Virat Klinbuayaem

Association between Detection of HIV-1 DNA Resistance Mutations by a Sensitive Assay at Initiation of Antiretroviral Therapy and Virologic Failure

BACKGROUND Antiretroviral therapy (ART) has become more available throughout the developing world during the past 5 years. The World Health Organization recommends nonnucleoside reverse-transcriptase inhibitor-based regimens as initial ART. However, their efficacy may be compromised by resistance mutations selected by single-dose nevirapine (sdNVP) used to prevent mother-to-child transmission of human immunodeficiency virus (HIV)-1. There is no simple and efficient method to detect such mutations at the initiation of ART. METHODS One hundred eighty-one women who were participating in a clinical trial to prevent mother-to-child transmission and who started NVP-ART after they had received sdNVP or a placebo were included in the study. One hundred copies of each patients HIV-1 DNA were tested for NVP-resistance point-mutations (K103N, Y181C, and G190A) with a sensitive oligonucleotide ligation assay that was able to detect mutants even at low concentrations (> or = 5% of the viral population). Virologic failure was defined as confirmed plasma HIV-1 RNA >50 copies/mL after 6 to 18 months of NVP-ART. RESULTS At initiation of NVP-ART, resistance mutations were identified in 38 (26%) of 148 participants given sdNVP (K103N in 19 [13%], Y181C in 8 [5%], G190A in 28 [19%], and > or = 2 mutations in 15 [10%]), at a median 9.3 months after receipt of sdNVP. The risk of virologic failure was 0.62 (95% confidence interval [CI], 0.46-0.77) in women with > or = 1% resistance mutation, compared with a risk of 0.25 (95% CI, 0.17-0.35) in those without detectable resistance mutations (P < .001). Failure was independently associated with resistance, an interval of <6 months between sdNVP and NVP-ART initiation, and a viral load higher than the median at NVP-ART initiation. CONCLUSIONS Access to simple and inexpensive assays to detect low concentrations of NVP-resistant HIV-1 DNA before the initiation of ART could help improve the outcome of first-line ART.

Long-term outcomes of HIV-infected children in Thailand: the Thailand Pediatric HIV Observational Database

OBJECTIVE To describe the outcomes of antiretroviral therapy (ART) in a large cohort of HIV-infected children in Thailand. METHODS The data were obtained from four collaborative referral sites around the country. Data from 2008 to March 2011 were collected prospectively, and data before 2008 were collected retrospectively. RESULTS Of the 1139 children, 599 (52.6%) were female, and the duration of ART was a median 2.9 years (interquartile range (IQR) 3.3-5.5 years). At ART initiation, the median age was 7.1 years (IQR 3.4-10.0 years), CD4 percentage was 9.0% (IQR 3.0-17.0%), and 61.3% were in World Health Organization (WHO) stage 3 or 4. Seventy-four percent were initiated on an NNRTI-based regimen. The death and lost to follow-up rates were 1.3 (95% confidence interval (CI) 1.1-1.6) and 2.2 (95% CI 1.6-2.6)/100 patient-years of follow-up, respectively. At the last clinic visit of 919 children, the median CD4 percentage was 27.0% (IQR 23.0-32.0%) and 80.2% had HIV-RNA <40 copies/ml. WHO stage 1 or 2 at ART initiation was associated with having a viral load <40 copies/ml (p < 0.002), and baseline CD4 ≥15% and starting with a three-drug regimen were associated with achieving CD4 ≥25% (p<0.001). CONCLUSIONS Although most children initiated ART at low CD4 levels, the majority achieved immune reconstitution and long-term virological control. Earlier treatment may improve these outcomes.

Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial

BACKGROUND Thai patients with HIV have higher exposure to HIV protease inhibitors than do white people and dose reduction might be possible. We compared the efficacy of low-dose with standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai patients with HIV. METHODS In this randomised, open-label, non-inferiority trial, we recruited patients aged 18 years or older who were receiving ritonavir-boosted protease-inhibitor-based antiretroviral therapy (ART) with HIV plasma viral loads of less than 50 copies per mL, an alanine aminotransferase concentration of less than 200 IU/L, and a creatinine clearance of at least 60 mL/min from 14 hospitals in Thailand. We excluded patients who had active AIDS-defining disease or opportunistic infections, had a history of an HIV viral load of 1000 copies per mL or more after 24 weeks of any ritonavir-boosted protease-inhibitor-based ART, used concomitant medications that could interact with the study drugs, were pregnant or lactating, had illnesses that might change the effect of the study drugs, or had a history of sensitivity to the study drugs. A biostatistician at the study coordinating centre randomly allocated patients (1:1) to switch the protease inhibitor for oral atazanavir 200 mg and ritonavir 100 mg or for atazanavir 300 mg and ritonavir 100 mg once daily, both with two nucleoside or nucleotide reverse transcriptase inhibitors at recommended doses. Randomisation was done with a minimisation schedule, stratified by recruiting centre, use of tenofovir, and use of indinavir as a component of the preswitch regimen. The primary endpoint was the proportion of patients with viral loads of less than 200 copies per mL at week 48, and we followed up patients every 12 weeks. Treatments were open label, the non-inferiority margin was -10%, and all patients who received at least one dose of study medication were analysed. This trial is registered with ClinicalTrials.gov, number NCT01159223. FINDINGS Between July 6, 2011, and Dec 23, 2013, we randomly assigned 559 patients: 279 to receive atazanavir 200 mg and ritonavir 100 mg (low dose) and 280 to atazanavir 300 mg and ritonavir 100 mg (standard dose). At week 48, 265 (97·1%) of 273 in the low-dose group and 267 (96·4%) of 277 in the standard-dose group had viral loads of less than 200 copies per mL (difference 0·68; 95% CI -2·29 to 3·65). Seven (3%) of 273 in the low-dose group and 21 (8%) of 277 in the standard-dose group discontinued their assigned treatment (p=0·01). 46 (17%) of 273 participants in the low-dose group and 97 (35%) of 277 in the standard-dose group had total bilirubin grade 3 or higher toxicity (≥3·12 mg/dL; p<0·0001). INTERPRETATION A switch to low-dose atazanavir should be recommended for Thai patients with well controlled HIV viraemia while on regimens based on boosted protease inhibitors. FUNDING The National Health Security Office and Kirby Institute for Infection and Immunity in Society.

New-Onset Diabetes and Antiretroviral Treatments in HIV-Infected Adults in Thailand.

Background:Use of several antiretrovirals (ARVs) has been shown to be associated with a higher risk of diabetes in HIV-infected adults. We estimated the incidence of new-onset diabetes and assessed the association between individual ARVs and ARV combinations, and diabetes in a large cohort in Thailand. Methods:We selected all HIV-1–infected, nondiabetic, antiretroviral-naive adults enrolled in the Program for HIV Prevention and Treatment cohort (NCT00433030) between January 2000 and December 2011. Diabetes was defined as confirmed fasting plasma glucose ≥126 mg/dL or random plasma glucose ≥200 mg/dL. Incidence was the number of cases divided by the total number of person-years of follow-up. Association between ARVs and ARV combinations, and new-onset diabetes was assessed using Cox proportional hazards models. Results:Overall, 1594 HIV-infected patients (76% female) were included. Median age at antiretroviral therapy initiation was 32.5 years. The incidence rate of diabetes was 5.0 per 1000 person-years of follow-up (95% confidence interval: 3.8 to 6.6) (53 cases). In analyses adjusted for potential confounders, exposure to stavudine + didanosine [adjusted hazard ratio (aHR) = 3.9; P = 0.001] and cumulative exposure ≥1 year to zidovudine (aHR = 2.3 vs. no exposure; P = 0.009) were associated with a higher risk of diabetes. Conversely, cumulative exposure ≥1 year to tenofovir (aHR = 0.4 vs. no exposure; P = 0.02) and emtricitabine (aHR = 0.4 vs. no exposure; P = 0.03) were associated with a lower risk. Conclusions:The incidence of diabetes in this predominantly female, young, lean population was relatively low. Although stavudine and didanosine have now been phased out in most antiretroviral therapy programs, our analysis suggests a higher risk of diabetes with zidovudine, frequently prescribed today in resource-limited settings.

