AIDS Vaccine Trial Begins in the Western Hemisphere’s Hardest-hit Country
1er avril 2001 (International AIDS Vaccine Initiative)
NEW YORK, 1 April 2001 (International AIDS Vaccine Initiative)
by Anne-christine d’Adesky
Haiti : Scaling The Mountains
There is a Creole proverb that has long been a metaphor for Haiti’s struggles : Deye mon, genyen mon—Beyond mountains, more mountains. From above, the island appears as a jagged range of overlapping barren crests completely denuded of trees—somber evidence of this once-lush Caribbean nation’s steady decline into abject poverty. The loss of its forests was both a cause and a result : as poor Haitians cut down trees to get wood for cooking fires, the soil left behind could no longer hold water, turning the country into a dust bowl that is unable to grow enough food. Today, the world’s first independent black republic is the poorest country in the Western Hemisphere, with an annual per capita income of less than US$ 300. High on the mountains, rural villages offer scenes of poverty so dire they vie with images from sub-Saharan Africa or the slums of India. Hunger is everywhere and so is AIDS : with 8 million people in Haiti, nearly 400,000 have HIV—the highest prevalence rate outside of Africa.
Yet there is renewed hope on many fronts. Earlier this year, President, Jean-Bertrand Aristide, a firebrand populist leader, took office for the second time and has vowed to lift up the country. Although the political situation remains rocky, the new government has energized efforts to tackle Haiti’s thorniest problems, from a crumbling physical infrastructure to the AIDS epidemic.
With this new political backing, Haiti’s efforts to build an HIV vaccine program reached an important milestone on 27 March : immunization of the first two volunteers in the country’s first HIV vaccine clinical trial, at a treatment and research clinic run by GHESKIO (the Haitian Study Group on Opportunistic Infections and Kaposi’s Sarcoma) in Port-au-Prince. The Phase II trial, a test of the canarypox ALVAC vCP205 vaccine, with or without a boost of VaxGen’s gp120 protein, is being carried out under the auspices of the NIH’s HIV Vaccine Trials Network (HVTN) at sites in Haiti, Brazil, and Trinidad/Tobago, with 40 low-risk volunteers at each of the three sites.
For the GHESKIO clinic and its energetic director, physician Jean Pape, the hope is that this study will be the first of many, and a prelude to a Phase III efficacy trial-as well as a model for how to do high-quality clinical research under the dire conditions common to many developing countries. "For now, we are getting our feet wet," he says. "We are going to do the Phase II and show that we have the infrastructure for a bigger trial, for a Phase III." That means confronting such deep-seated problems as a weak health infrastructure, a shattered economy, high unemployment, residual political instability, and a 70% rate of illiteracy, as well as anticipating daily logistical hurdles like bad roads, telephone lines and energy blackouts.
Pape remains unfazed by these obstacles. "There have always been problems in Haiti and we have always worked, often without a net," he says matter-of-factly. "These are not reasons to not move ahead. You must build the infrastructure and train the people. That can be done. In fact, that is what we are doing."
In preparing for the trial, the Haitian team has relied on a formula that has served them well : pragmatism, a public avoidance of politics, flexibility, close collaboration with outside partners and—a key factor—transparency. They’ve paid particular attention to informing community and political leaders about their research activities in advance, and to educating the media, who are now crucial allies. The clinic also works closely with several longtime collaborators from abroad, including Cornell University Medical College (Ithaca, NY, Pape’s alma mater), the University of Michigan (Ann Arbor) and Vanderbilt University (Nashville, Tennessee), a "parent" site for the current trial.
Pape also cites high-level political will as a key factor. "From the beginning, the Haitian government made it clear that they want to go to Phase III trials," he explains. "Aristide himself is very interested. He sees the suffering caused by AIDS and he wants to do something. So do all four of Haiti’s recent health ministers and the entire cabinet."
