 3 rapid HIV antibody tests were assessed at 5 clinical trial sites in Africa and 1 site in the United States using a minimum of 100 HIV antibody positive samples and 100 HIV antibody negative samples at each site. The overall sensitivity and specificity for the OraSure OraQuick, Abbott Determine, and Trinity Unigold tests were 99.3%, 99.8%, and 98.5%, respectively, and 99.3%, 99.4%, and 99.5%, respectively. There were no instances at any site in which false-negative or false-positive results were obtained for the same sample on more than 1 rapid test kit. The results of this study provide assurance that for these diverse sites in Africa, the accuracy of these kits is quite good. Given the excellent accuracy, relatively fast turnaround time, and minimal infrastructure required, these rapid tests for HIV antibody provide a very attractive and accurate testing format.

Experiences in conducting multiple community-based HIV prevention trials among women in KwaZulu-Natal, South Africa.

BACKGROUND: South Africa, with its scientific capacity, good infrastructure and high HIV incidence rates, is ideally positioned to conduct large-scale HIV prevention trials. The HIV Prevention Research Unit of the South African Medical Research Council conducted four phase III and one phase IIb trials of women-initiated HIV prevention options in KwaZulu-Natal between 2003 and 2009. A total of 7046 women participated, with HIV prevalence between 25% and 45% and HIV incidence ranging from 4.5-9.1% per year. Unfortunately none of the interventions tested had any impact on reducing the risk of HIV acquisition; however, extremely valuable experience was gained, lessons learned and capacity built, while the communities gained associated benefits. EXPERIENCE: Our experience in conducting these trials ranged from setting up community partnerships to developing clinical research sites and dissemination of trial results. Community engagement included setting up community-based research sites with approval from both political and traditional leaders, and developing community advisory groups to assist with the research process. Community-wide education on HIV/sexually transmitted infection prevention, treatment and care was provided to over 90,000 individuals. Myths and misconceptions were addressed through methods such as anonymous suggestion boxes in clinic waiting areas and intensive education and counselling. Attempts were made to involve male partners to foster support and facilitate recruitment of women. Peer educator programmes were initiated to provide ongoing education and also to facilitate recruitment of women to the trials. Recruitment strategies such as door-to-door recruitment and community group meetings were initiated. Over 90% of women enrolled were retained. Community benefits from the trial included education on HIV prevention, treatment and care and provision of ancillary care (such as Pap smears, reproductive health care and referral for chronic illnesses). Social benefits included training of home-based caregivers and sustainable ongoing HIV prevention education through peer educator programmes. CHALLENGES: Several challenges were encountered, including manipulation by participants of their eligibility criteria in order to enroll in the trial. Women attempted to co-enroll in multiple trials to benefit from financial reimbursements and individualised care. The trials became ethically challenging when participants refused to take up referrals for care due to stigma, denial of their HIV status and inadequate health infrastructure. Lack of disclosure of HIV status to partners and family members was particularly challenging. Some of the ethical dilemmas put to the test our responsibility as researchers and our obligation to provide health care to research participants. CONCLUSION: Conducting these five trials in a period of six years provided us with invaluable insights into trial implementation, community participation, recruitment and retention, provision of care and dissemination of trial results. The critical mass of scientists trained as clinical trialists will continue to address the relentless HIV epidemic in our setting and ensure our commitment to finding a biomedical HIV prevention option for women in the future.