Conducting international clinical trials requires patience, dedication, and years of diligent work — and all this before the first study participant ever receives treatment. But thanks to years of such preparatory work by the Hutchinson Center's Statistical Center for HIV/AIDS Research and Prevention (SCHARP), the HIV Prevention Trials Network (HPTN) is now enrolling participants in two multinational trials designed to test non-vaccine methods for preventing the spread of HIV, the virus that causes AIDS. With as many as seven years spent developing the trials — referred to as HPTN 035 and HPTN 052 — reaching the enrollment stage is a cause for celebration. Every day spent planning and preparing for a trial is another day that disease sufferers must wait to obtain lifesaving treatments, thus beginning enrollment marks an important transition from planning into action.
SCHARP serves as the Statistical Data Management Center, or primary statistical center, for many HPTN trials as well as for the HIV Vaccine Trials Network (HVTN). The HPTN is a worldwide clinical trials network that develops and tests the safety and efficacy of nonvaccine interventions to prevent the transmission of HIV, while the HVTN is a global network that tests preventive HIV vaccines. Both networks were established in 1999 and grew out of the HIV Network for Prevention Trials, which was established in 1993 by a grant from the National Institutes of Health's Division of AIDS.
HPTN 035 is a Phase II/IIb trial (see sidebar) to determine the effectiveness of two vaginal microbicide gels — topically applied substances developed specifically to prevent the transmission of HIV and other sexually-transmitted infections — in preventing the transmission of HIV through vaginal intercourse. In the study, HIV-negative women receive one of two candidate microbicides, which they insert intra-vaginally with an applicator before sex, or a placebo gel that does not contain any active ingredient. A fourth group of women does not receive any gel. Women in all four groups receive risk-reduction counseling and condoms.
HPTN 052 examines the effectiveness of anti-retroviral therapy (ART) on blocking HIV transmission within couples when one of the partners is HIV positive and the other is not. ARTs are drugs that act against a class of viruses called retroviruses, of which HIV is a member. "In our study, all the [ART] drugs we're using have been approved in this country, but the difference is now they are being tried as a prevention technique to keep the other partner from being infected," said Melissa Kaufman, a project manager for HPTN 052. All the couples receive primary care and couples counseling addressing how to reduce their risk of HIV transmission, but half the couples get ART drugs from the outset of the study while the other half will receive ART only when the infected partner shows signs of illnesses associated with HIV/AIDS or when their CD4 cell count drops below a certain threshold.
HPTN 035 includes seven sites in the sub-Saharan African countries of Malawi (Lilongwe and Blantyre), Zimbabwe, South Africa, Tanzania, Zambia and a site in Philadelphia, while HPTN 052 has sites in Brazil (Rio de Janeiro and Porto Alegre), India (Chennai and Pune), Malawi (Lilongwe and Blantyre), Thailand, Zimbabwe, and one in Boston. Currently, HPTN 035 has enrolled close to 100 participants at the sites in Philadelphia, South Africa, and in Lilongwe, Malawi. In HPTN 052, enrollment has started at the Lilongwe site. Each study will eventually enroll a total of around 3,500 participants across all sites.
Cultural and ethical challenges
As part of the preparation for the trials, SCHARP operations staff travel to each site to conduct training sessions for the local site staff. "Usually the trainings are pretty involved. They're anywhere from four to six days, and we basically do all the training on the data management and data collection," said Missy Cianciola, a project manager for HPTN 035. When the study is completed, SCHARP faculty statisticians like Dr. Benoît Mâsse, who is the lead statistician for HPTN 052 and co-lead statistician with Dr. Barbra Richardson for HPTN 035, evaluate the statistical data to determine the effectiveness of the prevention techniques. SCHARP also has input in the study designs, formulates the data-analysis plans and regularly conducts study-monitoring reviews to ensure that the study is progressing according to plan. "This is one of the benefits of being a part of a large network like HPTN," Mâsse said. "You can check on the mechanics of the study often because you have the people and the system set up to do that."
Conducting international HIV-prevention trials involves many challenges that domestic trials do not. "A lot of places we go have nothing, not even a building," Mâsse said. Hlabisa, South Africa, is one such primitive site that maintains a tribal infrastructure. In order for the trial to proceed, the tribal chief must endorse the study in a formal ceremony. For HPTN 035, this included the principal investigator for the study personally bestowing a goat upon the tribal chief. Also, many people in Africa still use traditional medicine. "There, it's just as common for people to go to a medicine man as it is to go to a regular doctor," said Leslie Cottle, who is also a project manager for HPTN 052. An important aspect in planning the trials is ensuring that they work with the social norms of the community being studied.
In addition to the challenges that a primitive infrastructure presents, there are ethical issues inherent in international trials that do not accompany domestic clinical trials. To begin with, there is an ethical trade-off of sorts involved in simply planning the trials. It is critically important to design the trial properly to minimize ethical conflicts and to ensure that the study results are valid and interpretable. However, while researchers plan, every day thousands of people are infected with the disease in these countries, many of which have an HIV prevalence higher than 30 percent. In fact, prospective study participants often test positive for HIV for the first time during the screening process, which is an especially difficult issue for site staff to deal with.
Outreach and education
Another ethical issue is making sure that participants are fully informed about the clinical trials process. "So much effort goes into explaining the concept of informed consent, how it's a participant's choice [to participate] throughout the study and also the concept of randomization and how that works. People have put a lot of work into that," Cianciola said. It is important that participants understand that they may or may not receive the experimental treatment and that even if they do, there is no guarantee of the treatment's effectiveness. These issues are especially difficult to explain to people who have limited knowledge of Western medicine.
The HPTN study sites use several methods to overcome these ethical challenges. "There's been a lot of work to develop different pictorial tools and other methods to make sure that the information gets across to the participants," Cianciola said. To help develop a good relationship between community members and the study administrators, the people who work at the study site are mostly from the local community, including the investigator in charge and most of the nurses, counselors and other staff. The HPTN places a strong emphasis on involving the community in the entire trial process from planning to completion. "Site staff members do a lot of outreach and education before a participant ever shows up at the clinic. So much work goes into educating the community on a large scale," said Corey Leburg, who, like Cianciola, is one of the project managers for HPTN 035.
The principal investigators for the statistical data centers of HPTN and HVTN are Dr. Thomas Fleming and Dr. Steven Self, respectively. Since its inception, HPTN has completed 18 trials, while six are ongoing and four others are scheduled to begin this fall. The SCHARP team recently completed a grant application to extend the HPTN another seven years. This grant also includes plans to develop at least one more network in addition to the existing HPTN and HVTN which will focus exclusively on clinical trials of microbicides for HIV prevention. "I think a microbicide has got a better chance of getting to market first, and of being effective, than an HIV vaccine does," Mâsse said.
In addition to the statistical center at SCHARP, the HPTN network includes a central lab facility at Johns Hopkins University and a core facility at Family Health International in North Carolina. The network has 18 international study sites in 13 different countries in addition to six study sites in the United States. For more information visit http://www.hptn.org.
Phase I: Uses a small sample of healthy volunteers, identifies safe dosage and immediate side effects.
Phase II: Medium-sized sample of disease sufferers and/or healthy volunteers, expanded test for safety and effectiveness in the target population.
Phase IIb: Shares elements of Phase II and Phase III trials.
Phase III: Large sample of disease sufferers and/or susceptible participants, expanded test for effectiveness and longer-term side effects; often compares product to a standard treatment.