RESEARCH METHODOLOGY
5.5 DESCRIPTION OF THE MICROBICIDE TRIAL (HPTN035 STUDY)
(http://www.hptn.org/research_studies/hptn035.asp). HPTN 035 was conducted by a team of African and U.S. researchers associated with the Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network established and funded in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID), with co-funding by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). HPTN035 was a multi-center clinical research study that was aimed at evaluating the safety and effectiveness of two candidate vaginal microbicides, BufferGel and 0.5% PRO 2000/5 Gel (P), for the prevention of HIV infection in women. The study was conducted between February 2005 and September 2008 through a partnership involving US and African researchers and was conducted in various countries including Malawi, South Africa, United States, Zambia and Zimbabwe. As mentioned previously, in Malawi the study was conducted at two sites namely UNC Lilongwe and Johns Hopkins Project in Blantyre.
The primary objectives of this study were as follows:
• To evaluate the safety of Buffergel and 0.5% PRO 2000/5 Gel (P) when applied intravaginally by women at risk for sexually-transmitted HIV infection.
• To estimate the effectiveness of Buffergel and 0.5% PRO 2000/5 Gel (P) in preventing HIV infection among at-risk women.
The secondary objectives included the following:
• Estimating the effectiveness of Buffergel and 0.5% PRO 2000/5 Gel (P) in preventing the following among women at risk for sexually-transmitted HIV infection: bacterial vaginosis, chlamydia infection, genital ulcer disease, gonorrhea infection, herpes simplex virus-2 infection, pregnancy, syphilis infection, trichomoniasis and
• Assessing the acceptability of Buffergel and 0.5% PRO 2000 Gel (P) for use as a vaginal microbicide.
HPTN 035 was as a combination Phase II/Phase IIb trial designed to determine whether either candidate microbicide had sufficient promise to be considered for testing in a larger Phase III trial. According to the WHO/UNAIDS/IAVI Expert Group (2007), design and implementation of phase IIB 'test of concept' trials (phase IIB-TOC), which are also referred to as 'proof of concept' trials, is important in efforts to accelerate HIV vaccine and microbicide development.
Phase IIb trials provide a flexible approach to screen various AIDS vaccine candidates and to direct further vaccine development in a shorter timeframe. This accelerates the development of the most promising vaccine candidates or approaches, thereby ensuring optimal usage of the limited resources available for large efficacy trials (Excler, Rida, Priddy, Fast & Koff, 2007).
It was hoped that by directing research efforts and accelerating the development of candidate vaccines or microbicides, the Phase IIb trials would lead to the saving of human lives by ensuring that effective products are licenced for marketing within the shortest possible period.
In the HPTN035 trial, the first primary objective of the microbicide study which was related to safety was the focus of the Phase II portion of the study. Taken together, the two primary objectives of the study relating to safety and effectiveness, formed the Phase IIb portion of the study. The Phase II portion of the study involved intensive safety evaluations among the first 799 women enroled. The Phase IIb portion involved the first 799 women and an additional 2,300 women.
The study was a four-arm, multi-site, randomised controlled trial comparing BufferGel and 0.5% PRO 2000/5 Gel (P) with a placebo gel and with no gel. The three study gel arms were double-blinded. HPTN 035 was not designed to compare the two gels, but rather to compare
each against a placebo gel with no active ingredient, and with no gel at all. Women took part in the study for 12 to 30 months (20 months on average) and completed monthly clinic visits throughout their participation. The population for the study consisted of sexually active HIV- uninfected women above 18 years from the following study sites: Blantyre, Malawi; Lilongwe, Malawi; Durban, South Africa; Hlabisa, South Africa; Lusaka, Zambia; Harare, Zimbabwe;
Philadelphia, USA
In total 3,099 HIV-negative women were recruited at seven clinical research sites in Malawi, South Africa, Zambia, Zimbabwe and the United States. Participants were randomly assigned in approximately equal numbers to one of four study groups: BufferGel, PRO 2000 gel, placebo gel, and no gel. Women assigned to the three gel groups were instructed to apply gel up to one hour before sexual intercourse using pre-filled applicators. The three gels were similar in appearance and packaged in identical applicators so that neither researchers nor participants would know which women were using which gel during the study. Participants assigned to the three study gel groups were instructed to apply a single dose of their randomly assigned product − BufferGel, 0.5% PRO 2000/5 Gel (P), or placebo gel − intravaginally up to 60 minutes before each act of vaginal intercourse using single-use, pre-filled applicators.
