Suwat Chariyalertsak

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

BACKGROUND Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. METHODS In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. RESULTS As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). CONCLUSIONS The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

BACKGROUND Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. METHODS We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. RESULTS The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). CONCLUSIONS Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).

Case-Control Study of Risk Factors for Penicillium marneffei Infection in Human Immunodeficiency Virus-Infected Patients in Northern Thailand

A case-control study was done in Chiang Mai, Thailand, comparing risk-related behavior and exposures in 80 incident cases of disseminated Penicillium marneffei infection in patients with AIDS and 160 control patients with AIDS who did not have P. marneffei infection. All subjects were admitted to Chiang Mai University Hospital between December 1993 and October 1995. Cases were younger than controls (16-30 years vs. > 30 years of age; odds ratio [OR] = 2.22; 95% CI, 1.22-4.07). Patients with a recent history of occupational or other exposure to soil, especially during the rainy season (May to October), were more likely to present with P. marneffei infection (OR = 1.91; 95% CI, 1.04-3.52). History of exposure to or consumption of bamboo rats, the only known nonhuman hosts of P. marneffei, was not a risk factor for infection. Our data suggest that recent exposure to a potential environmental reservoir of organisms in the soil may be associated with disseminated P. marneffei infections among patients with AIDS in Northern Thailand.

Rhizomys sumatrensis and Cannomys badius, new natural animal hosts of Penicillium marneffei

The incidence of Penicillium marneffei infection has increased substantially, especially in persons with HIV infection. Very little is known about the natural reservoirs or animal hosts of P. marneffei. This pathogenic fungus was first isolated from a species of bamboo rat (Rhizomys sinensis) in Vietnam and later from another rodent species, R. pruinosus. We studied a total of 75 captured bamboo rats; P. marneffei could be isolated from the internal organs of 13 of 14 (92.8%) of large bamboo rats, R. sumatrensis, and of 3 of 10 reddish-brown small bay bamboo rats, Cannomys badius (30%). All 51 greyish-black C. badius were negative on culture. Among R. sumatrensis, P. marneffei were frequently recovered from the lungs (85.7%), spleen (50%) and liver (28.6%). Of the 28 soil samples collected from the bamboo rat burrows and the 67 from the residential areas of patients with P. marneffei infection, P. marneffei was isolated from one soil sample collected from a burrow of R. sumatrensis. The mycological characteristics of P. marneffei isolates from bamboo rats and humans were very similar. Our data indicate that R. sumatrensis and C. badius may be important animal hosts of P. marneffei in northern Thailand.

Global epidemiology of HIV infection in men who have sex with men

Epidemics of HIV in men who have sex with men (MSM) continue to expand in most countries. We sought to understand the epidemiological drivers of the global epidemic in MSM and why it continues unabated. We did a comprehensive review of available data for HIV prevalence, incidence, risk factors, and the molecular epidemiology of HIV in MSM from 2007 to 2011, and modelled the dynamics of HIV transmission with an agent-based simulation. Our findings show that the high probability of transmission per act through receptive anal intercourse has a central role in explaining the disproportionate disease burden in MSM. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiological data show substantial clustering of HIV infections in MSM networks, and higher rates of dual-variant and multiple-variant HIV infection in MSM than in heterosexual people in the same populations. Prevention strategies that lower biological transmission and acquisition risks, such as approaches based on antiretrovirals, offer promise for controlling the expanding epidemic in MSM, but their potential effectiveness is limited by structural factors that contribute to low health-seeking behaviours in populations of MSM in many parts of the world.

Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study

BACKGROUND The effect of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. We aimed to assess these factors in a cohort of HIV-negative people at risk of infection. METHODS In our cohort study, men and transgender women who have sex with men previously enrolled in PrEP trials (ATN 082, iPrEx, and US Safety Study) were enrolled in a 72 week open-label extension. We measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. We assessed PrEP uptake, adherence, sexual practices, and HIV incidence. Statistical methods included Poisson models, comparison of proportions, and generalised estimating equations. FINDINGS We enrolled 1603 HIV-negative people, of whom 1225 (76%) received PrEP. Uptake was higher among those reporting condomless receptive anal intercourse (416/519 [81%] vs 809/1084 [75%], p=0·003) and having serological evidence of herpes (612/791 [77%] vs 613/812 [75%] p=0·03). Of those receiving PrEP, HIV incidence was 1·8 infections per 100 person-years, compared with 2·6 infections per 100 person-years in those who concurrently did not choose PrEP (HR 0·51, 95% CI 0·26-1·01, adjusted for sexual behaviours), and 3·9 infections per 100 person-years in the placebo group of the previous randomised phase (HR 0·49, 95% CI 0·31-0·77). Among those receiving PrEP, HIV incidence was 4·7 infections per 100 person-years if drug was not detected in dried blood spots, 2·3 infections per 100 person-years if drug concentrations suggested use of fewer than two tablets per week, 0·6 per 100 person-years for use of two to three tablets per week, and 0·0 per 100 person-years for use of four or more tablets per week (p<0·0001). PrEP drug concentrations were higher among people of older age, with more schooling, who reported non-condom receptive anal intercourse, who had more sexual partners, and who had a history of syphilis or herpes. INTERPRETATION PrEP uptake was high when made available free of charge by experienced providers. The effect of PrEP is increased by greater uptake and adherence during periods of higher risk. Drug concentrations in dried blood spots are strongly correlated with protective benefit. FUNDING US National Institutes of Health.

