Pravan Suntharasamai

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.

EFFECT OF PRIMAQUINE ON GAMETOCYTES OF PLASMODIUM FALCIPARUM IN THAILAND

Sm,—Mr Ledingham and his colleagues (May 31, p. 1168) reported interesting findings on central rewarming using a modified Sengstaken tube in ansesthetised dogs. The rate of rewarming will, to some extent, depend upon the integrity of autonomic reflexes which tend to restore normal body temperature. Anaesthetic agents disrupt normal temperature regu’ lation, and it is not surprising that the temperature of the control animals did not rise during the four hour study, notwithstanding the radiant heat bulb. From the temperature curves shown of one rewarmed dog, the high skin temperature seen when the core temperature was only 35°C, highlights this point. The technique would appear to be of great value in the type of case described, where a patient is effectively poikilothermic as a result of traumatic or drug induced brain dysfunction, but the response may be different in hypothermia induced by exposure to low ambient temperature in otherwise normal people.

ECONOMICAL MULTIPLE-SITE INTRADERMAL IMMUNISATION WITH HUMAN DIPLOID-CELL-STRAIN VACCINE IS EFFECTIVE FOR POST-EXPOSURE RABIES PROPHYLAXIS

An economical post-exposure regimen of Mérieux human diploid-cell-strain vaccine (HDCSV) was compared with Semple vaccine (SV), the most widely used vaccine in Asia. 155 patients bitten by animals proved to be rabid received either conventional courses of SV (34 severe and 43 mild cases) or HDCSV, 0.1 ml intradermally, at eight sites on day 0, at four sites on day 7, and at one site on days 28 and 91 (36 severe and 42 mild cases). All severely bitten patients were given equine anti-rabies serum (EARS), 80 IU/kg on day 0. There were no deaths from rabies in either group. Follow-up was 97.5% at 1 year and 93% at 2 years. 88% of patients given HDCSV alone had detectable neutralising antibody on day 7 in contrast to 2% given SV alone. Antibody persisted until 1 year in all sera tested from HDCSV patients in contrast to only 48% of SV sera. The high dose of EARS resulted in pronounced suppression of response to HDCSV. There were no serious systemic side-effects but local side-effects were significantly more common in the SV group. The multiple-site intradermal HDCSV regimen was at least as effective as SV. The amount of HDCSV used was 30% of the conventional dose.

Endogenous Interleukin-10 Modulates Proinflammatory Response in Plasmodium falciparum Malaria

Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 are implicated in the pathogenesis of severe Plasmodium falciparum malaria. In this study, the effect of IL-10 on their production by peripheral blood mononuclear cells (PBMC) from acutely infected patients was examined. Exogenous IL-10 inhibited malarial antigen-induced cytokine production by reducing mRNA accumulation. Maximal inhibition occurred when IL-10 was added in the first 2 h of stimulation. Conversely, the addition of anti-IL-10 markedly enhanced TNF-alpha, IL-1beta, and IL-6 production. The effect was significantly greater on PBMC from patients with uncomplicated infection than PBMC from patients with severe disease. Kinetics studies showed that TNF-alpha, IL-6, and IL-1beta were produced within 2-4 h of stimulation, while IL-10 was first detectable after 8 h. These findings suggest that IL-10 counter-regulates the proinflammatory response to P. falciparum. Severe falciparum malaria may be associated with an inadequate negative feedback response by IL-10.

Phase I/II study of a candidate vaccine designed against the B and E subtypes of HIV-1.

SummaryA phase I/II trial of a candidate vaccine to prevent HIV infection was carried out in Bangkok, Thailand, testing AIDSVAX B/E (VaxGen, Inc., Brisbane, CA), a bivalent subunit vaccine prepared by combining recombinant gp120 from a subtype B virus (HIV-1MN) with gp120 from a subtype E virus (HIV-1A244) in alum adjuvant. The studies provide human data on the immunogenicity of various dose combination of non–subtype B vaccine antigens. The results suggest that AIDSVAX B/E is safe and immunogenic in humans. The optimal dose for humans in developing countries was 300 μg of each antigen (B and E). Clade E responses were measurably increased by immunizing with gp120 B/E over B alone. Using the B/E combination did not interfere with the response to either clade. Antibodies to AIDSVAX B/E were able to bind to oligomeric gp120 on the surface of cells infected with primary isolates of HIV-1.

Semi-quantitative measurement of Plasmodium falciparum antigen PfHRP2 in blood and plasma

Plasmodium falciparum histidine rich protein 2 (PfHRP2) antigen was measured semi-quantitatively in whole blood, plasma, and supernatants and red blood cells of cultures in vitro using the dipstick ParaSight-F test and also by a quantitative antigen-capture enzyme-linked immunosorbent assay (ELISA). In vitro, PfHRP2 was secreted mainly during the second half of the asexual cycle with a marked rise during schizont development and rupture. The total PfHRP2 secreted before schizogony corresponded to approximately 4% of that contained in the red blood cells. In samples from 55 patients with acute falciparum malaria, the level of detection by ELISA corresponded to parasitaemias of 100/microL for whole blood and 1600/microL for separated plasma. Whole blood PfHRP2 levels were correlated significantly with admission parasitaemia (r = 0.76, P < 0.0001) and the stage of parasite development (r = 0.43, P < 0.01). Although whole blood PfHRP2 concentrations were higher in severe malaria, plasma concentrations of PfHRP2 were considerably higher in severe malaria (median titre 1:320, range zero to 1:1280) than in uncomplicated malaria (median titre 1:5, range zero to 1:80; P < 0.0001). The ratio of whole blood to plasma PfHRP2 was lower in severe than in uncomplicated malaria (median 4, range 0.25 to 256, versus 64, range 4 to 1280; P < 0.0001). With plasma samples the intensity of colour change on the dipstick correlated well with more precise measurement of optical density in the ELISA (r = 0.88, P < 0.0001). These results suggest that measurement of PfHRP2 in plasma could provide an alternative approach to the assessment of the parasite biomass, and thus prognosis, in severe malaria, and that this could be done simply by using the currently available dipsticks.

