Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study.

Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.

Predictors of clinical progression in HIV-1-infected adults initiating combination antiretroviral therapy with advanced disease in the Asia-Pacific region: results from the TREAT Asia HIV observational database.

The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm(3) in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings.

Determinants of epidermal nerve fibre density in antiretroviral-naïve HIV-infected individuals.

OBJECTIVES: Distal leg epidermal nerve fibre density (ENFD) is a validated predictor of small unmyelinated nerve fibre damage and neuropathy risk in HIV infection. As pre-existing damage may increase the risk of neuropathy following antiretroviral (ARV) therapy, particularly when the regimen contains stavudine (d4T), we assessed the relationship between ENFD and various parameters including mitochondrial factors in HIV-infected Thai individuals naïve to ARV therapy. METHODS: Distal leg and proximal thigh ENFDs were quantified in HIV-infected Thai individuals without neuropathy prior to randomization to a HIV clinical trial that focused on mitochondrial toxicity issues. We assessed their association with various clinical and immunovirological parameters as well as with peripheral blood mononuclear cell (PBMC) mitochondrial (mt) DNA copies/cell, oxidative phosphorylation (OXPHOS) complex I (CI) and complex IV (CIV) enzyme activities, and mt 8-oxo-deoxyguanine (8-oxo-dG) break frequencies. RESULTS: In 132 subjects, the median (interquartile range) ENFD (fibres/mm) values were 21.0 (16.2-26.6) for the distal leg and 31.7 (26.2-40.0) for the proximal thigh. By linear regression, lower CD4 count (P < 0.01), older age (P < 0.01), increased body mass index (BMI) (P = 0.04), increased height (P = 0.02), and higher PBMC OXPHOS activity as measured by CIV activity (P = 0.02) were associated with lower distal leg ENFD. CONCLUSIONS: Older age, increased height, higher BMI, poorer immunological status and higher PBMC OXPHOS activity are associated with lower distal leg ENFD in HIV-infected subjects free of neuropathy prior to initiation of first-time ARV therapy.

Assessing adherence in Thai patients taking combination antiretroviral therapy.

In settings where medications and viral load (VL) monitoring are limited by cost, clinicians need reliable ways to assess patient adherence to therapy. We assessed sensitivity and specificity of two self-reported adherence tools (a visual analogue scale [VAS] and the CASE [Center for Adherence Support Evaluation] adherence index), against a standard of detectable VL, with 288 patients from three sites in Thailand. We also assessed predictors of non-adherence. The sensitivity and specificity of the VAS <95% and CASE adherence index ≤11 against a VL >50 copies/mL were 26% and 90%, 19% and 95%, respectively. Against a VL ≥1000 copies/mL sensitivities increased to 55% and 36%, respectively, and specificities were unchanged. Attending a clinic not staffed by HIV specialists (odds ratio [OR] 3.14; 95% confidence interval [CI] 1.19-8.34) and being educated to primary school level or less (OR 2.24; 95% CI 1.01-4.94) were associated with self-reported adherence <95% on the VAS in multivariate analysis. Adherence assessed by the VAS was a more accurate predictor of detectable VL. Policy-makers in resource-limited settings should ensure that treatment centres are staffed with well-trained personnel aware of the importance of good patient adherence.

Cardiovascular risk assessment in persons with HIV infection in the developing world: comparing three risk equations in a cohort of HIV-infected Thais.