Emtricitabine-Tenofovir Concentrations and Pre-Exposure Prophylaxis Efficacy in Men Who Have Sex with Men

PrEP drug concentrations associated with ≥90% reduction in HIV acquisition in men who have sex with men are achieved with daily dosing. PrEParing to Stop HIV Acquisition Pre-exposure prophylaxis (PrEP) using the antiretroviral drugs emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a recently proven strategy for preventing HIV acquisition. These drugs require phosphorylation in mononuclear cells to the pharmacologically active triphosphate moieties, called emtricitabine-triphosphate (FTC-TP) and tenofovir-diphosphate (TFV-DP). The iPrEx study was a randomized placebo-controlled trial of daily oral doses of FTC-TDF as PrEP in HIV-negative men who have sex with men. Participants all received a comprehensive package of HIV prevention services. HIV infections were reduced by 44% overall in the FTC-TDF arm relative to placebo. HIV risk was reduced by more than 90% among those having detectable drug in blood, indicating that adherence was a powerful determinant of drug efficacy at preventing HIV acquisition. A new study by Anderson et al. estimates specific drug concentrations and adherence levels associated with protection from HIV-1 acquisition in the iPrEx trial. A regression analysis predicted that a TFV-DP concentration of 16 fmol/106 peripheral blood mononuclear cells (PBMCs) (95% confidence interval, 3 to 28) was associated with a 90% reduction in HIV acquisition relative to placebo in the iPrEx study. To determine the number of tablets required to achieve this drug concentration, TFV-DP concentrations from another study called STRAND were used to establish expected TFV-DP concentrations. TFV-DP was detected in the blood at all dosing levels in all participants with a median (interquartile range) TFV-DP concentration of 11 fmol/106 PBMCs (6 to 13) after two doses per week, 32 fmol/106 PBMCs (25 to 39) after four doses per week, and 42 fmol/106 PBMCs (31 to 47) after seven doses per week. When the iPrEx study’s regression model was used to analyze the STRAND TFV-DP concentrations, the predicted HIV risk reductions were 76, 96, and 99% for two, four, and seven doses per week, respectively. These findings suggest that PrEP using oral FTC-TDF tablets is a robust intervention for preventing HIV acquisition among men who have sex with men. Drug concentrations associated with protection from HIV-1 acquisition have not been determined. We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.

Antiretroviral therapy for the prevention of HIV-1 transmission

BACKGROUND An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. METHODS We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. RESULTS Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. CONCLUSIONS The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).

Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial

BACKGROUND Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. METHODS The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. FINDINGS 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. INTERPRETATION Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. FUNDING US National Institute of Allergy and Infectious Diseases.

Clinical Presentation and Risk Behaviors of Patients with Acquired Immunodeficiency Syndrome in Thailand, 1994–1998: Regional Variation and Temporal Trends

From 1994 through 1998, the clinical and demographic features and risk behaviors of 101,945 adolescent and adult patients with acquired immunodeficiency syndrome (AIDS) were reported to the Ministry of Public Health in Thailand. The number of reported cases of AIDS infection increased from 12,005 in 1994 to 24,722 in 1997. Nearly 40% of the cases were reported from the northern provinces, which contained only approximately 20% of the adult population. About 80% of cases were among male patients, and 87% had been acquired via sexual contact. Tuberculosis was the most commonly reported opportunistic infection, occurring in 28.9% of patients; it was more commonly reported among injection drug abusers, especially in Bangkok. Pneumocystis carinii pneumonia and cryptococcal meningitis each occurred in nearly 20% of patients and were more frequently reported in patients with risk factors related to sex than in injection drug abusers. Penicillium marneffei infections were reported in 6.8% of patients from the northern provinces but less frequently elsewhere. These data suggest that AIDS is common in Thailand, and human immunodeficiency virus-infected persons should be given prophylaxis for tuberculosis, fungal infections, and P. carinii pneumonia.