Important note: Information in this article was accurate in October 2001. The state of the art may have changed since the publication date. IAVI Report - October - November 2001
Patricia Kahn
Thailand's launch of the VaxGen Phase III trial in March 1999 represented another "first" for a nation that has been one of the world's most pro-active in efforts to reduce the spread of HIV. But beyond its being the first AIDS vaccine efficacy study in a developing country, the ongoing trial is breaking ground on another front of the prevention battle: finding ways to successfully reach, engage and retain large numbers of injecting drug users (IDUs)--a key population fueling the Asian epidemic, but one often viewed by vaccine developers as too difficult to work with for efficacy trials lasting several years.
"The trial is showing that you can follow injectors," says epidemiologist Chris Beyrer of the Johns Hopkins School of Public Health. "The cohort has much better retention than many other high-risk cohorts, such as commercial sex workers. This is really important." Beyrer, an expert on the AIDS epidemic in Southeast Asia, has long argued that the high prevalence and rampant spread of HIV in Asia's IDU populations means that "if a vaccine doesn't work in IDUs, we won't stop the epidemic." (See article.)
At the 2001 meetings cited in the lead article, plus an IAVI Report visit to the Bangkok Vaccine Evaluation Group (BVEG, the consortium of collaborators on the trial) and to the study site at Taksin Hospital, trial investigators discussed the study's progress, its 2,545-person cohort and some of the factors that help make it work.
The cohort is rooted in Bangkok's methadone treatment centers for heroin users--a rarity in Asia, where drug addiction is nearly always a matter for imprisonment and addicts are left to "cold turkey" withdrawal. (Across Asia, methadone is only available in Thailand and Hong Kong.) Bangkok is an exception: In 1980, the Bangkok Metropolitan Authority (BMA) opened a network of outpatient clinics where addicts can undergo a 45-day detoxification program with decreasing doses of methadone to help them get off heroin. While this approach alone has not solved the problem-there is a high rate of relapse, and long-term methadone maintenance is not available-it is a crucial step towards tackling addiction as a public health problem rather than a criminal one. Every year about 8,000 addicts (70% of them injectors) seek treatment through this system.
The present trial grew out of work begun in the early 1990s, when alarm over the country's exploding HIV epidemic, and support of the World Health Organization's Global Programme on AIDS, led Thailand's public health and scientific communities to begin building capacity for HIV vaccine trials-and to view the BMA clinics as a possible setting. The AIDSVAX® vaccine now in Phase III trials existed in a simpler form made from HIV subtype B, then the predominant subtype in both Thailand and the US, and was being moved by Genentech (VaxGen's parent company) towards US government-sponsored efficacy trials.
But in 1994, when the US decided against funding a Phase III trial-based on the vaccine's failure to neutralize primary (rather than laboratory-grown) strains of HIV--Thailand's scientists remained interested nevertheless, on the grounds that success or failure of past vaccines (including some tested in Thailand) was often not predictable from laboratory tests. The next year, the BMA, along with Tim Mastro at the US Centers for Disease Control's (CDC) Bangkok unit, Mahidol University, WHO and UNAIDS as collaborators, established a 1,200-person HIV-negative vaccine preparedness cohort in the 16 methadone clinics to determine HIV incidence, identify key risk factors for infection and assess volunteers' willingness to participate in vaccine trials. HIV prevalence at screening for enrollment was 30%, and the incidence of new infections in the cohort (followed through 1998) was 5.8 per 100 person-years, despite intensive prevention counseling. Surprisingly, the study also found that 79% of all new infections were with HIV subtype E, which by then predominated in heterosexual transmission in Thailand but reflected a major shift in the Bangkok IDU population away from subtype B. This finding led to a re-design of AIDSVAX® to incorporate subtype E gp120 alongside gp120 from the original lab-grown subtype B.