OBJECTIVE: There is growing concern regarding cardiovascular disease in HIV-infected individuals in developing countries such as Thailand. We evaluated the 10-year risk of coronary heart disease (CHD) in a Thai HIV-infected cohort using three cardiovascular risk equations, and assessed the level of agreement among their predictions. METHODS: We carried out a cross-sectional analysis of data on 785 Thai subjects followed prospectively in the HIV Netherlands Australia Thailand Collaboration (HIV-NAT) cohort study from 1996 to 2009. Cardiovascular risk factor history, along with relevant laboratory and clinical data, was collected at follow-up clinic visits. Ten-year risks of CHD were calculated using the Framingham, Ramathibodi-Electricity Generating Authority of Thailand (Rama-EGAT) and Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) risk equations. RESULTS: The mean age of the patients was 41.0 years; 55% of the subjects were male. The mean duration of antiretroviral therapy was 7.7 years. The prevalence of cardiovascular risk factors was low, with the most common risk factor being low high-density lipoprotein (HDL) (36.3%). The prevalence of high cardiovascular risk scores (defined as 10-year risk of CHD≥10%) was also low: 9.9, 2.1 and 0.8%, by the Framingham, Rama-EGAT and D:A:D scoring systems, respectively. Only eight subjects (1.0%) had a history of CHD. Bland-Altman plots showed that the Framingham equation predicted a higher risk of CVD compared with the Rama-EGAT and D:A:D equations, which agreed relatively well. CONCLUSION: The predicted cardiovascular risk in this HIV-infected Thai cohort was relatively low. The agreement among the Rama-EGAT and D:A:D risk scores suggests that both equations may be appropriate estimators of cardiovascular risk in this population.

Prediction of response to antiretroviral therapy by human experts and by the EuResist data-driven expert system (the EVE study).

OBJECTIVES: The EuResist expert system is a novel data-driven online system for computing the probability of 8-week success for any given pair of HIV-1 genotype and combination antiretroviral therapy regimen plus optional patient information. The objective of this study was to compare the EuResist system vs. human experts (EVE) for the ability to predict response to treatment. METHODS: The EuResist system was compared with 10 HIV-1 drug resistance experts for the ability to predict 8-week response to 25 treatment cases derived from the EuResist database validation data set. All current and past patient data were made available to simulate clinical practice. The experts were asked to provide a qualitative and quantitative estimate of the probability of treatment success. RESULTS: There were 15 treatment successes and 10 treatment failures. In the classification task, the number of mislabelled cases was six for EuResist and 6-13 for the human experts [mean±standard deviation (SD) 9.1±1.9]. The accuracy of EuResist was higher than the average for the experts (0.76 vs. 0.64, respectively). The quantitative estimates computed by EuResist were significantly correlated (Pearson r=0.695, P<0.0001) with the mean quantitative estimates provided by the experts. However, the agreement among experts was only moderate (for the classification task, inter-rater κ=0.355; for the quantitative estimation, mean±SD coefficient of variation=55.9±22.4%). CONCLUSIONS: With this limited data set, the EuResist engine performed comparably to or better than human experts. The system warrants further investigation as a treatment-decision support tool in clinical practice.

Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVES: Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. METHODS: Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (> or = 3, 1-2 or <1) or CD4 (> or = 3 or <3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (<400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively. RESULTS: Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) and 'Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P<0.001] and reporting 'Other' HIV exposures experienced reduced suppression (OR=0.28; P<0.001). CONCLUSION: Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites with VL testing less than once per year.

HIV stigma, disclosure and psychosocial distress among Thai youth living with HIV.

The objective of the present paper is to assess stigma and to create an abbreviated 12-item Stigma Scale based on the 40-item Berger's Stigma Scale for Thai youth living with HIV (TYLH). TYLH aged 16-25 years answered the 40-item Stigma Scale and the questionnaires on mental health, social support, quality of life and alcohol/substance use. Sixty-two (88.6%) of 70 TYLH reported at least one person knowing their serostatus. Men having sex with men were more likely to disclose the diagnosis to friends (43.9% versus 6.1%, P < 0.01) and less likely to disclose to families (47.6% versus 91.8%, P < 0.01). Women were more likely to disclose to families (90.2% versus 62.1%, P < 0.01) and less likely to disclose to friends (7.3% versus 31%, P < 0.05). The 12-item Stigma Scale was reliable (Cronbach's alpha, 0.75) and highly correlated with the 40-item scale (r = 0.846, P < 0.01). Half of TYLH had mental health problems. The 12-item Stigma Scale score was significantly associated with mental health problems (beta = 0.21, P < 0.05). Public attitudes towards HIV were associated with poorer quality of life (beta = -1.41, P < 0.01) and mental health problems (beta = 1.18, P < 0.01). In conclusion, the12-item Stigma Scale was reliable for TYLH. Increasing public understanding and education could reduce stigma and improve mental health and quality of life in TYLH.