Plasma and Intracellular Pharmacokinetics of Tenofovir Disoproxil Fumarate 300 mg Every 48 Hours vs 150 mg Once Daily in HIV-Infected Adults With Moderate Renal Function Impairment

BACKGROUND The approved tenofovir disoproxil fumarate (TDF) dose of 300 mg every 48 hours for adults with moderate renal impairment is often confusing and inconvenient. Using a new TDF formulation, we compared the pharmacokinetics of the standard dose with a dose of 150 mg once daily in HIV-infected adults. METHODS This was an open-label pharmacokinetic study. Virologically suppressed HIV-infected adults with a creatinine clearance 30 to <50 mL/minute receiving TDF 300 mg every 48 hours as part of a nonnucleoside reverse transcriptase inhibitor (NNRTI)- or lopinavir/ritonavir (LPV/r)-based regimen were enrolled. Intensive 48-hour blood sampling for pharmacokinetic assessment was performed at enrollment, after which the TDF dose was changed to 150 mg once daily. Two weeks later, 24-hour blood sampling was performed; subjects then returned to the standard dose. Tenofovir (TFV) pharmacokinetic parameters were calculated using a noncompartmental analysis. RESULTS Forty adults (55% female) were enrolled: 20 receiving NNRTI-based and 20 receiving LPV/r-based treatment. Median age was 56 years (range, 44-65 years), weight 51 kg (range, 38-80 kg), and creatinine clearance 43.9 mL/minute (range, 30.9-49.7 mL/minute). The TFV geometric mean ratio of the area under the curve (AUC0-48 h) for every 24 hours vs every 48 hours was 1.09 (90% confidence interval [CI], .98-1.22) and 1.00 (90% CI, .92-1.09) for patients receiving NNRTI- and LPV/r-based treatment, respectively. Concomitant LPV/r use markedly increased TFV plasma concentrations, and AUC0-48 h was 67% higher with the standard dose, whereas no differences in intracellular TFV diphosphate concentrations were observed. All subjects remained virologically suppressed, and no drug-related adverse events were reported. CONCLUSIONS TDF 150 mg every 24 hours provides comparable systemic exposure to the standard dose of 300 mg every 48 hours in patients with moderate renal impairment. CLINICAL TRIALS REGISTRATION NCT01671982.

Depression and anxiety were low amongst virally suppressed, long-term treated HIV-infected individuals enrolled in a public sector antiretroviral program in Thailand*

ABSTRACT HIV/AIDS and anxiety/depression are interlinked. HIV-infected patients suffering from depression may be at risk for poor adherence which may contribute to HIV disease progression. Additionally, an HIV diagnosis and/or using certain antiretroviral agents may trigger symptoms of anxiety/depression. The objective of the study was to assess the prevalence and factors associated with anxiety and depression in HIV-infected patients from the Thai National HIV Treatment Program. This cross-sectional study was performed from January 2012 to December 2012 in HIV-infected out-patients, aged ≥18 years, from three HIV referral centers. Symptoms of anxiety and depression were measured using the Thai-validated Hospital Anxiety and Depression Scale (HADS). A score of ≥11 was defined as having anxiety and depression. Associated factors were assessed by multivariate logistic regression. Totally 2023 (56% males) patients were enrolled. All patients received antiretroviral therapy (ART) for a mean duration of 7.7 years. Median CD4 was 495 cells/mm3. Ninety-five percent had HIV-RNA < 50 copies/ml. Thirty-three percent were currently on efavirenz (EFV)-based ART. The prevalence of anxiety and depression were 4.8% and 3.1%, respectively. About 1.3% had both anxiety and depression. In multivariate logistic models, the female sex [OR = 1.6(95%CI 1.1–2.3), p = .01], having adherence <90% [OR = 2.2(95%CI 1.5–3.4), p < .001], fair/poor quality of life (QOL) [OR = 7.2 (95%CI 3.6–14.2), p < .001] and EFV exposure [OR = 1.6(95%CI 1.1–2.3), p = .01], were independently associated with having anxiety or depression. Our findings demonstrated that prevalence of depression and anxiety was low amongst virally suppressed, long-term antiretroviral-treated HIV-infected individuals. Some key characteristics such as the female sex, poor adherence, poor/fair QOL and EFV exposure are associated with anxiety and depression. These factors can be used to distinguish who would need a more in-depth evaluation for these psychiatric disorders.