One of them is Gabriel Thimothe, head of the Haitian Medical Association and a former Minister of Public Health, who began pushing Haiti’s HIV vaccine effort a decade ago. In 1991, a United Nations mission visited the country to evaluate its potential for doing trials, but prospects then dimmed as Haiti’s political climate became more unstable. A decade later, Thimothe remains convinced of the need for Haiti to play a role. "I believe the vaccine project can benefit the Haitian community facing the burden of high prevalence and the socioeconomic impact of AIDS," he says. "Behavioral change is so slow. It’s time to act to avoid a catastrophe among the young population." In pushing the vaccine agenda politically, he also stresses the economic argument. "We must focus on the cost efficacy of a vaccine compared to therapy," he says.
Paving the way The road to the ALVAC trial has been long and rocky. It began in 1979 when Pape, then working on typhoid fever in Warren Johnson’s lab at Cornell, decided to return to Haiti and start a Cornell program on infantile diarrhea, still a leading killer of children there. In 1982, when a strange wasting disease began killing many Haitians, he and a few colleagues formed GHESKIO as a research group to study the phenomenon, again with Cornell’s backing.
At that time, Haiti’s infamous dictator, "Baby Doc" Duvalier was still in power, the country was in turmoil, and there was little foreign aid. AIDS, as it was later identified, was a stigma, a public pox on Haitians, homosexuals, heroin users and hemophiliacs—the so-called "4 H’s," as the media dubbed it. GHESKIO set up its small operation as a research and training facility at the National Institute of Laboratories and Research in the capital, on a road that degenerates into potholes and dust as it leads to the teeming "bidonvilles" where thousands of people live in a maze of tin roofs and mud paths without electricity or clean water.
"In 1983, we had a small microscope, an incubator, and a standard centrifuge," recalls Cornell’s Johnson. "We could do a standard blood test, stool and urine, but not a hell of a lot more."
Over the next decade, GHESKIO struggled to track the epidemic and initiate community education and prevention programs along with HIV testing and counseling. By 1994, the team had established several low and high-risk HIV-negative cohorts, including one with 500 people from serodiscordant couples (HIV-negative sexual partners of positive individuals) and another with HIV-negative women attending the STD clinic.
Pape’s group remained active during the difficult years that followed, carrying out two surveys of community attitudes about HIV vaccines—information later used to establish informed consent procedures for the current trial—and continuing to gain experience in caring for people with AIDS, many of whom also had tuberculosis and/or STDs. More recently they expanded their laboratory and clinic space, thanks to grants from Japanese and French groups
GHESKIO today : An integrated approach to HIV From this modest beginning, the GHESKIO clinic has grown into the hub of Haiti’s battle against AIDS : last year its staff of 116 provided free services for 10,000 people, including HIV testing and counseling (with about 30% testing positive), along with comprehensive STD and TB screening and care. The clinic is also a one-stop health center that offers primary care, mental health and family planning services integrated into an overall outreach program aimed at supporting families of HIV-positive individuals, who receive treatment for opportunistic infections but—except for a tiny pilot program—no HAART therapy.
However, that may soon change. With the aim of expanding the availability of HAART, GHESKIO has also begun working closely with a rural HIV clinic in Hinche called Zanmi Lasante, (Partners In Health, in Creole) led by Harvard’s Paul Farmer, who is pioneering a small DOT-HAART (Directly Observed Therapy) program in people with advanced AIDS. Both groups are now collaborating with researchers from David Ho’s laboratory at the Aaron Diamond AIDS Research Center in New York and Bruce Walker’s group at Harvard on a five-year plan to introduce widespread HAART treatment to Haiti. The proposal has been submitted for funding, and-if backed-will begin as early as this summer. On inauguration day for the ALVAC trial, GHESKIO also announced that it was awarded a grant from UNFPA (the United Nations Population Fund) to develop a program for preventing vertical transmission of HIV using anti-retroviral therapy.
On the research side, GHESKIO maintains a strong emphasis on tropical medicine, STDs, TB, and HIV, including studies of the host factors that protect against heterosexual HIV transmission, the clinical management of HIV in children, and the prevention and treatment of diarrhea in AIDS patients. It also provides training for laboratory technicians and counselors at the Haitian Red Cross, which is in charge of all blood products in the country, with additional funding from the Fogarty International Center for Advanced Study in the Health Sciences (through Cornell).
