IAVI Report - December 2000 / January 2001
Emily Bass

James Ludigo stands in front of a crowded room in a spare, concrete-walled church in a rural village in the Rakai district of southwestern Uganda. He wears a baseball cap and T-shirt from his employer, the Rakai Project. The shirt is emblazoned with an African scientist peering into a microscope, above the slogan, "Improving Health through Research." The crowd is rapt as Ludigo administers a light-hearted quiz. First off: "Name five things you don't like about the Rakai Project." An audience member raises his hand: "What if I can't come up with five things?" Ludigo widens his eyes in mock anger. "Well then," he says. "Your points will go down." The room erupts in laughter.

Ludigo demands the criticism with confidence. The Rakai Project has been a familiar presence in the district since 1988, when the first cases of HIV, then known as "slim," began to appear in clusters on the Tanzanian border. Over the past 12 years, Rakai Project researchers have tracked the course of the epidemic in an open cohort which has grown to include over 16,000 men and women in 56 communities. The Project's mobile clinics rove the district, visiting each village once every 10 months or so and providing care to all comers, whether they are participants in the research or not.

On this blustery day last September, a group of first-time attendees and experienced community leaders have gathered for a "sensitization" meeting that is part of the Rakai Project's latest undertaking: a two-year HIV vaccine preparedness effort to build capacity for conducting Phase III trials, in collaboration with the US Military HIV Research Program (based in Rockville), the Walter Reed Army Institute for Research (WRAIR) and the Henry M. Jackson Foundation. The Project follows on the heels of Uganda's first foray into clinical vaccine work — an NIH-sponsored Phase I study in Kampala in 1999–2000 — the first HIV vaccine trial on African soil.

The experience gained in that trial, along with strong support for vaccine development from the Ugandan government, bode well for the Rakai Project's future. So do the years of field work there and in a few other Ugandan communities. Yet none of this shields the Project from tough challenges ahead in keeping the cohort together and ensuring a role in future Phase III studies. Chief among them is securing long-term support for the cohort from international funders, who have usually favored time-limited grants for hypothesis-driven research over continuous support for basic infrastructure. (That should begin to change, however, with several international funders — including NIH, IAVI, the European Union and the US Military Program — now preparing to invest more heavily in supporting cohorts and trial infrastructure in developing countries.) Another is coordinating the agendas of the many Rakai collaborators, both within and outside Uganda, so they work synergistically and avoid conflict and overlap.

The Early Years

The groundwork for the Rakai Project was laid in 1987, when David Serwadda and Nelson Sewankambo, researchers at Makerere University in Kampala, first traveled to the district to identify people with a mysterious new disease. In 1985, antenatal surveillance data showed a seroprevalence of 11% among pregnant women. By 1990, the figure had soared to 30%, and Uganda was considered the epicenter of the epidemic in sub-Saharan Africa. The Rakai District, with prevalence rates as high as 40% in some areas, was ground zero.

As Serwadda and Sewankambo began their investigations, Uganda was embarking on the course that would make it a leader among African nations confronting AIDS. Instead of turning a blind eye, President Yoweri Museveni engaged religious and community leaders, doctors and health-care workers in a carefully-planned prevention campaign. This early response has had some success: by the end of 1999, national seroprevalence was 8.3%. But this figure masks sobering trends — for example, HIV prevalence among military recruits rose from 16% in 1992 to 27% in 1996, while infection rates now exceed 30% among men and women attending STDS clinics, according to UNAIDS.

In 1987, Columbia University's Maria Wawer, a public health expert with extensive experience in Africa, traveled to Rakai to meet with Serwadda and Sewankambo and explore possible collaborative projects. The commitment of Uganda's government and of its leading researchers convinced her that meaningful research could be done even as the country was recovering from decades of oppression and human rights atrocities under Idi Amin. "The infrastructure was in terrible shape but the human infrastructure was great," says Wawer. "People wanted to do good work and nothing was going to stop them."

The Rakai Project was born out of that initial meeting, using leftover funds from one of Wawer's grants as seed money. Then a four-year grant from the US National Institutes of Health (NIH) allowed the project to start in earnest; in 1988 the team began monitoring rates of new infections (seroincidence) and the proportion of infected people (seroprevalence) in the region and surveying local residents' knowledge, attitudes and behaviors surrounding HIV. At first the scale was small and simple: at night, Wawer recalls, they returned to a bare-bones local hotel where they processed the day's blood samples, often by candlelight, using a hand-cranked centrifuge. Over time the cohort was expanded and the Project lined up lab support for HIV testing from the Uganda Virus Research Institute (UVRI) in Entebbe.

Data from the cohort's early years provided a detailed picture of a mature epidemic. Seroprevalence for adults ages 15-59 hovered around 20% in 1990-1992, with wide variations among different communities — particularly trading centers (40.9%) versus agricultural villages (13.4%). Amid these soaring rates were some declines, for instance among pregnant women (from 25.4% to 20.1%). But that seemingly good news was dampened by the finding that seroincidence remained stable (at 2.1 infections per 100 years of person observation, or PYO), indicating that the reduction stemmed more from increased mortality among infected people than from declining infection rates.

