Publications by authors named "Sophie Le Coeur"

54 Publications

Cervical Human Papillomavirus Infection (HPV) and High Oncogenic Risk Genotypes among Women Living with HIV in Asia: A Meta-Analysis.

J Clin Med 2021 Apr 28;10(9). Epub 2021 Apr 28.

Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand.

Women living with HIV (WLHIV) are prone to harbor several high-risk human papillomavirus (HR-HPV) genotypes and to develop cervical cancerous lesions. Data on HPV prevalence in these women are needed to inform immunization programs, especially in Asia where few data are available. We conducted a systematic review and meta-analysis to estimate the prevalence of HPV and HR-HPV cervical infection in WLHIV in Asia and identify possible sources of heterogeneity for HR-HPV carriage. Pooled prevalence and its 95% confidence interval (95CI) were estimated using the inverse-variance weighting method. Linear regression weighted on study size was used to identify sources of heterogeneity. Among 7834 WLHIV (40 studies), the prevalence of HPV infection was 42.6% (95CI, 38.2% to 47.1%), and 34.6% (95CI, 30.3% to 39.1%) harbored HR-HPV genotypes, with significant heterogeneity across countries. In India, Thailand, and China, HPV-16 was the most frequent genotype (10.3%), followed by HPV-52 (5.4%), HPV-58 (5.0%), HPV-18 (4.1%), and HPV-33 (3.3%). In these women, most of whom were receiving antiretroviral therapy, we did not identify determinants of heterogeneity for HR-HPV infection. Our results underline the need for immunization programs based on nonavalent or new generation vaccines to prevent cervical cancer in WLHIV in Asia.
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http://dx.doi.org/10.3390/jcm10091911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125216PMC
April 2021

COVID-19 Epidemic: Early Shift in the Socioeconomic Profile of the Affected Population.

Int J Environ Res Public Health 2021 03 19;18(6). Epub 2021 Mar 19.

Institut National d'Etudes Démographiques (Ined), 9 Cours des Humanités, 93300 Aubervilliers, France.

The COVID-19 pandemic has given rise to a wealth of literature in the public health field [...].
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http://dx.doi.org/10.3390/ijerph18063185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003517PMC
March 2021

School trajectory disruption among adolescents living with perinatal HIV receiving antiretroviral treatments: a case-control study in Thailand.

BMC Public Health 2021 01 21;21(1):189. Epub 2021 Jan 21.

Institut national d'études démographiques (INED), Paris, France.

Background: Adolescents living with perinatal HIV often experience difficult living circumstances that can impact educational achievement and thus their transition to adult life. We explored their school trajectories and evaluated the contribution of perinatal HIV-infection, in Thailand, where education is free and compulsory until the age of 15.

Methods: We used data from the Teens Living with Antiretrovirals (TEEWA) study, a cross-sectional case-control study conducted from 2011 to 2014 in Thailand. Participants were 707 adolescents living with perinatal HIV (ALPHIV, cases) aged 12-19 receiving antiretroviral therapy in 19 hospitals throughout Thailand and 689 HIV-uninfected adolescents (controls) living in the same institutions or, for those living in family settings, randomly selected from the general population and individually matched for sex, age, and place of residence. School trajectory disruption was defined as ≥1 year of academic delay or as early school dropout (before 15 years of age). Logistic regression models were used to assess factors independently associated with disrupted school trajectory and to estimate the proportion of school disruption attributable to HIV-infection. We used multivariate imputations by chained equations (MICE) to manage missing data and performed two sensitivity analyses to evaluate the main model's reliability.

Results: The study population's median age was 14.5 years (58% female). School trajectory disruption was experienced by 37% of ALPHIV and 12% of the controls. After adjusting for sociodemographic factors, ALPHIV were 5 times more likely to experience disruption than controls (OR =5.2 [3.7-7.2]). About 50% of school trajectory disruption was attributable to HIV-infection. Males and adolescents living in institutions were more likely to experience school trajectory disruption (OR =1.8 [1.3-2.4] and OR =11.0 [7.7-15.8], respectively). Among ALPHIV, neurocognitive difficulties and growth delay were significantly associated with disruption (OR =3.3 [2.1-5.2] and OR =1.8 [1.3-2.6], respectively). For those living in families, disruption was also associated with having a caregiver who had less than a secondary-level education (OR =2.1 [1.1-3.9]) or having experienced stigmatization (OR =1.9 [1.2-3.1]).

Conclusions: HIV and contextual factors combine to aggravate the educational disadvantage among ALPHIV. The impact of this disadvantage on their life prospects, especially regarding access to higher education and professional achievement, should be further explored.
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http://dx.doi.org/10.1186/s12889-021-10189-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818931PMC
January 2021

Risky injection practices and HCV awareness in Chiang Mai Province, Thailand: a respondent-driven sampling study of people who inject drugs.