Education, prevention and monitoring the epidemic also remain key activities at the GHESKIO clinic and at the national level, and show that prevalence rates have dropped. Last year, a survey of nearly 3000 pregnant women showed a 4.5% rate (6.7% in urban areas and 2.9% in rural regions), compared to 6.2% in 1993. An earlier study of over 4400 pregnant women from the Cité Soleil (Port-au-Prince’s worst slum), showed rates of 10.3% in 1988 (JAIDS 3 : 721-727, 1990). To date, 90% of Haitian AIDS cases are heterosexually acquired, and males and females are about equally affected ; clade B predominates throughout the country. TB remains a primary risk factor for HIV disease, and STDs such as syphilis are considered co-factors. But here, too, the news is good : syphilis rates have dropped as Haitians have begun to heed a national prevention message promoting condom use and safer sex.
Building up to vaccine trials GHESKIO’s preparations for the ALVAC vaccine trial have meant tackling a variety of logistical and nuts-and-bolts issues. A crucial one has been recruiting and training local trial staff, which was done largely through GHESKIO’s HVTN partner site at Vanderbilt University. Peter Wright, head of the Vanderbilt site (and of the university’s Division of Pediatric Infectious Disease), has worked with Pape and his crew for seven years, and for this trial provided cross-training in areas ranging from pharmacy to data management to informed consent—resulting in a Haitian vaccine team that now includes nearly two dozen people.
Lab capacity has also been a major focus. HIV testing, viral load analysis and T-cell counts will be done on site, but for this trial the more specialized T-cell immune assays, including ELISPOT and CTL tests, will be carried out on shipped samples at the HVTN central lab in Berkeley, California (as will assays on the Brazilian and Trinidad/Tobago samples). Although there have been a few kinks in getting shipments cleared through US customs, Haiti’s close proximity to the US, says Wright, is "an asset that should not be overlooked in terms of shipment of supplies and samples and the ability of investigators to get back and forth to the States."
Haiti’s poor roads and telephone lines are potentially major obstacles, so to get around them the GHESKIO team relies on technology and extensive back-up systems. Staff are supplied with cell phones, while a state-of-the art computer system will track the volunteers and laboratory data-backed by technical support from a local computer firm, LOGITEK, and that rarest of miracles for Haiti : a dedicated 24-hour satellite hookup. Three power generators are in place to counter power blackouts, along with a staff "totally dedicated to the power supply," says Pape, and two companies on call around the clock to troubleshoot. A 4-wheel drive and several SUV’s are available to navigate Haiti’s potholes and help volunteers get to the clinic.
Establishing extensive infrastructure and support systems did cause some delays in launching the trial. Besides the factors described above, these have been attributed to a revision of the original trial protocol (to include the Brazil and Trinidad and Tobago sites), the cumbersome process of establishing cell lines from every volunteer (for use in CTL assays), changes from NIH’s former HIVNET network of trial sites to the present HVTN system, and regulatory and administrative issues on both sides. Since Creole, not French, is the primary language spoken by the majority of Haitians, it has also taken time to translate all the needed documents. Haiti’s shifting political climate was another contributor to delays, but Pape remained determined to secure this high-level support. "This must be Haiti’s trial, not merely GHESKIO’s," he says.
Yet, with the trial now underway, Cornell’s Warren Johnson is optimistic that the research will continue to move forward despite the many difficulties. "In terms of sustainability, the best prognosticator is your past history," he says. "I think the fact that we have continued to develop even during the worst of years, and to work effectively, speaks for itself." If anything, he feels Haiti "has always been looked at microscopically," holding the country to a high standard of research relative to many other poor nations.
The trial volunteers Compared to the logistical issues, working with volunteers and getting approvals for the trial have been relatively straightforward. GHESKIO’s vaccine team has held nine large community forums that included virtually all the country’s public and private health organizations, and ran information sessions for specialized press. These generated strong support for the vaccine trial, but also a caution against too much publicity in the general press—"because it would create an impression that we already have a vaccine," says Pape. People told us, "You should not create demand for a product you cannot provide."