The first NIH research grant ended in 1992, leaving the Rakai Project without support. And because there were no potential funding sources for the cohort's basic infrastructure or operations, says Serwadda, the only way forward was to frame a new research question. After a difficult year, that strategy paid off: NIH awarded the team a five-year grant to study the effects of STD management on HIV transmission. Johns Hopkins University joined as sponsors of the Project, with researchers Thomas Quinn and Ron Gray as new team members. The new study not only reinstated support for most of the original cohort but also funded a rapid scale-up, eventually enrolling over 15,000 volunteers.

The STD prevention study was the Project's first randomized control trial, giving participants and communities first-hand experience with concepts such as blinding, rigorous follow-up schedules and informed consent in the setting of a clinical trial. It also further strengthened the capacity of the Project's UVRI laboratory to conduct HIV and STD screening.

Trial by Fire

The results of the study drew widespread attention to the Rakai Project, for two very different reasons. The first was scientific. Unlike a similar 1995 trial in Tanzania, which found a 42% drop in HIV transmission associated with STD management, the Rakai study found no reduction in the treatment arm. This apparent contradiction was not only puzzling scientifically, but raised questions about the value of STD treatment in HIV prevention efforts. Yet a closer look at the two studies revealed several possible explanations. Chief among them are that STD control is likely to have far more impact on an immature epidemic like Tanzania's than on a mature one like Rakai's and that the trials differed in whether they provided STD treatment continuously (Tanzania) or intermittently (Rakai). Another possibility is that low overall risk for treatable STDs in the Rakai population, together with a high prevalence of bacterial vaginosis, overwhelmed the potential effects of the interventions.

The trial also landed Rakai investigators at the center of an ethical maelstrom. The controversy was sparked when the New England Journal of Medicine published a retrospective analysis of data on HIV transmission between serodiscordant couples, with Thomas Quinn of Johns Hopkins Hospital as lead author. In an accompanying editorial, Marcia Angell, then editor–in–chief of the Journal, criticized the ethics of the trial, particularly that HIV-negative partners had not been informed of their partners' status and that HIV-positive volunteers did not receive antiretroviral therapy. Major media, including the New York Times, picked up the story.

Yet the uproar that followed took place almost entirely outside of Uganda; domestically, the government, local scientists and Rakai residents remained supportive. Both of the criticized points had been extensively discussed locally via town-hall style meetings with participating communities, and the local ethics committee and the Data Safety Monitoring Board had also signed off on the trial. What's more, the decision not to disclose the volunteers' HIV status to their partners not only had strong local backing but was a key condition of participation for many volunteers, given the tremendous stigma surrounding HIV. "I know that in the US, physicians are permitted to inform people about the risk of sex with an index partner," says Rakai Project field director Noah Kiwanuka. (The US has partner notification laws in 32 states.) "But if you did that here, you'd be in very, very hot water."

And on the standard-of-care issue, Sewankambo pointed to gaps between vaccine trial participants and the general population as a decisive ethical factor. "By providing the ultimate, say, 'Boston' standard of care to experimental trial participants, are you making the standard way, way out of reach for nonparticipants?' he asks. "If you're doing that, it becomes very unethical."

Trial participants questioned by journalists following Angell's editorial also emphasized another point: the Project's positive impact on the community. "The community sees the Project as very Ugandan," says Wawer. "All of the senior management is Ugandan, and it was initiated by Uganda. So there is a real sense of pride in the community that they are part of it."

In the end, there were some hard lessons learned. The experience of being caught off-guard and scrambling to respond to criticism underscored the importance of being well-prepared for controversy. "It's like being accused of murder," says Rakai investigator Fred Wabwire. "Even if you are subsequently cleared, you still have the stigma of being accused. When the controversy arose, we had no media team. We spent months doing media instead of science." To Peter Mugyenyi, head of Kampala's Joint Clinical Research Centre (and investigator in the earlier canarypox trial), the episode highlighted the need to emphasize to outsiders that the trial design was discussed and approved locally. It also pointed to the role that a standing community advisory board, which does not exist in the Rakai Project, could play in addressing contentious issues in the future.

The New Challenge: Becoming a Phase III Trial Site

The current vaccine preparedness work in Rakai was launched in 1999 and has two components. The smaller one, the Molecular Epidemiological Research (MER) nested sub-study, is gathering data on the biological and immunological profiles of newly–acquired HIV infections in a group of 600 age-matched HIV-positive people and negative controls. It also tracks trends in recombination. To date, Francine McCutchan of the Henry M. Jackson Foundation has analyzed 40 full-length sequences from the region and identified the main subtypes and recombinants in circulation (see table).