BMC Public Health 2020 Sep 24;20(1):1450. Epub 2020 Sep 24.

French National Research Institute for Sustainable Development (IRD), IRD174/PHPT, 195 Kaew Nawarat Road (3-4 Fl.) Wat Ked, Muang Chiang Mai, 50000, Thailand.

Background: People who inject drugs (PWID) are the most exposed to hepatitis C virus (HCV). In Thailand, drug use is highly criminalized, and harm reduction services are scarce. This study estimates risky injection practices and assesses the proportion of HCV awareness and screening in the PWID population in Northern Thailand.

Methods: We used respondent-driven sampling (RDS) to recruit PWID in Chiang Mai Province. Social and behavioural data were collected through face-to-face interviews at an addiction treatment facility. Weighted population estimates were calculated to limit biases related to the non-random sampling method. Univariate and multivariate analyses were performed to study factors associated with HCV awareness and screening.

Results: One hundred seventy-one PWID were recruited between April 2016 and January 2017. Median age was 33 (Interquartile range: 26-40) years, 12.2% were women, and 49.4% belonged to a minority ethnic group. Among participants, 76.8% injected heroin, 20.7% methadone, and 20.7% methamphetamine. We estimate that 22.1% [95% CI: 15.7-28.6] of the population had shared needles in the last 6 months and that 32.0% [95% CI: 23.6-40.4] had shared injection material. Only 26.6% [95% CI: 17.6-35.6] had heard of HCV. Factors independently associated with knowledge of HCV included belonging to a harm reduction organization (adjusted odds ratio (aOR) = 5.5 [95% CI: 2.0-15.3]) and voluntary participation in a drug rehabilitation programme (aOR = 4.3 [95% CI: 1.3-13.9]), while Lahu ethnicity was negatively associated (aOR = 0.3 [95% CI: 0.1-0.9]). We estimate that 5% of the PWID population were screened for HCV; the only factor independently associated with being screened was membership of a harm reduction organization (aOR = 5.7 [95% CI: 1.6-19.9]).

Conclusion: Our study reveals that the PWID population is poorly informed and rarely screened for HCV, despite widespread risky injection practices. A public health approach aimed at reducing the incidence of HCV should target the PWID population and combine harm reduction measures with information and destigmatization campaigns. Civil society organizations working with PWID are a major asset for the success of such an approach, based on their current positive interventions promoting awareness of and screening for HCV.
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http://dx.doi.org/10.1186/s12889-020-09549-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517806PMC
September 2020

Perinatal Antiretroviral Intensification to Prevent Intrapartum HIV Transmission When Antenatal Antiretroviral Therapy Is Initiated Less Than 8 Weeks Before Delivery.

J Acquir Immune Defic Syndr 2020 07;84(3):313-322

Institut de Recherche pour le Développement (IRD) U174/PHPT, Marseille, France.

Introduction: Infants born to women living with HIV initiating combination antiretroviral therapy (cART) late in pregnancy are at high risk of intrapartum infection. Mother/infant perinatal antiretroviral intensification may substantially reduce this risk.

Methods: In this single-arm Bayesian trial, pregnant women with HIV receiving standard of care antiretroviral prophylaxis in Thailand (maternal antenatal lopinavir-based cART; nonbreastfed infants 4 weeks' postnatal zidovudine) were offered "antiretroviral intensification" (labor single-dose nevirapine plus infant zidovudine-lamivudine-nevirapine for 2 weeks followed by zidovudine-lamivudine for 2 weeks) if their antenatal cART was initiated ≤8 weeks before delivery. A negative birth HIV-DNA polymerase chain reaction (PCR) followed by a confirmed positive PCR defined intrapartum transmission. Before study initiation, we modeled intrapartum transmission probabilities using data from 3738 mother/infant pairs enrolled in our previous trials in Thailand using a logistic model, with perinatal maternal/infant antiretroviral regimen and predicted viral load at delivery as main covariates. Using the characteristics of the women enrolled who received intensification, prior intrapartum transmission probabilities (credibility intervals) with/without intensification were estimated. After including the transmission data observed in the current study, the corresponding Bayesian posterior transmission probability was derived.

Results: No intrapartum transmission of HIV was observed among the 88 mother/infant pairs receiving intensification. The estimated intrapartum transmission probability was 2·2% (95% credibility interval 0·5-6·1) without intensification versus 0·3% (0·0-1·6) with intensification. The probability of superiority of intensification over standard of care was 94·4%. Antiretroviral intensification appeared safe.

Conclusion: Mother/infant antiretroviral intensification was effective in preventing intrapartum transmission of HIV in pregnant women receiving ≤8 weeks antepartum cART.
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http://dx.doi.org/10.1097/QAI.0000000000002350DOI Listing
July 2020

Incidence and risk factors of loss to follow-up among HIV-infected children in an antiretroviral treatment program.