Deferred modification of antiretroviral regimen following documented treatment failure in Asia: results from the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVE: The aim of the study was to examine the rates and predictors of treatment modification following combination antiretroviral therapy (cART) failure in Asian patients with HIV enrolled in the TREAT Asia HIV Observational Database (TAHOD). METHODS: Treatment failure (immunological, virological and clinical) was defined by World Health Organization criteria. Countries were categorized as high or low income by World Bank criteria. RESULTS: Among 2446 patients who initiated cART, 447 were documented to have developed treatment failure over 5697 person-years (7.8 per 100 person-years). A total of 253 patients changed at least one drug after failure (51.6 per 100 person-years). There was no difference between patients from high- and low-income countries [adjusted hazard ratio (HR) 1.02; P=0.891]. Advanced disease stage [Centers for Disease Control and Prevention (CDC) category C vs. A; adjusted HR 1.38, P=0.040], a lower CD4 count (>or=51 cells/microL vs. or=400 HIV-1 RNA copies/mL vs. <400 copies/mL; adjusted HR 2.69, P<0.001) were associated with a higher rate of treatment modification after failure. Compared with patients from low-income countries, patients from high-income countries were more likely to change two or more drugs (67%vs. 49%; P=0.009) and to change to a protease-inhibitor-containing regimen (48%vs. 16%; P<0.001). CONCLUSIONS: In a cohort of Asian patients with HIV infection, nearly half remained on the failing regimen in the first year following documented treatment failure. This deferred modification is likely to have negative implications for accumulation of drug resistance and response to second-line treatment. There is a need to scale up the availability of second-line regimens and virological monitoring in this region.

Anal squamous intraepithelial lesions among HIV positive and HIV negative men who have sex with men in Thailand.

OBJECTIVES: To evaluate the prevalence and risk factors of anal squamous intraepithelial lesions (ASIL), the putative anal cancer precursor, in Asian HIV positive and HIV negative men who have sex with men (MSM). METHODS: Men who underwent anal Pap smear reported clinical, sociodemographic and behavioural information collected through questionnaire and interview between January 2007 and April 2008. Chi(2) and logistic regression were used to evaluate ASIL prevalence and risk factors among HIV positive and HIV negative MSM. RESULTS: Of the 174 MSM (mean age 32.1 years), 118 (67.8%) were HIV positive. Overall, 27% had abnormal anal cytology: 13.2% had atypical squamous cells of undetermined significance (ASC-US), 11.5% had low-grade squamous intraepithelial lesion (LSIL) and 2.3% had high-grade squamous intraepithelial lesion (HSIL). Prevalence of ASIL was higher among HIV positive than HIV negative MSM (33.9% vs 12.5%; p = 0.003). Among HIV positive MSM, 16.1% had ASC-US, 14.4% had LSIL and 3.4% had HSIL and 7.1%, 5.4% and 0% in HIV negative MSM, respectively. Anal condyloma was detected in 22% of HIV positive and 16.1% (9/56) of HIV negative MSM (p = 0.5). In HIV positive MSM, anal condyloma (OR 3.42, 95% CI 1.29 to 9.04; p = 0.01) was a significant risk factor for ASIL. Highly active antiretroviral therapy use and CD4+ T cell count were not associated with ASIL. CONCLUSIONS: One-third of HIV positive and 12.5% of HIV negative MSM had ASIL. Thus, as greater numbers of HIV positive MSM live longer due to increasing access to HAART worldwide, effective strategies to screen and manage anal precancerous lesions are needed.

A low dose of ritonavir-boosted atazanavir provides adequate pharmacokinetic parameters in HIV-1-infected Thai adults.