The approvals process was also relatively smooth. GHESKIO has had a strong Institutional Review Board (IRB) in place since 1983, and later added a National Bioethics Committee for evaluating research activities ; both approved the ALVAC trial in a record three months, says Pape. There is also a strong Community Advisory Board (CAB), whose members include two people with HIV, religious leaders (Protestant, Catholic, and Voudouist), secondary school educators, and medical students. "They wanted to make sure the vaccine does not give people AIDS, and that volunteers are not used as guinea pigs," says Pape. "There was a lot of debate, but I don’t think we’ll have any problem going forward."
That is being borne out by the recruitment : as of this March, over 1000 people had volunteered for the vaccine trial, some from the original low-risk cohorts established in the early 1990s. Potential volunteers are given three intensive one-hour counseling sessions, plus a follow-up test of their understanding.
The 40 final participants chosen represent a diverse pool, including people from the bidonvilles, although overall they are somewhat more educated than the typical clinic patients (due to the emphasis on selecting people who best could understood the informed consent process). They will continue to get HIV counseling and be closely monitored, and if any test HIV-positive during the trial, offered HAART therapy. "Although we did not promise any volunteer that they would be provided with triple drug therapy if they seroconverted, we feel we have a moral responsibility to do so, and we will provide therapy to anyone who becomes infected," says Pape. The drugs will be supplied by Cornell and the New York chapter of the Haitian Medical Association Overseas. "This approach of not telling volunteers up front that they would get HAART....will encourage volunteers to continue having protected sex," he explains.
The Haitian researchers view HIV vaccine efforts as an incentive that will encourage more people to get tested, and—with the addition of antiretroviral drugs into the mix-into treatment. "It’s been harder to persuade people [to get tested] without anything to offer them," Pape states frankly. "They don’t see the point, and I don’t blame them." And the scientists see the ALVAC trial as a building block to incorporate these efforts into a more comprehensive national AIDS program, alongside improved treatment.
Eyeing the future Paul Farmer, leader of the pilot treatment program in Hinche, shares these views, along with the aspiration to conduct a Phase III trial in the future. He hopes the present trial can serve as a stepping stone to this goal, professing himself undaunted by the logistical challenges—although he works in a region where donkeys do better than SUVs in climbing the steep hills. "I think [a Phase III trial] is altogether feasible," says Farmer. "GHESKIO has a bigger and better infrastructure than we do, and I think even we could pull this off, especially if there’s a shared commitment to treating those already sick with antiretrovirals."
Looking ahead towards that end, Pape’s team is already busy screening potential future volunteers, to show that they can put together large HIV-negative cohorts. That entails expanding their high-risk cohorts (such as serodiscordant couples and commercial sex workers) and building lab capacity to perform T-cell immune assays and handle much higher sample numbers. In addition, jokes Wright, "they will have to clone several Dr. Papes."
"The major problem all international sites will face is the need to have an infrastructure in place at least one year before initiating a Phase III trial," says Pape, eyeing the next major challenge. "To me that is the most difficult thing to convey to those providing financial support." Deye mon, genyen mon. o
Anne-christine d’Adesky is a New York-based AIDS journalist. She is US Coordinator of the Global ACCTS (the AIDS Collaborative for Care, Treatment and Support), a US-Africa treatment information project for resource-poor nations. (e-mail : email@example.com).
Phase II "Prime-Boost" Trial to Begin in Brazil, Haiti, and Trinidad
IAVI Report, April-June 2000
by Sam Avrett
A consortium of vaccine trial sites in Rio de Janeiro, Port-au-Prince, and Port of Spain will begin enrolling volunteers in June 2000 for a Phase II HIV vaccine trial. Planned since March 1998, it will be the first international multi-site Phase II trial of a preventive HIV vaccine, and only the fourth Phase II preventive HIV vaccine trial ever conducted.