PLoS One 2019 17;14(9):e0222082. Epub 2019 Sep 17.

Institut de recherche pour le développement (IRD, France), U174 -PHPT, Chiang Mai, Thailand.

Introduction: The success of antiretroviral treatment (ART) programs can be compromised by high rates of patient loss to follow-up (LTFU). We assessed the incidence and risk factors of LTFU in a large cohort of HIV-infected children receiving ART in Thailand.

Methods: All children participating in a multicenter cohort (NCT00433030) between 1999 and 2014 were included. The date of LTFU was 9 months after the last contact date. ART interruption was defined as ART discontinuation for more than 7 days followed by resumption of treatment. Baseline and time-dependent risk factors associated with LTFU were identified using Fine and Gray competing risk regression models with death or referral to another hospital as competing events.

Results: Of 873 children who were followed during a median of 8.6 years (interquartile range 4.5-10.6), 196 were LTFU, 73 died, and 195 referred. The cumulative incidence of LTFU was 2.9% at 1 year, 7.3% at 5 years and 22.2% at 10 years. Children aged 13 years and more had a 3-fold higher risk (95% confidence interval 2.06-4.78) of LTFU than those younger. Children who had interrupted ART within the previous year had a 2.5-fold higher risk (1.12-5.91) than those who had not. The risk of LTFU was lower in children stunted (height-for-age Z-scores <-2 SD) (0.42-0.96) or underweight (weight-for-age Z-scores <-2 SD) (0.24-0.97).

Conclusion: Adolescence, ART interruption and absence of growth deficit were associated with LTFU. These may be warnings that should draw clinicians' attention and possibly trigger specific interventions. Children with no significant growth retardation may also be at risk of LTFU.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222082PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748564PMC
March 2020

Impact of antiretroviral treatment on height evolution of HIV infected children.

BMC Pediatr 2019 08 17;19(1):287. Epub 2019 Aug 17.

Institut de recherche pour le développement (IRD) UMI 174-PHPT, Marseille, France.

Background: Antiretroviral treatment (ART) has been shown to have a beneficial effect on the weight evolution but its effect on height remains unclear. We described patterns of height evolution and identified predictors of catch-up growth in HIV-infected children on ART.

Methods: To describe the height evolution from birth to adulthood, we developed a nonlinear mixed effect model using data from perinatally HIV-infected children who initiated ART from 1999 to 2013 in a prospective cohort study in Thailand. The main covariates of interest were: sex, ART regimen (dual nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based), baseline CD4 percentage, HIV-RNA load and CDC HIV Classification stage and occurrence of AIDS-defining events.

Results: A total 477 children (43% boys) contributed 18,596 height measurements over a median duration of 6.3 years on ART (interquartile range, 3.0 to 8.3). At ART initiation, median age was 6.2 years (1.8 to 9.6), 16% of children were underweight (weight-for-age z-score < - 2), 49% presented stunting (height-for-age z-score < - 2), and 7% wasting (weight-for-height z-score < - 2). The most frequent regimen at ART initiation was NNRTI-based (79%). A model with 4 components, birth length and 3 exponential functions of age accounting for the 3 growth phases was developed and show that the height-growth velocity was inversely associated with the age at ART initiation, the adult height was significantly lower in those who had experienced at least one AIDS-defining event while, as expected, the model found that adult height in females was lower than in males. Age at ART initiation, type of ART regimen, CDC stage, CD4 percentages, and HIV-RNA load were not associated with the final height.

Conclusions: The younger the children at ART initiation, the greater the effect on height-growth velocity, supporting the World Health Organization's recommendation to start ART as early as possible. However, final adult height was not linked to the age at ART initiation.
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http://dx.doi.org/10.1186/s12887-019-1663-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697969PMC
August 2019

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

PLoS Med 2018 03 1;15(3):e1002514. Epub 2018 Mar 1.

National Institute of Child Health and Human Development (NICHD), US National Institutes of Health, Rockville, Maryland, United States of America.

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia.

Methods And Findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria.

Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.
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http://dx.doi.org/10.1371/journal.pmed.1002514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832192PMC
March 2018

Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study.

PLoS Med 2018 01 30;15(1):e1002491. Epub 2018 Jan 30.

Perinatal Prevention of AIDS Initiative, Odessa, Ukraine.

Background: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.

Methods And Findings: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.

Conclusions: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.
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http://dx.doi.org/10.1371/journal.pmed.1002491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790238PMC
January 2018

Contribution of Maternal Antiretroviral Therapy and Breastfeeding to 24-Month Survival in Human Immunodeficiency Virus-Exposed Uninfected Children: An Individual Pooled Analysis of African and Asian Studies.

Clin Infect Dis 2018 05;66(11):1668-1677

University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team IDLIC, France.