AN ECONOMICAL REGIMEN OF HUMAN DIPLOID CELL STRAIN ANTI-RABIES VACCINE FOR POST-EXPOSURE PROPHYLAXIS

Vaccine regimens using 0.1 ml human diploid cell strain vaccine (HDCSV) given intradermally (id) in single and multiple sites, or with aluminum hydroxide adjuvant given subcutaneously (sc), were compared with the regimens of HDCSV and Semple vaccine currently suggested by WHO. Some groups were also given human rabies-immune globulin (HRIG). Neutralising antibody titres were monitored for 3 months. Antibody was detected earliest in subjects given 0.1 ml HDCSV id at each of eight sites. The highest antibody titres from day 14 onwards were found after intramuscular (im) administration of HDCSV, but the multiple-site id regimen, which requires only one quarter of the volume of vaccine required for the im regimen, gave similar results, provided that a booster was given on day 91. This finding suggests that a treatment schedule based on this regimen would be suitable for post-exposure prophylaxis. Adjuvanted vaccine gave similar results to the same amount of antigen given id. Semple vaccine produced the lowest titres. HRIG, given at the high dose of 40 IU per kg, suppressed the antibody response to some of the regimens.

Failure of interferon alfa and tribavirin in rabies encephalitis.

OBJECTIVE--To test the effect of interferon alfa and tribavirin (ribavirin) in patients with rabies encephalitis. DESIGN--An open trial of chemotherapy and intensive care in patients with early rabies. SETTING--The intensive care unit of a Bangkok hospital. PATIENTS--Four conscious men with clinical rabies encephalitis. INTERVENTIONS--Rapid virological diagnosis of rabies. Treatment with intravenous and intraventricular injections of high doses of lymphoblastoid interferon alfa in three patients and tribavirin in one patient. Intensive care was given throughout. MAIN OUTCOME MEASURES--Rabies infection confirmed by antigen detection and virus isolation. Rabies neutralising antibody and specific IgM sought in serum and cerebrospinal fluid. Interferon concentrations monitored before and during treatment in three patients. RESULTS--Interferon alfa treatment produced high concentrations in serum and cerebrospinal fluid. All four patients died after 5 1/2 to 12 1/2 days of treatment with no evidence of virostatic or clinically beneficial effects from either treatment. CONCLUSION--Interferon alfa treatment is not effective in rabies encephalitis. The use of tribavirin warrants further study, possibly combined with new therapeutic methods.

Lack of increased HIV risk behavior among injection drug users participating in the AIDSVAX B/E HIV vaccine trial in Bangkok, Thailand.

Objective: To determine whether HIV vaccine trial participation leads to increased risk behavior through beliefs about vaccine protection against infection. Methods: Changes in risk behavior were evaluated among 2545 injection drug users participating in the AIDSVAX®B/E vaccine trial in Bangkok, enrolled from March 1999 to August 2000. Demographic characteristics, beliefs and risk behavior were assessed at baseline and every 6 months thereafter. Risk-reduction counseling was provided at every study visit. Generalized estimation–equation logistic regression analysis was used to study trends in risk behavior and associated factors. Results: Participants were 93.4% male, their median age was 26 years, and 67.2% had at least secondary education. At baseline, 61.3% were receiving methadone detoxification and 20.9% were receiving methadone maintenance. From baseline to the 12-month follow-up visit, injection drug use decreased from 93.8% to 66.5% (P < 0.001) and needle sharing from 33.0% to 17.5% (P < 0.001). Multivariate analyses showed earlier follow-up time (at baseline and 6 months) and believing the vaccine to be efficacious associated with more-frequent injecting; younger age and lower education associated with less-frequent injecting. Earlier follow-up time (at baseline), younger age, and injection of methamphetamine and midazolam were associated with more-frequent needle sharing; methadone treatment and injecting less than weekly were associated with less-frequent needle sharing. Conclusions: Injection drug use and needle sharing decreased during the first 12 months of the trial. No increases in risk behavior in relation to beliefs about vaccine protection against HIV infection could be identified.

MULTI-SITE INTRADERMAL AND MULTI-SITE SUBCUTANEOUS RABIES VACCINATION: IMPROVED ECONOMICAL REGIMENS

Neutralising antibody responses to six post-exposure regimens of human diploid cell strain rabies vaccine with or without human rabies immune globulin (HRIG) were studied in 98 patients. The total amount of vaccine used was 22-34% of that required by conventional regimens. Vaccine was given at multiple sites intradermally or subcutaneously with or without adjuvant. Antibody was detectable within 7 days of the first dose in all subjects only in the groups given 0.1 ml intradermally at 8 sites. From day 14 onwards all groups showed an excellent antibody response; there was little difference between the various regimens. Suppression of the response to 8-site intradermal vaccination by a large dose of HRIG could be prevented by giving the second dose of vaccine on day 7 rather than day 14.