Several dose-finding studies of boosted protease inhibitors have demonstrated that doses lower than those recommended in Caucasian populations exhibit in the Thai population similar pharmacokinetic (PK) properties with sustained virological suppression but reduced toxicity. We therefore evaluated the PK profiles of lower than the standard doses of atazanavir/ritonavir (ATV/RTV) in 22 adult Thai patients with well-suppressed human immunodeficiency virus 1 (HIV-1) infection. The PK parameters of ATV/RTV at a dosage of 200/100 mg once daily, plus two nucleoside reverse transcriptase inhibitors, were significantly lower than those associated with a dosage of 300/100 mg once daily in the same patients. In addition, the PK parameters for the lower dosage in these Thai patients were comparable to historical data from Caucasian cohorts who received the standard dose of ATV/RTV (300/100 mg). None of the patients showed subtherapeutic values of <0.15 mg/l at any time point. Bilirubin concentration decreased significantly after dose reduction, and viral load remained at <50 copies/ml in all subjects. Therefore, ATV/RTV at a dose of 200/100 mg once daily (plus appropriate backbone medication) warrants further long-term efficacy studies, particularly in patients of Thai and other Asian ethnicities.

Preference for CD4-guided versus continuous HARRT in Thailand.

Nineteen patients who completed a 27-month CD4-guided structured treatment interruption (STI) trial that showed similar efficacy in STI and continuous arms were asked to choose CD4-guided versus continuous HAART after the study ended. Six chose STI and 13 chose continuous HAART. Reasons for not choosing STIs were fear of developing HIV-related illnesses (38%), fear of CD4 drop (30.8%), fear of viral load increase (7.7%) and ease (7.7%). Those who preferred CD4-guided HAART had a higher median CD4 count nadir during STI and fewer on-off cycles. This study provides an important insight into the preference of patients towards STI in a resource-limited setting.

Transtheoretical model and risky sexual behaviour in HIV + youth in Thailand.

The purpose of the study was to determine the applicability of the Transtheoretical Model for predicting unprotected intercourse in HIV+ Thai youth. Questionnaires and interviews about sexual behaviour, readiness to change, self-efficacy, substance use, emotional distress and social support were obtained from 70 HIV+ Thai youth (ages 17 to 25). Path analysis suggested the model was an excellent fit with the data. Readiness to change but not self-efficacy was directly related to unprotected intercourse acts. This differed from HIV+ youth in the US where self-efficacy fully mediated the relationship between readiness to change and condom use. In the Thai sample, social support and self-efficacy were indirectly related to unprotected intercourse through stage of change. Substance use was unrelated to unprotected intercourse, but rates of use were low. Potential cultural differences in the construct of self-efficacy and its relationship to risky behaviours in Thailand require further study. However, results highlight the potential of prevention interventions that increase readiness to change through boosting self-efficacy and social support specific to practicing safer sex while addressing mental health concerns.

Nevirapine-associated toxicity in HIV-infected Thai men and women, including pregnant women.

OBJECTIVES: The aim of the study was to determine the incidence of, and risk factors for, nevirapine (NVP)-associated hepatotoxicity and rash in HIV-infected Thai men and women, including pregnant women, receiving NVP-containing highly active antiretroviral therapy (HAART). METHODS: NVP-containing HAART was prescribed to eligible men and women enrolled in the Prevention of Mother-To-Child Transmission of HIV (PMTCT) and MTCT-Plus programmes. All pregnant women received zidovudine (ZDV)/lamivudine (3TC)/NVP from >14 weeks of gestational age if their CD4 cell count was 28 weeks if their CD4 cell count was >200 cells/microL. Patients followed for at least 8 weeks after starting HAART or until delivery were included in the analyses. RESULTS: Of 409 patients, 244 were pregnant women, 87 were nonpregnant women and 78 were men. Hepatotoxicity occurred in 15.6% of all patients. Men had a significantly higher rate of asymptomatic hepatotoxicity (P=0.021). Pregnant women receiving HAART for PMTCT (92% had CD4 cell counts >250 cells/microL) had a significantly higher rate of symptomatic hepatotoxicity (P=0.0003) than pregnant women receiving HAART for therapy. Rash occurred in 16.1% of all patients. The patients' sex and baseline CD4 cell count were not associated with the risk of hepatotoxicity or rash. NVP was discontinued in 4.2% and 6.8% of patients because of hepatotoxicity and rash, respectively. CONCLUSIONS: The incidence of NVP-related hepatotoxicity and rash in Thai adults is similar to incidences reported for other populations. While larger studies are needed, our data support continued use of NVP-containing regimens as first-line treatment in developing countries for HIV-infected patients, including pregnant women. Pregnant women with high CD4 cell counts may experience higher rates of symptomatic hepatotoxicity and thus require careful clinical and laboratory monitoring.