Background: Human immunodeficiency virus (HIV)-infected pregnant women increasingly receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggest HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but most evidence relates to the pre-ART era, breastfeeding of limited duration, and considerable maternal mortality. Maternal ART and prolonged breastfeeding while on ART may improve survival, although this has not been reliably quantified.

Methods: Individual data on 19 219 HEU children from 21 PMTCT trials/cohorts undertaken from 1995 to 2015 in Africa and Asia were pooled to estimate the association between 24-month mortality and maternal/infant factors, using random-effects Cox proportional hazards models. Adjusted attributable fractions of risks computed using the predict function in the R package "frailtypack" were used to estimate the relative contribution of risk factors to overall mortality.

Results: Cumulative incidence of death was 5.5% (95% confidence interval, 5.1-5.9) by age 24 months. Low birth weight (LBW <2500 g, adjusted hazard ratio (aHR, 2.9), no breastfeeding (aHR, 2.5), and maternal death (aHR, 11.1) were significantly associated with increased mortality. Maternal ART (aHR, 0.5) was significantly associated with lower mortality. At the population level, LBW accounted for 16.2% of 24-month mortality, never breastfeeding for 10.8%, mother not receiving ART for 45.6%, and maternal death for 4.3%; combined, these factors explained 63.6% of deaths by age 24 months.

Conclusions: Survival of HEU children could be substantially improved if public health practices provided all HIV-infected mothers with ART and supported optimal infant feeding and care for LBW neonates.
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http://dx.doi.org/10.1093/cid/cix1102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961296PMC
May 2018

Brief Report: AIDS-Defining Events and Deaths in HIV-Infected Children and Adolescents on Antiretrovirals: A 14-Year Study in Thailand.

J Acquir Immune Defic Syndr 2018 01;77(1):17-22

Institut de recherche pour le développement (IRD) UMI 174-PHPT, Marseille, France.

Background: Data are scarce on the long-term clinical outcomes of perinatally HIV-infected children and adolescents receiving antiretroviral therapy (ART) in low/middle-income countries. We assessed the incidence of mortality before (early) and after (late) 6 months of ART and of the composite outcome of new/recurrent AIDS-defining event or death >6 months after ART start (late AIDS/death) and their associated factors.

Methods: Study population was perinatally HIV-infected children (≤18 years) initiating ART within the Program for HIV Prevention and Treatment observational cohort (NCT00433030). Factors associated with late AIDS/death were assessed using competing risk regression models accounting for lost to-follow-up and included baseline and time-updated variables.

Results: Among 619 children, "early" mortality incidence was 99 deaths per 1000 person-years of follow-up [95% confidence interval (CI): 69 to 142] and "late" mortality 6 per 1000 person-years of follow-up (95% CI: 4 to 9). Of the 553 children alive >6 months after ART initiation, median age at ART initiation was 6.4 years, CD4% 8.2%, and HIV-RNA load 5.1 log10 copies/mL. Thirty-eight (7%) children developed late AIDS/death after median time of 3.3 years: 24 died and 24 experienced new/recurrent AIDS-defining events (10 subsequently died). Factors independently associated with late AIDS/death were current age ≥13 years (adjusted subdistribution hazard ratio 4.9; 95% CI: 2.4 to 10.1), HIV-RNA load always ≥400 copies/mL (12.3; 95% CI: 4.0 to 37.6), BMI-z-score always <-2 SD (13.7; 95% CI: 3.4 to 55.7), and hemoglobin <8 g/dL at least once (4.6; 95% CI: 2.0 to 10.5).

Conclusions: After the initial 6 months of ART, being an adolescent, persistent viremia, poor nutritional status, and severe anemia were associated with poor clinical outcomes. This supports the need for novel interventions that target children, particularly adolescents with poor growth and uncontrolled viremia.
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http://dx.doi.org/10.1097/QAI.0000000000001571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047734PMC
January 2018

Assessment of Nevirapine Prophylactic and Therapeutic Dosing Regimens for Neonates.

J Acquir Immune Defic Syndr 2017 08;75(5):554-560

*PHPT/IRD 174, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; †Department of Immunology and Infectious Diseases, Harvard T.H Chan School of Public Health, Boston, MA; ‡Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom; §Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand; ‖Institut d'Etudes Démographiques, Paris, France; ¶Institut de Recherche pour le Développement (IRD) UMI 174-PHPT, Marseille, France; #Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand; **Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA; ††Department of Pediatric, Health Promotion Center Region 10, Chiang Mai, Thailand; ‡‡Department of Pediatric, Banglamung Hospital, Chonburi, Thailand; §§Department of Pediatric, Nopparat Rajathanee Hospital, Bangkok, Thailand; ‖‖Department of Pediatric, Hat Yai Hospital, Hat Yai, Thailand; ¶¶Department of Pediatric, Samutprakarn Hospital, Samut Prakan, Thailand; ##Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom; and ***EAU7323 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Background: Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates.

Methods: The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies.

Results: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks.

Conclusion: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.
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http://dx.doi.org/10.1097/QAI.0000000000001447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508655PMC
August 2017

Human Papillomavirus infection and cervical lesions in HIV infected women on antiretroviral treatment in Thailand.

J Infect 2017 05 28;74(5):501-511. Epub 2017 Feb 28.

Institut de recherche pour le développement (IRD) UMI 174-PHPT, Marseille, France; Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; Institut National d'Etudes Démographiques (Ined), UR-5, Paris, France; Harvard T.H. Chan School of Public Health, Boston, MA, United States.

Objectives: To estimate the prevalence and factors associated with Human Papillomavirus (HPV) infection, HPV genotypes and cytological/histological high-grade (HSIL+/CIN2+) lesions.

Methods: We conducted a cross-sectional study within a prospective cohort of HIV-infected women on combination antiretroviral therapy (cART). Cervical specimens were collected for cytology and HPV genotyping (Papillocheck). Any women with High-Risk-HPV (HR-HPV), and/or potentially HR-HPV (pHR-HPV) and/or ASC-US or higher (ASC-US+) lesions were referred for colposcopy. Factors associated with HR-HPV infection and with HSIL+/CIN2+ lesions were investigated using mixed-effects logistic regression models.

Results: 829 women were enrolled: median age 40.4 years, on cART for a median of 6.9 years, median CD4 cell-count 536 cells/mm3, and 788 (96%) with HIV-viral load<50copies/mL. Of 214 (26%) infected with HPV: 159 (19%) had ≥1 HR-HPV, of whom 38 (5%) HPV52, 22 (3%) HPV16, 9 (1%) HPV18; 21 (3%) had pHR-HPV, 34 (4%) low risk-HPV infection, and 56 (26%) had multiple genotypes. Younger age, low CD4 cell-counts and low education were independently associated with HR-HPV infection. 72 women (9%) had ASC-US+ and 28 (3%) HSIL+/CIN2+ lesions. HR-HPV infection was independently associated with HSIL+/CIN2+ lesions.

Conclusion: The prevalence of HPV infection and of cervical lesions was low. The HPV genotype distribution supports the use of 9-valent vaccine in Thailand.
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http://dx.doi.org/10.1016/j.jinf.2017.02.007DOI Listing
May 2017

Factors influencing antiretroviral treatment suboptimal adherence among perinatally HIV-infected adolescents in Thailand.

PLoS One 2017 16;12(2):e0172392. Epub 2017 Feb 16.

Institut de recherche pour le développement (IRD) 174-PHPT, Chiang Mai, Thailand.

Background: Existing studies have suggested decreased adherence and rebound in mortality in perinatally HIV-infected adolescents receiving antiretroviral therapy (ART) as compared to adults and young children.

Methods: We used both quantitative and qualitative approaches to identify factors influencing adherence among perinatally infected adolescents in Thailand. We analyzed data from 568 pairs of perinatally infected adolescents (aged 12-19) and their primary caregivers in the Teens Living With Antiretrovirals (TEEWA) study, a cross-sectional survey conducted in 2010-2012. We also conducted 12 in-depth interviews in 2014 with infected adolescents or their primary caregivers to elicit experiences of living with long-term ART.

Results: From the quantitative analysis, a total of 275 (48.4%) adolescents had evidence of suboptimal adherence based on this composite outcome: adolescents self-reported missing doses in the past 7 days, caregiver rating of overall adherence as suboptimal, or latest HIV-RNA viral load ≥1000 copies/ml. In multivariate logistic regression analysis, younger age, having grandparents or extended family members as the primary caregiver, caregiver-assessed poor intellectual ability, having a boy/girlfriend, frequent online chatting, self-reported unhappiness and easiness in asking doctors questions were significantly associated with suboptimal adherence. From the in-depth interviews, tensed relationships with caregivers, forgetfulness due to busy schedules, and fear of disclosing HIV status to others, especially boy/girlfriends, were important contributors to suboptimal adherence. Social and emotional support and counseling from peer group was consistently reported as a strong adherence-promoting factor.

Conclusion: Our findings highlight unique barriers of ART adherence among the perinatally infected adolescents. Future interventions should be targeted at helping adolescents to improve interpersonal relationships and build adaptive skills in recognizing and addressing challenging situations related to ART taking.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172392PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312953PMC
September 2017

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

J Pediatric Infect Dis Soc 2017 Jun;6(2):161-167

Institut de Recherche Pour le Développement, Unité Mixte Internationale 174-Program for HIV Prevention and Treatment, Marseille, France.

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.
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http://dx.doi.org/10.1093/jpids/piw090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907848PMC
June 2017

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

J Clin Pharmacol 2016 09 24;56(9):1076-83. Epub 2016 Feb 24.

Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, France.

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, children's 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.
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http://dx.doi.org/10.1002/jcph.701DOI Listing
September 2016

Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy.

Antivir Ther 2016 22;21(5):435-40. Epub 2015 Oct 22.

Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand.

Background: Antiretroviral (ARV) regimens used for the prevention of mother-to-child transmission of HIV have evolved over time. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV RNA viral load (VL) during pregnancy.

Methods: A total of 1,833 VL measurements from ARV-naive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either zidovudine (ZDV) monotherapy, ZDV plus lopinavir/ritonavir (LPV/r), or ZDV plus lamivudine (3TC) plus LPV/r. VL time-course during pregnancy was described as a function of pretreatment VL and treatment duration using an Emax non-linear mixed-effect model. VL reduction and median time to achieve a VL<50 copies/ml were estimated for each regimen.

Results: Among 745 women, 279 (37%), 145 (20%) and 321 (43%) received ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of 10 weeks of treatment were 0.5, 2.7 and 2.9 log10 copies/ml with ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. At delivery, 1%, 57% and 63% of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+3TC+LPV/r had a VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r reduced the time to achieve a VL<50 copies/ml and the higher the pretreatment VL, the larger the effect 3TC had on reducing the time to VL<50 copies/ml.

Conclusions: The addition of 3TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL<50 copies/ml was shorter. This beneficial effect of 3TC is crucial for prevention of mother-to-child transmission in women who receive ARVs late and with high pretreatment VL.
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http://dx.doi.org/10.3851/IMP3001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440230PMC
January 2018

HIV-related stigma experiences: Understanding gender disparities in Thailand.

AIDS Care 2016 19;28(2):170-8. Epub 2015 Oct 19.

a Institut National d'Etude Démographique (INED), Centre Population & Développement UMR 196 (Paris Descartes-IRD) , Paris , France.

This paper assesses the relationship between gender and HIV-related stigma experiences among people living with HIV (PLHIV) - enacted and anticipated stigma - and PLHIV caregivers - courtesy stigma - in Northern Thailand, along with the underlying reasons for stigmatising attitudes towards PLHIV - instrumental and symbolic stigma - expressed in the general population. We used data from the Living With Antiretrovirals (LIWA) study conducted on all PLHIV receiving antiretroviral treatment in four district hospitals in Northern Thailand (n = 513) and on a community sample of adults from the general population (n = 500). Women living with HIV and female caregivers of PLHIV reported higher rates of HIV-related stigma experiences than men. Gender interacted with other predictors - the period of HIV diagnosis and age - to increase the level of stigma experienced. Among the general population, attitudes of contact avoidance were infrequent. However, stereotypes depicting PLHIV as blameworthy were highly pervasive, with women perceived as the "victims" of their spouse's irresponsible sexual behaviours. In this context, women were yet more often subjected to HIV-related stigma than men, in particular women diagnosed in the pre-antiretroviral therapy era and younger female caregivers. The role of gender in shaping disparities in HIV-related stigma experiences is discussed.
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http://dx.doi.org/10.1080/09540121.2015.1096888DOI Listing
April 2018

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

AIDS 2015 Nov;29(18):2497-507

aUnité Mixte Internationale 174, Institut de Recherche pour le Développement (IRD)-PHPT, Chiang Mai, Thailand bDepartment of Immunology and Infectious, Diseases, Harvard School of Public Health, Boston, Massachusetts, USA cDepartment of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand dUnité Mixte de Recherche 196, Centre Français de la Population et du Développement, (INED-IRD-Paris V University), Paris, France eDepartment of Statistics, Faculty of Science, Chiang Mai University, Chiang Mai fSanpatong Hospital, Ministry of Public Health, Sanpatong gSamutprakarn Hospital, Ministry of Public Health, Samutprakarn hBanglamung Hospital, Ministry of Public Health, Chonburi, Thailand iChildren's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA jFamily Health Research Center, Mahidol University, Bangkok, 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/μl 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.
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http://dx.doi.org/10.1097/QAD.0000000000000865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871947PMC
November 2015

Modeling of In-Utero and Intra-Partum Transmissions to Evaluate the Efficacy of Interventions for the Prevention of Perinatal HIV.

PLoS One 2015 19;10(5):e0126647. Epub 2015 May 19.

EAU08 Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France; CIC1419 INSERM, Cochin-Necker, Paris, France.

Background: Antiretroviral treatments decrease HIV mother-to-child transmission through pre/post exposure prophylaxis and reduction of maternal viral load. We modeled in-utero and intra-partum HIV transmissions to investigate the preventive role of various antiretroviral treatments interventions.

Methods: We analysed data from 3,759 women-infant pairs enrolled in 3 randomized clinical trials evaluating (1) zidovudine monotherapy, (2) zidovudine plus perinatal single-dose nevirapine or (3) zidovudine plus lopinavir/ritonavir for the prevention of mother-to-child transmission of HIV in Thailand. All infants were formula-fed. Non-linear mixed effect modeling was used to express the viral load evolution under antiretroviral treatments and the probability of transmission.