Participants in all four groups received ongoing HIV risk reduction counselling, condoms, and diagnosis and treatment of sexually transmitted diseases.
According to Microbicide Trials Network [MTN] (2009), BufferGel, developed by ReProtect, Inc., U.S.A., was developed as a vaginal defense enhancer designed to boost the natural acidity of the vagina in the presence of seminal fluid. Semen reduces the acidity of the vagina, making it more receptive for pathogens that cause sexually transmitted infections, such as HIV. PRO 2000, developed by Indevus Pharmaceuticals, Inc, in U.S.A., is an entry/fusion inhibitor designed to hamper HIV’s ability to attach to and infect healthy cells (MTN, 2009). In
HPTN035, researchers tested the low dose 0.5 percent concentration of PRO 2000. Both candidate microbicides had undergone extensive laboratory study and, before HPTN 035, were tested in other early-phase human safety clinical studies involving women in both developed and developing countries. The pre-clinical laboratory research suggested that the gels may reduce the sexual transmission of HIV, while the early-phase clinical studies indicated the gels were well-tolerated and safe and could be considered for further testing in larger trials (MTN, 2009).
In terms of participant safety, a detailed informed consent process was put in place to ensure that participants understood the procedures, risks and benefits of the study, and that they were not obliged to participate and could leave the study, without consequence, at any time. The informed consent documents, while being site specific, were developed from a single template provided by the sponsor. At each site, researchers were responsible for ensuring that the informed consent forms were relevant for the specific site and community advisory boards (CABs) at each site were responsible for reviewing the forms and providing inputs.
Participant safety was monitored by the researchers and clinical staff at each site. Designated researchers and staff comprised the study’s Protocol Safety Review Team at each site. The team was expected to ensure that all adverse events were reported to the central data processing unit and that all serious adverse events were reported to the local ethics committees, drug regulatory authorities and also the study’s central monitoring unit. The study also had a central independent Data and Safety Monitoring Board (DSMB) which was responsible for reviewing study data after every four months throughout the duration of the study. According to evidence available through the HPTN035 protocol, the research team members were expected to play an important role in reducing risky behaviours among participants by providing free condoms, risk reduction counselling, and testing and treatment for STIs. Nevertheless, some women were expected to become infected with HIV while participating in the study, and these women were
given the option to remain in the study if they wished. Women who acquired HIV during the study were counselled and referred by study staff to local medical care and support
programmes offering psychosocial services and HIV care, including antiretroviral therapy (MTN, 2009).
Upon conclusion of the HPTN 035 trial in September 2008, it was established that 194 out of 3099 women in the study had become infected with HIV. Of these infections, 36 occurred in the PRO 2000 group, 54 in the BufferGel group, 51 in the placebo gel group, and 53 among those who did not use gel (MTN, 2009). Based on these data, PRO 2000 was 30 percent effective compared with no gel. BufferGel had no detectable effect on preventing HIV infection. Overall, the researchers concluded that the effect of the two test products was not statistically significant. Both microbicides were found to be well-tolerated and did not result in any significant adverse events. The study demonstrated for the first time the promise of a vaginal microbicide gel for preventing HIV infection in women. In the final analysis, although the volunteers in the PRO 2000 study arm had a 30 percent lower rate of HIV infection compared with the other three study groups, this finding was not statistically significant.
Approximately 33 percent efficacy would have been considered statistically significant (MTN, 2009). The researchers therefore concluded that additional clinical evidence was necessary for them to more conclusively determine whether PRO 2000 prevents HIV infection in women. Of note was the fact that HPTN 035 had successfully retained a majority of its enrolees, with 94 percent completing their participation (MTN, 2009). Throughout the study, participants reported regular use of the investigational gels (81 percent of sex acts), and nearly all (99 percent) said they would use the products if approved for HIV prevention. Reported condom usage also was high throughout the course of the trial, with 74 percent of women reporting condom usage during most of their sexual encounters (MTN, 2009).