Experience with the use of a first-line regimen of stavudine, lamivudine and nevirapine in patients in the TREAT Asia HIV Observational Database.

BACKGROUND: The antiretroviral treatment (ART) combination of stavudine, lamivudine and nevirapine (d4T/3TC/NVP) is the most frequently used initial regimen in many Asian countries. There are few data on the outcome of this treatment in clinic cohorts in this region. METHODS: We selected patients from the TREAT Asia HIV Observational Database (TAHOD) who started their first ART regimen with d4T/3TC/NVP. Treatment change was defined as cessation of therapy or the addition or change of one or more drugs. Clinical failure was defined as diagnosis with an AIDS-defining illness, or death while on d4T/3TC/NVP treatment. RESULTS: The rate of treatment change among TAHOD patients starting d4T/3TC/NVP as their first antiretroviral treatment was 22.3 per 100 person-years, with lower baseline haemoglobin (i.e. anaemia) associated with slower rate of treatment change. The rate of clinical failure while on d4T/3TC/NVP treatment was 7.3 per 100 person-years, with baseline CD4 cell count significantly associated with clinical failure. After d4T/3TC/NVP was stopped, nearly 40% of patients did not restart any treatment and, of those who changed to other treatment, the majority changed to zidovudine (ZDV)/3TC/NVP and less than 3% of patients changed to a protease inhibitor (PI)-containing regimen. The rates of disease progression on the second-line regimen were similar to those on the first-line regimen. CONCLUSION: These real-life data provide an insight into clinical practice in Asia and the Pacific region. d4T/3TC/NVP is maintained longer than other first-line regimens and change is mainly as a result of adverse effects rather than clinical failure. There is a need to develop affordable second-line antiretroviral treatment options for patients with HIV infection in developing countries.

Predictive factors for immunological and virological endpoints in Thai patients receiving combination antiretroviral treatment.

BACKGROUND: Routine CD4 count and HIV viral load monitoring is a financial barrier in developing countries. METHODS: We assessed factors associated with CD4 counts < or =200 cells/microL and detectable viral load in Thai HIV-infected patients receiving antiretroviral therapy (ART) at the HIV Netherlands Australia Thailand Research Collaboration and the Thai Red Cross AIDS Research Centre (HIV-NAT). Univariate and multivariate Cox proportional hazards models for multiple treatment failures were used to determine factors related to CD4 counts < or =200 cells/microL and detectable viral load. Multivariate Cox proportional hazards models for CD4 counts < or =200 cells/microL were developed with and without viral load in order to build models applicable to contexts in which viral load is not available. RESULTS: Four hundred and seventeen patients were included in the study. Fifty-four per cent were male, and the median CD4 count and log(10) viral load at baseline were 283 cells/microL and 4.3 log(10) HIV-1 RNA copies/mL, respectively. Independent factors related to CD4 count < or =200 cells/microL were CD4 count at baseline [hazards ratio (HR) 0.20/100 cells/microL; 95% confidence interval (CI) 0.17-0.23] and changes in CD4 count (HR 0.22/100 cells/microL; 95% CI 0.17-0.28). Factors in multivariate models (in which viral load was considered for inclusion) were CD4 count at baseline (HR 0.21/100 cells/microL; 95% CI 0.18-0.24), changes in CD4 count (HR 0.25/100 cells/microL; 95% CI 0.19-0.32) and detectable viral load (HR 1.94; 95% CI 1.20-3.13). Predictive factors (independent of viral load) were triple ART or highly active antiretroviral therapy (HAART) (HR 0.28; 95% CI 0.22-0.36) and detectable viral load at baseline (HR 2.96; 95% CI 2.24-3.91). Conclusions CD4 count at baseline and changes in CD4 count were important in predicting CD4 counts < or =200 cells/microL. Triple ART and detectable viral load at baseline were important in predicting detectable viral load.

Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors.

Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes.

Demographic predictors of a positive HIV test result among clients attending a large metropolitan voluntary counselling and testing centre in Thailand.

OBJECTIVES: The Thai Red Cross Anonymous Clinic in Bangkok, established in 1991, was the first centre in Asia to provide anonymous, voluntary counselling and testing for HIV infection. We present outcomes of testing for the period 1997-2004. METHODS: Newcomers to the Thai Red Cross Anonymous Clinic were invited to complete a brief questionnaire concerning HIV risk behaviour and personal characteristics. The questionnaire was linked by code numbers to the HIV test result. Information obtained from the pretest questionnaire and HIV antibody test results from January 1997 to December 2004 were analysed. Data are presented as means [with standard deviation (SD)], medians [with interquartile range (IQR)] or percentages. Multivariate analysis using logistic regression was performed to identify factors predicting a positive HIV test result. RESULTS: Over the 8-year study period, 65,807 new clients attended the clinic. Two-thirds were male and the mean age was 31.7 years (SD 9 years), and more than half were single. The proportion of high-school graduates was 43%, and 36% earned more than 10,000 Baht a month (40 Baht:1 US dollar). Of 54,578 new clients who had an HIV test during the study period, 17.5% had a positive test result. In multivariate analysis, predictive factors for HIV positivity included female gender, age group 25-34 years, widowed status (women), residence outside Bangkok, birthplace in a northern province, no formal schooling, farmer as profession, and salary less than 5000 Baht a month (the current legal minimum daily wage set by the Thai Ministry of Labor is 181 Baht). CONCLUSIONS: With nearly 7000 clients newly tested for HIV infection each year, the Anonymous Clinic in Bangkok has provided a unique epidemiological window into the patterns of HIV infection in the Thai capital.

Effects of nandrolone decanoate compared with placebo or testosterone on HIV-associated wasting.

Objectives Current research is unclear about the most effective pharmacological agents for managing the loss of weight and fat-free mass common in HIV/AIDS. The aim of this study was to compare nandrolone decanoate with placebo and testosterone. Methods The study was a multicentre randomized double-blind placebo-controlled trial. Three hundred and three adult HIV-positive male patients with a weight loss of 5-15% in the last 12 months, or a body mass index of 17-19 kg/m(2), or a body cell mass/height ratio lower than 13.5 kg/m, were randomly assigned to receive nandrolone decanoate (150 mg), testosterone (250 mg) or placebo intramuscularly every 2 weeks for 12 weeks. Fat-free mass, weight, immune markers and perception of treatment were the main outcome measures. Results Treatment with nandrolone resulted in significantly greater increases in fat-free mass [mean increase 1.34 kg; 95% confidence interval (CI) 0.60; 2.08 kg] and in weight (mean increase 1.48 kg; 95% CI 0.82; 2.14 kg) compared with placebo. The mean increase in weight with nandrolone of 1.00 kg (95% CI 0.27; 1.74 kg) when compared with testosterone was significant, although the difference in fat free mass did not reach significance (mean increase 0.69 kg; 95% CI-0.13; 1.51 kg). Patient perception of benefit was significantly greater in the nandrolone group when compared with both the placebo and the testosterone groups. Conclusions Treatment with nandrolone decanoate increased body weight when compared with placebo and testosterone. Nandrolone decanoate treatment resulted in greater increases in fat-free mass than placebo and demonstrated a trend for a significant increase when compared with testosterone.

Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009.

OBJECTIVE: Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity. METHODS: Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat. RESULTS: Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved. CONCLUSIONS: IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.