Funded by the U.S. National Institutes of Health (NIH), the trial will enroll 120 people, 40 at each site. The research protocol received final approval from nearly all governmental and institutional review boards in late March (with a decision from Trinidad and Tobago’s AIDS Vaccine Ethics Committee still pending as the IAVI Report went to press). All three sites are now making final preparations for enrollment.
The trial will evaluate a "prime-boost" combination HIV vaccine with two components : a canarypox vector (vCP1452, manufactured by Paris-based Aventis Pasteur) carrying multiple genes from an HIV subtype B strain, and an envelope protein fragment (gp120MN, produced by VaxGen of San Francisco) from a lab-adapted, B subtype-derived strain. Its main goal is to generate more data on the safety and immunogenicity of the canarypox vector, alone and in combination with the envelope subunit vaccine. It will also raise the level of operational experience in conducting an international multi-site trial, including the collection of data and laboratory samples, building laboratory capacity, and recruiting populations for HIV vaccine trials, all of which may pave the way for future HIV vaccine trials in these countries. (A Phase III trial of canarypox plus gp120 is now under consideration by leaders of the NIH-funded Vaccine Trials Network.)
According to research staff at the sites, the major challenge in preparing for the trial was the political process rather than the science. "There was a remarkably solid basis of collaboration and support among the team of researchers from Brazil, Haiti, Trinidad and Tobago, the U.S. NIH and Family Health International," said Trinidadian researcher Farley Cleghorn, "and this allowed planning to go very smoothly. Yet the approval processes within our own country and in others took a year to complete." Mauro Schechter, principal investigator of the Rio de Janeiro site, described a similar experience. "By and large, most people at the various Brazilian agencies tried to be helpful, and because AIDS touches everyone, most government officials understood the need for this research," he said. "But, since this is the first international multi-center trial, often officials were not able to tell us precisely what approvals and documents were needed, and from which ministry or agency. Now we know our way through the maze."
Community groups in all three countries were involved early in planning for the trial. "Our community advisory board reviewed and commented on the protocol and informed consent forms, and we will be glad to see this trial finally enrolling," said Alexandre do Valle Menezes, head of the Rio PWA group, Grupo Pela Vidda.
The trial will randomize 120 participants into three groups : 45 participants to receive three doses of the combination of vCP1452 plus gp120MN (by intramuscular injection), 45 to receive three doses of vCP1452 only, and 30 to receive placebo. The trial volunteers will be mostly heterosexuals at low risk for HIV, along with some homosexual men at the Brazilian site. In addition to producing more immunogenicity data on these vaccine products, the trial will collect data on whether host factors such as HLA type, nutritional status or concurrent infections affect the immune responses generated by these vaccines.
The vCP1452 construct is the latest refinement in a series of canarypox vectors developed by Aventis Pasteur. Containing parts of HIV-1 genes env, gag, pol, and nef together with vaccinia promoter sequences that boost gene expression, vCP1452 has already been tested in approximately 50 volunteers and has shown no safety problems. Preliminary data from a U.S.-based trial (AVEG 034) with 90 volunteers indicate that vCP1452 elicits significantly higher levels and frequencies of cellular immune responses than two other canarypox products (vCP1433 and vCP205), although vaccinees are still being followed so these results are not yet final. In total, canarypox-based HIV vaccine candidates have been tested for safety and immunogenicity in nearly 1,000 people in the U.S., France, and Uganda.
The subunit gp120MN envelope protein is a VaxGen product that pre-dates their bivalent gp120B/B1qaz product now in Phase III trials in the U.S., Thailand, and the Netherlands. Derived from an early subtype B strain that was adapted to grow in cultured cells, the gp120MN protein has been tested for safety and immunogenicity in approximately 1,300 volunteers in the U.S. and Thailand.
The clinical trial sites for the current international Phase II trial are the Hospital Escola São Francisco de Assis in Rio de Janeiro, Brazil ; the Institut National de Laboratoire et de Recherches in Port-au-Prince, Haiti ; and the Medical Research Foundation in Port of Spain, Trinidad.
Sam Avrett was the founding executive director of the AIDS Vaccine Advocacy Coalition.