Nicolas Salvadori

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.

Treatment Failure in HIV-Infected Children on Second-line Protease Inhibitor–Based Antiretroviral Therapy

BACKGROUND Human immunodeficiency virus (HIV)-infected children failing second-line antiretroviral therapy (ART) have no access to third-line antiretroviral drugs in many resource-limited settings. It is important to identify risk factors for second-line regimen failure. METHODS HIV-infected children initiating protease inhibitor (PI)-containing second-line ART within the Program for HIV Prevention and Treatment observational cohort study in Thailand between 2002 and 2010 were included. Treatment failure was defined as confirmed HIV type 1 RNA load >400 copies/mL after at least 6 months on second-line regimen or death. Adherence was assessed by drug plasma levels and patient self-report. Cox proportional hazards regression analyses were used to identify risk factors for failure. RESULTS A total of 111 children started a PI-based second-line regimen, including 59 girls (53%). Median first-line ART duration was 1.9 years (interquartile range [IQR], 1.4-3.3 years), and median age at second-line initiation was 10.7 years (IQR, 6.3-13.4 years). Fifty-four children (49%) experienced virologic failure, and 2 (2%) died. The risk of treatment failure 24 months after second-line initiation was 41%. In multivariate analyses, failure was independently associated with exposure to first-line ART for >2 years (adjusted hazard ratio [aHR], 1.8; P = .03), age >13 years (aHR, 2.9; P < .001), body mass index-for-age z score < -2 standard deviations at second-line initiation (aHR, 2.8; P = .03), and undetectable drug levels within 6 months following second-line initiation (aHR, 4.5; P < .001). CONCLUSIONS Children with longer exposure to first-line ART, entry to adolescence, underweight, and/or undetectable drug levels were at higher risk of failing second-line ART and thus should be closely monitored.

Efavirenz concentrations and probability of HIV replication in children

In 188 HIV-infected children receiving efavirenz, a lower mid-dose (C12) was associated with a higher risk of HIV-1 viral load >400 copies/mL (P = 0.03). Simulations for a normalized population receiving US Food and Drug Administration weight-band dosing predicted that 15% of children would have a C12 below target threshold (<1.0 mg/L) with a 23% risk of viral replication.

Incidence of Tuberculosis and Associated Mortality in a Cohort of Human Immunodeficiency Virus-Infected Children Initiating Antiretroviral Therapy

Abstract Background. We assessed the incidence of tuberculosis, risk factors for tuberculosis, and the contribution of tuberculosis on mortality in a large cohort of human immunodeficiency virus (HIV)-infected children <15 years of age initiating first-line antiretroviral therapy (ART) between 1999 and 2012 in Thailand, one of the 22 high tuberculosis burden countries. Methods. A physician reviewed and classified tuberculosis cases. Incidence was the number of children with incident tuberculosis, defined as a first or recurrent tuberculosis diagnosis >30 days after ART initiation, divided by the total person-years of follow-up (PYFU). Risk factors for incident tuberculosis were identified using Fine and Gray’s competing risks models, with death from other causes treated as a competing event, and risk factors for death were identified using Cox models. Results. At ART initiation, 670 children (55% female) had a median age of 6.4 years (interquartile range, 2.0–9.6), body mass index-for-age z-score −0.8 (−1.9 to 0.0), HIV ribonucleic acid viral load 5.1 log10 copies/mL (4.6–5.6), and CD4 9% (3–17). Median duration of follow-up was 7.7 years. Tuberculosis incidence was 7 per 1000 PYFU (95% confidence interval [CI], 5–11) and decreased with ART duration. Lower age-adjusted hemoglobin, hematocrit, and CD4 at ART initiation were associated with a higher risk of incident tuberculosis. Of the 30 incident tuberculosis cases, 9 died. Diagnosis of incident tuberculosis was associated with mortality (unadjusted hazard ratio = 10.2, 95% CI = 4.8–21.5, P < .001 and adjusted hazard ratio = 5.4, 95% CI = 2.5–11.7, P < .001). Conclusions. Incident tuberculosis was strongly associated with mortality. CD4 counts or hemoglobin or hematocrit levels may prompt clinicians to consider a possible tuberculosis infection.

Potential Missed Opportunities Related to the Systematic Screening for Hepatitis B Surface Antigen in Thailand

Background: In Thailand, hepatitis B surface antigen (HBsAg) testing is part of routine antenatal screening. We assessed the association between characteristics of pregnant women attending Samut Prakan Provincial Hospital antenatal care clinic (ANC) and their Hepatitis B virus (HBV) infection status. Methods: This is a cross-sectional study of pregnant women ≥ 18 yrs presenting at the ANC between August 1st, 2013 and June 30th, 2015. Data on socio-demographics, general physical examination, obstetrical and medical history and knowledge of HBV status were collected. Comparisons were performed using the Wilcoxon-Mann- Whitney test or Fisher’s exact test. Results: A total of 115 pregnant women, 18 HBsAg positive and 97 negative, participated. The women had a median age of 27.1 yrs (interquartile range (IQR): 22.4 to 31.5) at a median 28.0 weeks gestational age (IQR: 26.1 to 29.7). Forty-five (39%) reported being born abroad. Sixteen (14%) did not receive primary education. The women’s household contained a median of 3 persons (IQR: 2 to 4). None of these characteristics differed between HBsAg positive and negative women. HBsAg positive women were more likely to know their HBV status than HBsAg negative women [6 (33%)] vs. 12 [(12%), p=0.04] and their previous live offsprings’ HBV status [9 (60%)] vs. 21 [(26%), p=0.01]. In contrast, they were less likely to know their partner’s HBV status [3 (17%)] vs. 50 [(52%), p=0.009]. Conclusion: HBV chronic infection was not associated with any characteristics, which justifies systematic screening for HBsAg during antenatal care. The vast majority of women were not able to report their and their partner’s HBsAg status, underlining potential missed opportunities to be followed for their hepatitis B infection.

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz‐Based Regimens

Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral‐naive children in Thailand, we assessed indirect response models to describe the evolution of high‐ and low‐density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav) according to their assumed status of “fast” or “slow” metabolizers of efavirenz were performed. At treatment initiation, childrens median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z‐score 0.01 (–1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in “fast” metabolizers and 97 mg/dL in “slow” metabolizers of efavirenz. The population pharmacokinetic‐pharmacodynamic (PK‐PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment.