Suphak Vanichseni

Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Antiretroviral pre-exposure prophylaxis reduces sexual transmission of HIV. We assessed whether daily oral use of tenofovir disoproxil fumarate (tenofovir), an antiretroviral, can reduce HIV transmission in injecting drug users. METHODS In this randomised, double-blind, placebo-controlled trial, we enrolled volunteers from 17 drug-treatment clinics in Bangkok, Thailand. Participants were eligible if they were aged 20-60 years, were HIV-negative, and reported injecting drugs during the previous year. We randomly assigned participants (1:1; blocks of four) to either tenofovir or placebo using a computer-generated randomisation sequence. Participants chose either daily directly observed treatment or monthly visits and could switch at monthly visits. Participants received monthly HIV testing and individualised risk-reduction and adherence counselling, blood safety assessments every 3 months, and were offered condoms and methadone treatment. The primary efficacy endpoint was HIV infection, analysed by modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00119106. FINDINGS Between June 9, 2005, and July 22, 2010, we enrolled 2413 participants, assigning 1204 to tenofovir and 1209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0·35 per 100 person-years) and 33 in the placebo group (0·68 per 100 person-years), indicating a 48·9% reduction in HIV incidence (95% CI 9·6-72·2; p=0·01). The occurrence of serious adverse events was much the same between the two groups (p=0·35). Nausea was more common in participants in the tenofovir group than in the placebo group (p=0·002). INTERPRETATION In this study, daily oral tenofovir reduced the risk of HIV infection in people who inject drugs. Pre-exposure prophylaxis with tenofovir can now be considered for use as part of an HIV prevention package for people who inject drugs. FUNDING US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration.

The epidemiology of HIV infection and AIDS in Thailand.

There were very few AIDS cases reported in Thailand as of 1988, where HIV was introduced relatively late in the course of the AIDS pandemic. Thailand was therefore classified as an epidemiologic pattern III country with regard to the HIV/AIDS pandemic. Also in 1988, however, Thailand experienced a major and rapid increase in HIV prevalence among IV drug users (IVDU). The Thai experience with HIV after the rapid spread first among IVDUs has been successive waves of HIV transmission to female prostitutes, then to their non-IVDU male clients, and then into the non-prostitute wives and girlfriends of these latter men in the general population. Three years after being declared a pattern III country, 300,000 people in Thailand were estimated to be infected out of a population of 55 million. Reasons for this unprecedented rapid spread of HIV infection may eventually come from research on sexual behavior and related diseases given the lack of evidence for human host genetic factors or particularly virulent etiologic agent factors to explain the phenomenon. The reason and dynamics behind the timing and rapidity of the 1988 epidemic among IVDUs for now remains unknown. The authors note that the scenario of HIV transmission observed in Thailand also seems to be unfolding in neighboring countries. HIV infection among female prostitutes and heterosexual men is consistently highest in the northern Thai provinces adjacent to Myanmar and Laos. This paper reviews the epidemiology and prevention of HIV infection and AIDS in Thailand, updating previous reports and commentary, and including previously unpublished or not widely available data.

Quantitative Detection of Increasing HIV Type 1 Antibodies after Seroconversion: A Simple Assay for Detecting Recent HIV Infection and Estimating Incidence

We have devised a simple enzyme immunoassay (EIA) that detects increasing levels of anti-HIV IgG after seroconversion and can be used for detecting recent HIV-1 infection. Use of a branched peptide that included gp41 immunodominant sequences from HIV-1 subtypes B, E, and D allowed similar detection of HIV-specific antibodies among various subtypes. Because of the competitive nature of the capture EIA, a gradual increase in the proportion of HIV-1-specific IgG in total IgG was observed for 2 years after seroconversion. This was in contrast to results obtained with the conventional EIA using the same antigen in solid phase, which plateaus soon after seroconversion. The assay was used to test 622 longitudinal specimens from 139 incident infections in the United States (subtype B) and in Thailand (subtypes B and E). The assay was also performed with an additional 8 M urea incubation step to assess the contribution of high-avidity antibodies. Normalized optical density (OD-n) was calculated (ODspecimen/ODcalibrator), using a calibrator specimen. An incremental analysis indicated that a cutoff of 1.0 OD-n and a seroconversion period of 160 days offered the best combination of sensitivity and specificity for classifying incident or long-term infections. The urea step increased the seroconversion period to 180 days with similar sensitivity and specificity. Separate analysis of B and E subtype specimens yielded the same optimal OD-n threshold and similar seroconversion periods. The assay was further validated in African specimens (subtypes A, C, and D) where the observed incidence was within 10% of the expected incidence. This assay should be useful for detecting recent HIV-1 infection and for estimating incidence among diverse HIV-1 subtypes worldwide.