The preparedness study also found that infection risk in this group was strongly associated with injection behavior rather than sexual risk, even in the cohort's few women (although women's' overall risk was higher). Needle exchange remains unacceptable in Thailand and is not possible even within the trial setting. Although volunteers commonly obtained sterile needles and syringes from pharmacies, where they are widely available for low prices, sharing remained a key risk factor, probably stemming partly from volunteers' fear of arrest if caught with injecting materials. Furthermore, over 43% of the volunteers reported being incarcerated at some point during the study, and injecting while in prison was a key source of infection--especially for people going through withdrawal, whose desperation can lead them to ignore clear risks, according to BVEG's Suphak Vanichseni.
Moving from the preparedness work to the Phase III cohort went fairly smoothly, says Vanichseni, although recruitment took a few months longer than anticipated--due partly to a drop in the number of injectors in Bangkok, a trend accompanying the steep, nation-wide rise in methamphetamine use. To compensate, the trial team added two mobile units and did additional recruiting farther afield of Bangkok proper.
As with the earlier cohort, the study population consists largely of people with more stable lives than common stereotypes of IDUs suggest. About 70% are employed (30% in stable jobs), many as motorcycle taxi drivers, others as day workers in manual occupations, and over 60% have steady partners. The cohort is overwhelmingly male (93.5%), and most of the enrolled women are partners of other volunteers. While "a certain group of the IDUs is marginalized," says Frits van Griensven of the Bangkok CDC, which collaborates on the trial, "most lead rather normal lives." According to Pakorn Sukklam, a counselor at the Taksin Hospital site, very few resort to criminality to buy heroin, which is available relatively cheaply, and in much purer form, compared with Western countries. This stability is reflected in the cohort's very high retention rate: 97.4% at one year, says Vanichseni.
At the IPAAC meeting, Vanichseni presented a summary of risk behaviors in the cohort. At the trial's start (baseline), methadone treatment alone had reduced injection frequency from 3-4 times to once daily on average, but 94% of the volunteers reported injecting within the past 6 months; one year into the trial, the figure was 72%, with 16% reporting needle-sharing (33% at baseline). Incarceration remains frequent, but--a key factor in the trial's high retention rate--a long-negotiated arrangement with police allows trial staff to conduct follow-up visits with imprisoned volunteers.
Kachit Choopanya, the trial's principal investigator, also attributes the high retention rate to the bond between participants and trial counselors. "It's a holdover from methadone treatment, when [the volunteers] saw their health care worker every day," he says. "That creates a very trusting relationship, and is one of the main reasons we can retain people." Counseling sessions take a harm-reduction approach to lowering HIV risk, starting with discussions of stopping injection altogether, then moving to reinforcing the importance of sterile equipment, and to ways of sterilizing used equipment with bleach, and counseling on safe sex.
As 2001 drew to a close, there were two new developments in the trial. On 1 October, the BMA officially changed its treatment recommendations for HIV-infected people from two-drug therapy to HAART, and the trial--which linked its treatment policy to the BMA's--followed suit. According to Jordan Tappero, who heads the CDC's Bangkok unit, volunteers who became infected during the trial and have already started on two anti-retrovirals (for CD4 counts below 500) were switched to a three-drug regimen; since 1 October, HIV-infected volunteers naive to ARVs are being offered HAART when their CD4 count falls below 200, or for symptomatic HIV infection. Although Thailand's national guidelines on AIDS treatment call for HAART, in practice the public health system cannot pay for it, and only a few thousand Thais (mostly self-paying) receive triple-drug therapy.
Second, the CDC has launched a sub-study of HIV transmission in participants who become infected (drawn from both the placebo and vaccine arms, which are still blinded). Volunteers and their partners are invited to enroll for intensive counseling on preventing transmission, analysis of HIV subtype and monitoring of viral parameters (such as viral load in blood and semen) to look for possible vaccine effects on transmission rate.
An interim analysis of the trial data will be carried out in late 2002 (at the two-year timepoint), and the trial is scheduled to run until mid- 2003.
011010
IAVI2001-1003
©2001. The IAVI Report.
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2001. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.