Results: Median viral load was 4 log10 copies/mL (Interquartile range: 3.36-4.56) before antiretroviral treatments initiation. An Emax model described the viral load time-course during pregnancy. Half of the maximum effect of zidovudine (28% decrease) and lopinavir/ritonavir (72% decrease) were achieved after 98 and 12 days, respectively. Adjusted on viral load at baseline (Odds ratio = 1.50 [95% confidence interval: 1.34, 1.68] per log10 copies/mL increment), antiretroviral treatments duration (OR = 0.80 [0.75, 0.84] per week increment) but not the nature of antiretroviral treatments were associated with in-utero transmission. Adjusted on gestational age at delivery (<37 weeks, OR = 2.37 [1.37, 4.10]), baseline CD4 (Odds ratio = 0.79 [0.72, 0.88] per 100 cells/mm3 increment) and predicted viral load at delivery (OR = 1.47 [1.25, 1.64] per log10 copies/mL increment), single-dose nevirapine considerably reduced intra-partum transmission (OR = 0.32 [0.2, 0.51]).

Conclusion: These models determined the respective contributions of various antiretroviral strategies on prevention of mother-to-child transmission. This can help predict the efficacy of new antiretroviral treatments and/or prevention of mother-to-child transmission strategies particularly for women with no or late antenatal care who are at high risk of transmitting HIV to their offspring.

Trial Registration: This analysis is based on secondary data obtained from three clinical trials. ClinicalTrials.gov. NCT00386230, NCT00398684, NCT00409591.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126647PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438074PMC
April 2016

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

J Acquir Immune Defic Syndr 2015 Aug;69(4):453-9

*Department of Statistics, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand; †Institut de recherche pour le développement (IRD) UMI 174-PHPT, Chiang Mai, Thailand; ‡Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; §Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA; ‖Nakornping Hospital, Chiang Mai, Thailand; ¶Prapokklao Hospital, Chantaburi, Thailand; #Chonburi Hospital, Chonburi, Thailand; **Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; ††Hat Yai Hospital, Songkla, Thailand; ‡‡Nong Khai Hospital, Nong Khai, Thailand; §§Samutsakhon Hospital, Samutsakhon, Thailand; ‖‖Mahasarakham Hospital, Mahasarakham, Thailand; ¶¶Sanpatong Hospital, Chiang Mai, Thailand; ##Institut National d'Etudes Démographiques, Paris, France; ***Sorbonne Universités, INSERM UPMC UMR_S938, APHP, Univ Paris 06, Paris, France; and †††INSERM U1153, Team ECSTRA, Université Paris Diderot-Paris 7, Hôpital Saint-Louis, Paris, France.

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 ≥ 2 00 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.
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http://dx.doi.org/10.1097/QAI.0000000000000647DOI Listing
August 2015

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

Clin Infect Dis 2015 Jul 1;61(1):95-101. Epub 2015 Apr 1.

Institut de Recherche pour le Développement, UMI 174-PHPT Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Thailand Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1093/cid/civ271DOI Listing
July 2015

No relationship between drug transporter genetic variants and tenofovir plasma concentrations or changes in glomerular filtration rate in HIV-infected adults.

J Acquir Immune Defic Syndr 2015 Apr;68(4):e56-9

*Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand †EAU08 University Paris Descartes and CIC1419 Inserm, Paris, France ‡Hopital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France §Unite de Recherche clinique, AP-HP, Hopital Tarnier, Paris, France ‖Institut de Recherche pour le Développement (IRD) UMI 174-Program for HIV Prevention and Treatment (PHPT), Marseille, France ¶Lamphun Hospital, Lamphun, Thailand #Maha Sarakham Hospital, Maha Sarakham, Thailand **Hat Yai Hospital, Songkhla, Thailand ††Harvard School of Public Health, Boston, MA ‡‡Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.

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http://dx.doi.org/10.1097/QAI.0000000000000504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334716PMC
April 2015

Psychometric assessment of health-related quality of life and symptom experience in HIV patients treated with antiretroviral therapy.

Qual Life Res 2015 Jun 7;24(6):1407-18. Epub 2014 Dec 7.

Patient-Centered Outcomes Research, Paris Sorbonne Cité, EA, 7334 (REMES), University Paris Diderot, Paris, France,

Purpose: Symptoms which are found to cluster consistently can have synergistic effects on patient outcomes and therefore may serve to predict morbidity or disentangle disease progression from comorbid conditions. Self-report HIV-specific symptom and HRQL measures were jointly analyzed in HIV-positive patients under different antiretroviral treatment regimens.