Intersubtype Human Immunodeficiency Virus Type 1 Superinfection following Seroconversion to Primary Infection in Two Injection Drug Users

ABSTRACT In this study, we describe two cases of human immunodeficiency virus type 1 (HIV-1) intersubtype superinfection with CRF01_AE and subtype B strains, which occurred in two injection drug users participating in a prospective cohort study in Bangkok, Thailand. In both cases, the superinfecting strain was detected by molecular and serologic analyses several weeks after complete seroconversion to the primary infection with a strain belonging to a different subtype. Superinfection occurred despite specific T-cell and humoral antibody responses to the primary virus. In both cases, cross-subtype immune responses were limited or absent prior to the second infection. These data show that, in some individuals, the quality and quantity of the immune response elicited by primary HIV-1 infection may not protect against superinfection. This finding has important implications for vaccine design. HIV-1 vaccines, at a minimum, will need to include potent, broadly protective, conserved immunogens derived from several group M subtypes.

Continued high HIV-1 incidence in a vaccine trial preparatory cohort of injection drug users in Bangkok, Thailand

Background A large epidemic of HIV-1 subtype B began among injection drug users (IDUs) in Bangkok in 1988. Despite ongoing prevention efforts, HIV-1 prevalence among IDUs remained at 30–50% through the 1990s. ObjectivesTo measure the incidence of HIV-1 infection and related risk factors to guide prevention efforts and to evaluate the feasibility of conducting an HIV vaccine efficacy trial. Design and methodsA prospective cohort study in which IDUs attending methadone treatment programs in Bangkok were screened during 1995–1996 for enrollment into the study. IDUs found to be HIV-seronegative on two occasions were offered enrollment with follow-up visits every 4 months. On each visit participants were evaluated with a questionnaire and serologic testing. ResultsA total of 1209 HIV-negative IDUs were enrolled. Through the end of 1998, the overall HIV-1 incidence rate was 5.8 (95% confidence interval, 4.8–6.8) per 100 person–years of follow-up. HIV-1 subtypes E and B accounted for 79 and 21% of infections, respectively. On multivariate analysis, HIV-1 seroconversion was primarily associated with the frequency of heroin injection, the sharing of injection equipment, and incarceration, especially with drug injection. Sexual behavior was not associated with increased risk for HIV-1. Risk factors for infection with HIV-1 subtypes E and B were similar. ConclusionHIV-1 transmission risk remains high among Bangkok IDUs despite methadone treatment and other current prevention strategies. There is an urgent need to address this ongoing epidemic, especially in jails and prisons. This study led to the initiation in 1999 of a phase III HIV-1 vaccine efficacy trial in this population.

Determination of HIV-1 subtypes in injecting drug users in Bangkok, Thailand, using peptide-binding enzyme immunoassay and heteroduplex mobility assay : evidence of increasing infection with HIV-1 subtype E

ObjectivesTo evaluate the sensitivity, and specificity of peptide-binding enzyme immunoassay (PEIA), and heteroduplex mobility assay (HMA) for the determination of HIV-1 subtypes B, and E; to determine the proportions of infections due to subtypes B, and E over time;, and to generate data on DNA sequences of the C2-V3 region of the env genes. MethodsHIV-1 subtyping was conducted by PEIA, and HMA on blood specimens obtained from 97 injecting drug users (IDU) infected with HIV between 1988, and 1993. Genetic sequencing was performed on 84 specimens. ResultsBoth laboratory methods were highly sensitive, and specific for the determination of HIV-1 subtypes B, and E. The two tests were complementary; samples which could not be typed by HMA were correctly typed by PEIA, and vice versa. While subtype B accounted for 80.4% (78 out of 97) of infections overall, the proportion of new infections due to subtype E increased from 2.6% (one out of 38) in 1988–1989 to 25.6% (11 out of 43) in 1990–1991, and to 43.8% (seven out of 16) in 1992–1993 (4cH2 for linear trend, P< 0.001). ConclusionsHMA, and PEIA are practical, sensitive, and specific laboratory methods for the determination of HIV-1 subtypes in Thailand, and may be useful in other geographic areas to define the molecular epidemiology of the global HIV-1 pandemic. Data suggest that the proportion subtype E infections have increased among Bangkok IDU from 1988 through 1993.

Estimating the number of HIV-infected injection drug users in bangkok : a capture-recapture method

OBJECTIVES The purpose of the study was to estimate the number of injection drug users infected with the human immunodeficiency virus (HIV) in Bangkok to allow planning for health services for this population. METHODS A two-sample capture-recapture method was used. The first capture listed all persons on methadone treatment for opiate addiction from April 17 through May 17, 1991, at 18 facilities in Bangkok. The second capture involved urine testing of persons held at 72 Bangkok police stations from June 3 through September 30, 1991. Persons whose urine tests were positive for opiate metabolites or methadone were included on the second list. RESULTS The first capture comprised 4064 persons and the recapture 1540 persons. There were 171 persons included on both lists, yielding an estimate of 36,600 opiate users in Bangkok. Existing data indicate that 89% of opiate users in Bangkok inject drugs and that about one third are infected with HIV, yielding an estimate of approximately 12,000 HIV-infected injection drug users in Bangkok in 1991. CONCLUSIONS During the 1990s the number of cases of acquired immunodeficiency syndrome (AIDS) and other HIV-related diseases, including tuberculosis, in the population of HIV-infected injection drug users in Bangkok will increase dramatically, placing new demands on existing health care facilities. The capture-recapture method may be useful in estimating difficult-to-count populations, including injection drug users.

Viral load differences in early infection with two HIV-1 subtypes.

ObjectivesInformation on early HIV-1 infection has come primarily from studies of persons infected with subtype B in North America and Europe; much less is known about other subtypes. The purpose of the present study was to compare the virologic and immunologic parameters following seroconversion among recently-infected persons infected with either of two different HIV-1 subtypes. MethodA prospective cohort study was carried out at methadone treatment clinics administered by the Bangkok Metropolitan Administration, Thailand. A total of 130 HIV-1-infected seroconverters (103 with HIV-1 subtype E and 27 with subtype B) were included in the study. The main outcome measures were serial HIV-1 RNA viral load, natural killer cell percentage, CD4 and CD8 lymphocyte counts since seroconversion. ResultsThe demographic and behavioral characteristics of persons with either subtype were similar. Median RNA viral levels at the earliest time within 3 months of seroconversion were more than three times higher for persons infected with subtype E than subtype B (63 100 versus 18 050 copies/ml, P = 0.001). However, this difference decreased over time such that viral loads were similar at 12, 18, and 24 months following seroconversion. The CD4 and CD8 lymphocyte counts were similar in infections with either subtype during the entire period up to 24 months post-seroconversion. ConclusionsHigher viral loads associated with subtype E may result from inter-subtype biological differences; however, the epidemiological dynamics of transmission in Bangkok may have also contributed to this phenomenon.

Risk factors and HIV seropositivity among injecting drug users in Bangkok

Bangkok experienced an extremely rapid spread of HIV infection among drug injectors in 1987 and 1988. This study examines risk factors for HIV infection and deliberate risk-reduction efforts by drug injectors. Two subsamples of injecting drug users were recruited in November 1989, a group in drug-use treatment (n = 342) and a group new to the treatment system (n = 259). Subjects were interviewed about AIDS risk behavior, and a blood sample was collected for HIV testing. Seroprevalence was 39 and 27% in the in-treatment sample and the new-to-treatment sample, respectively. The in-treatment sample seroprevalence rate is similar to rates observed 6 and 12 months earlier. Three factors were independently associated with HIV infection: subsample, having been in prison, and sharing injection equipment with two or more individuals in the previous 6 months. Deliberate risk reduction was reported by 92% of individuals, with 59% reporting that they had stopped sharing injection equipment. It appears that large-scale risk reduction has greatly slowed HIV transmission among drug injectors in Bangkok.

HIV/AIDS-related behavior change among injecting drug users in different national settings

ObjectivesTo identify factors associated with effective AIDS behavior change among injecting drug users (IDU) in different national settings. DesignCross-sectional surveys of IDU, with determination of HIV status. Trends in city HIV seroprevalence among IDU also used to validate effectiveness of behavior change. Setting and participantsSubjects recruited from drug-use treatment programs and outreach efforts in Bangkok, Thailand (n = 601), Glasgow, Scotland (n = 919), New York City, USA (n = 2539), and Rio de Janeiro, Brazil (n = 466). ResultsEvidence for the effectiveness of self-reported risk reduction was available for all cities. Univariate followed by multiple logistic regression analyses were used to identify factors associated with self-reported AIDS behavior change. Separate analyses were conducted for each city. Talking about AIDS with drug-using friends was significantly associated with behavior change in all four cities. Talking with sex partners about AIDS, educational level, knowing that someone can be HIV-infected and still look healthy, and having been tested previously for HIV were each significantly associated with behavior change in three of the four cities. ConclusionsDespite the substantial differences in these national settings, there were common factors associated with effective risk reduction. In particular, risk reduction appears to occur through social processes rather than through individual attitude change. HIV prevention programs need to explicitly incorporate social processes into their work.