While MER fills in the molecular details, the Community Health Epidemiological Research project (CHER) takes on the big picture, examining community awareness, interest, and assumptions about vaccines and trials. Of 10,848 respondents in the first CHER survey, according to Kiwanuka, 99% had heard of vaccines in general and 84% were vaccinated against at least one infectious disease. Some of the most striking findings involved gender: for example, over 90% of those surveyed believed that vaccines were useful for women and children, but only 27% thought that they were also for men. Women were less likely to report knowledge of HIV vaccines, perhaps because of limited access to radio and other forms of news, and a slightly lower level of education than men.

Two more CHER surveys will be completed within the coming year. In addition, the US military HIV research program will establish a vaccine research center at Makerere University, to include clinic suites and a laboratory for T-cell assays, including flow cytometry, as well as HIV testing and viral load monitoring.

Beyond 2001, the US military will continue to work with the Rakai Project, says Merlin Robb, chief of the military program's vaccine research department and head of its Africa program. But its activities will probably be limited to targeted subsets of the population rather than to the entire cohort — a scale-back necessitated by the Army's small AIDS vaccine program and its ongoing involvement in Kenya, Tanzania and Thailand, in addition to Uganda.

Facing the Future

Looking ahead, the Rakai Project faces a challenging period. There are still no concrete plans to test a specific vaccine in the region. One potential candidate — still a few years off, and dependent on early trial results — is the subtype A HIV-canarypox construct under development at Aventis Pasteur, slated to enter Phase I studies in Kampala in the last quarter of 2001 under US military program sponsorship. Robb says that favorable results from the ongoing VaxGen trial could also affect the military's plans in Uganda. "Should [the gp120 vaccine] prove efficacious, that would certainly change our strategies and timelines for East Africa," says Robb. Another issue, ironically, could be the falling seroincidence: at 1.5 PYO, it is approaching the lower threshold for conducting efficacy trials, according to Don Burke, director of the Johns Hopkins Center for Immunization Research and an experienced hand in developing country vaccine trials — although other strengths of the Rakai Project could justify running larger trials to accommodate a lower rate.

Perhaps the biggest looming uncertainty is how to fund the cohort once the Army cuts back and other short-term grants, including one from the Gates Foundation, run out. "We'll be able to keep activities and research going," says Maria Wawer. "But the fundamental follow–up of everybody in 50–odd villages, so we can look at HIV dynamics — I don't necessarily see the way clear after the next couple of years."

One possibility is to continue research work on prevention interventions, under the auspices of NIH's HIV Prevention Trials Network (HPTN). Currently, the Rakai Project is conducting an HPTN-funded study of improved penile hygiene as a strategy for reducing transmission, and Project investigators are seeking funds for other prevention studies. Yet such HPTN funding would not guarantee support for the whole cohort — although it would keep the Project integrated into the US government-funded vaccine effort.

Another avenue for Rakai would be acceptance into NIH's HIV Vaccine Trials Network (HVTN). Peter Mugyenyi at the JCRC is also pursuing this option, since his NIH funding ended when the canarypox trial wound down. But both the Rakai Project and the JCRC have been invited by NIH to respond to the next Request for Proposals, and Mugyenyi is hopeful that a strong application will improve their prospects.

Yet by turning to a mixed bag of potential funders, the Project will continue to face the difficulties posed by shifting international partners, each with their own research priorities. "It gets more complicated the more collaborators you have," says Nelson Sewankambo. That's why the ability to manage multiple partners is emerging as a key survival skill for Rakai. "It helps when local collaborators set the terms and say, right from the word go, that room should be left open for other collaborators," Sewankambo adds, so they can avoid being limited by the priorities of a single partner. Beyond that, the Ugandans are looking to their US collaborators to keep one another informed and to coordinate their agendas, rather than merely tolerating one another, he says.

Americans in Rakai and at home echo the need for more effective collaboration. The large institutions, including the US Centers for Disease Control and Prevention (CDC), NIH and US military programs, are each pursuing their goals with "little effective communication" according to Burke. "There is courteous exchange of what is already largely public information, but as far as I can tell, no serious attempt to plan together," he says. In his view, better communication could also help the Rakai Project develop future sources of support — such as the vaccine program of the CDC, which supports epidemiology and infrastructure-building.

Burke also believes that more coordination is needed within Uganda. He points out that "the elements of Phase I/II capability are disconnected from Phase III — they've been supported by different funding streams and treated as separate projects. So one of the first things to do is to improve coherence in-country." That will require increased collaboration among Uganda's leading institutions, including the JCRC, UVRI, Makerere University and Mulago Hospital and the British Medical Research Council.

The Ugandan government is currently revising its 1992 national vaccine strategy plan, with a focus on increasing such coordination. These changes are promising. Still, open questions about the cohort's future fuel a sense of urgency. "Our need is a vaccine. In Rakai, we are ready for a Phase III trial," says Fred Wabwire. "We wanted it yesterday. We have tried our best to occupy the cohort by doing some other studies, but as soon as possible, we need to get a vaccine and use the infrastructure while it is still optimal."

Emily Bass is Senior Correspondent for the amfAR Treatment Insider, and a former senior writer for HIV Plus magazine.

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