Evolution of hematological parameters in HIV-1-infected patients with and without thalassemia carriages during highly active antiretroviral therapy.

Abstract Objectives: To assess the effects of highly active antiretroviral therapy (HAART) on hematological parameters in HIV-1-infected patients with and without thalassemia carriages. Methods: Prospective study was conducted in HIV-1-infected Thai patients receiving HAART. Their hematological parameters were measured at baseline and during follow-up of 1 year. β-thalassemia and hemoglobin-E trait were diagnosed using HPLC. PCR-genotyping techniques were used to investigate α-thalassemia-1 Southeast Asian type deletion and β-thalassemia mutation. The changes of hematological parameters were compared according to thalassemia carriage. Results: During follow-up, increased levels of CD4 counts, hemoglobin, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the groups of patients with and without thalassemia. The changes in mean hemoglobin level, MCV, and MCH in both groups appeared parallel, with consistently lower levels in patients with thalassemia. At Months 6 and 12, mean MCV of patients with thalassemia was shifted from microcytic levels (<80 fL) to normocytic levels (80–100 fL) while their mean MCH was increased to normal levels (27–31 pg). Conclusion: Although HAART altered hematological parameters such as MCV and MCH, it did not induce worsening anaemia, especially in patients with thalassemia carriages. However, the increased levels of MCV and MCH crucially affect the thalassemia screening.

Randomized noninferiority trial of two maternal single-dose nevirapine-sparing regimens to prevent perinatal HIV in Thailand.

Objectives:Perinatal single-dose nevirapine (sdNVP) selects for resistance mutations. The objective of this trial was to compare two maternal sdNVP-sparing regimens with standard zidovudine (ZDV)/sdNVP prophylaxis. Design:PHPT-5 was a randomized, partially double-blind placebo-controlled, noninferiority trial in Thailand (NCT00409591). Study participants were women with CD4+ of at least 250 cells/&mgr;l and their infants. Methods:All women received ZDV from 28 weeks’ gestation and their newborn infants for one week. Women were also randomized to receive NVP-NVP (reference): maternal intrapartum sdNVP with a 7-day ‘tail’ of ZDV along with lamivudine, and infant NVP (one dose immediately, another 48 h later); infant-only NVP: maternal placebos for sdNVP and the ‘tail’, with infant NVP; LPV/r: maternal LPV/r starting at 28 weeks. Infants were formula-fed. HIV-diagnosis was determined by DNA-PCR. Results:Four-hundred and thirty-five women were randomized between January 2009 and September 2010. Accrual was terminated prematurely following a change in Thai guidelines recommending antiretroviral combination therapy for all pregnant women. Data on 405 mothers and 407 live-born children were analyzed. Baseline characteristics were similar between arms. Intent-to-treat transmission rates were 3.8% (95% confidence interval: 1.2–8.6) in NVP-NVP, 1.6% (0.2–5.6) in infant-only NVP, and 1.4% (0.4–5.1) in LPV/r arms. As-treated rates were 2.2% (0.5–6.4), 3.2% (0.9–7.9), and 1.5% (0.2–5.2), respectively. Factors independently associated with transmission were prophylaxis duration less than 8 weeks (adjusted odds ratio 15.5; 3.6–66.1) and viral load at baseline at least 4 log10copies/ml (adjusted odds ratio 10.9; 1.3–91.5). Regimens appeared well tolerated. Conclusion:Transmission rates in all arms were low but noninferiority was not proven. Antiretroviral prophylaxis for at least 8 weeks before delivery is necessary to minimize transmission risk.

Chronic kidney disease incidence and survival of Thai HIV-infected patients

Objectives: As data on chronic kidney disease (CKD) incidence among Asian HIV patients has been limited, the present study aimed to estimate the CKD incidence in HIV-infected patients who received standard antiretroviral therapy in Thailand and to compare baseline demographics and clinical characteristics of the patients who developed CKD with those who do not. Design: A multicenter, observational prospective cohort of HIV patients with normal kidney functions who received standard antiretroviral therapy. Methods: CKD was diagnosed based on the KDIGO 2012 criteria, using Chronic Kidney Disease Epidemiology Collaboration based estimated glomerular filtration rate with and without urine protein. The cumulative probability of CKD incidence was analyzed using Kaplan–Meier estimation. Results: Of 5552 patients, 96 patients with pre-existing CKD and 26 patients with incomplete data were excluded, and 5430 patients were analyzed. Their mean age was 39.87 years, 41.52% were women, and 49.45% were homosexual. They were followed up for 49.41 months on average, with 229 incident cases (4.22%) being identified during 22 035 person-years at risk. Overall CKD incidence rate was 10.39 per 1000 person-years. Average time to CKD was 26.4 months (95% confidence interval: 24.44–28.83). The adjusted relative hazard significantly increased by 8.6% and 10.3% for each additional year of patient age and each additional log10 copies/ml of HIV viral load, respectively. Patients with diabetes mellitus and hypercholesterolemia had significantly higher adjusted relative hazard (3.37 and 1.41; P < 0.001 and P = 0.014), respectively. Conclusion: CKD incidence among the Thai HIV-infected patients was lower than in white and non-Southeast Asian populations. Diabetes, hypercholesterolemia, age, and HIV viral load were the significant risk factors. Trial registration: ClinicalTrials.gov identifier: NCT01328275.

Risk factor for isoniazid-resistance among pulmonary tuberculosis patients in Northern Thailand

Abstract The objective of this study was to analyze factors associated with isoniazid-resistance among pulmonary tuberculosis patients in Northern Thailand. Data was obtained from 36 hospitals in the area under supervision of The Office of Communicable Disease Prevention and Control Region 10, Chiang Mai, in which information of tuberculosis patients who had received isoniazid and was tested for resistance to the drug between 2003 and 2007 was collected. There were 504 patients who could be included in the analysis. These patients were divided into 2 groups through matching method (1:3) by using genders and age variables. There were 126 patients who were put into a “Case” group where patients showed resistance to isoniazid and 378 patients who were put into a “Control” group where patients showed no signs of resistance to the drug. Factors associated with isoniazid-resistance were assessed using univariate and multivariate conditional logistic regression analyses. It was found that 23.0% of patients in the case group and only 7.4% in the control group were relapsed patients. And, of these relapsed patients, the percentages of patients who had received treatment more than twice before were 27.6 and 10.7, respectively. After a univariate analysis, the following statistically significant factors contributing to the drug resistant condition were found: 1) type of patient 2) drug resistant tuberculosis mycobacterium infection 3) nontuberculoses mycobacterium infection 4) type of standard drugs treatment used, and 5) drugs’ side effect. When other variables were controlled, it was found that relapsed patient is 5.5 times more likely to be drug resistant than new patient. (95% confidence interval: 2.3–13.0). The results of this research indicated that doctors and healthcare personnel should be aware of whether the patient is a relapsed or a new patient and to closely monitor patient’s reaction to the treatment.