Methods: The responses of N = 365 patients from four countries to the 9-item Physical Health and Symptom dimension of the PROOQL-HIV questionnaire and an HIV Symptom checklist were analyzed. Item response modeling and multidimensional scaling were used to derive HRQL scores free of any differential item functioning related to gender and target language and to summarize symptom co-expression in patients under protease inhibitor treatment(PI, N = 164, 45%) versus other medication (Non-PI).

Results: Women reported poorer HRQL (p = 0:037), and HRQL did not differ between the target languages of French, English, and Thai. Fatigue, muscular pain, or difficulties falling asleep was the most frequently reported symptoms [35%). PI versus Non-PI patients exhibited different pattern of symptoms with lipodystrophy-related and gastrointestinal symptoms forming well-separated clusters in the PI group. A higher number of symptoms were associated with lower HRQL (p < 0:001), and patients taking PIs reported lower HRQL (p = 0:003). Patients in both groups who reported fatigue, sexual dysfunction, or several lipodystrophy-related symptoms had poorer quality of life.
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http://dx.doi.org/10.1007/s11136-014-0880-8DOI Listing
June 2015

Marital sex among people living with HIV receiving antiretroviral treatment in northern Thailand.

Cult Health Sex 2014 24;16(8):898-915. Epub 2014 Jun 24.

a Institut National d'Etudes Démographiques , Paris , France.

Before the advent of effective antiretroviral treatment (ART), the sexuality of people living with HIV was mostly discussed in terms of risk. To assess the extent to which ART allows people living with HIV to regain a regular sexual life, we surveyed all HIV-infected people treated in four hospitals in Northern Thailand and a control group from the general population matched by sex, age and residence. Data included socio-demographic and health characteristics, frequency of sexual intercourse in the last month and condom use. Our findings indicate that people living with HIV less often live in steady partnership (50% of the HIV-infected people versus 79% of the controls). After adjusting for factors known to influence sexuality, their probability of being sexually active was estimated to be about half that of the controls. When sexually active, men had a reduced sexual activity compared to controls (2.8 intercourse in the last month versus 4.0), while levels of reported sexual activity were similar among women (2.2 versus 2.8, respectively). Consistent condom use was high among people living with HIV (66% for women and 70% for men).
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http://dx.doi.org/10.1080/13691058.2014.920047DOI Listing
May 2015

Cost-effectiveness of early infant HIV diagnosis of HIV-exposed infants and immediate antiretroviral therapy in HIV-infected children under 24 months in Thailand.

PLoS One 2014 14;9(3):e91004. Epub 2014 Mar 14.

Institut de Recherche pour le Développement (IRD)-Programs for HIV Prevention and Treatment (PHPT), Chiang Mai, Thailand; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.

Background: HIV-infected infants have high risk of death in the first two years of life if untreated. WHO guidelines recommend early infant HIV diagnosis (EID) of all HIV-exposed infants and immediate antiretroviral therapy (ART) in HIV-infected children under 24-months. We assessed the cost-effectiveness of this strategy in HIV-exposed non-breastfed children in Thailand.

Methods: A decision analytic model of HIV diagnosis and disease progression compared: EID using DNA PCR with immediate ART (Early-Early); or EID with deferred ART based on immune/clinical criteria (Early-Late); vs. clinical/serology based diagnosis and deferred ART (Reference). The model was populated with survival and cost data from a Thai observational cohort and the literature. Incremental cost-effectiveness ratio per life-year gained (LYG) was compared against the Reference strategy. Costs and outcomes were discounted at 3%.

Results: Mean discounted life expectancy of HIV-infected children increased from 13.3 years in the Reference strategy to 14.3 in the Early-Late and 17.8 years in Early-Early strategies. The mean discounted lifetime cost was $17,335, $22,583 and $29,108, respectively. The cost-effectiveness ratio of Early-Late and Early-Early strategies was $5,149 and $2,615 per LYG, respectively as compared to the Reference strategy. The Early-Early strategy was most cost-effective at approximately half the domestic product per capita per LYG ($4,420 in Thailand 2011). The results were robust in deterministic and probabilistic sensitivity analyses including varying perinatal transmission rates.

Conclusion: In Thailand, EID and immediate ART would lead to major survival benefits and is cost- effective. These findings strongly support the adoption of WHO recommendations as routine care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091004PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954590PMC
December 2014

Five-year trends in antiretroviral usage and drug costs in HIV-infected children in Thailand.

J Acquir Immune Defic Syndr 2013 Sep;64(1):95-102

Program for HIV Prevention and Treatment, Institut de Recherche pour le Développement IRD UMI 174-PHPT, France.

Background: As antiretroviral treatment (ART) programs mature, data on drug utilization and costs are needed to assess durability of treatments and inform program planning.

Methods: Children initiating ART were followed up in an observational cohort in Thailand. Treatment histories from 1999 to 2009 were reviewed. Treatment changes were categorized as: drug substitution (within class), switch across drug class (non nucleoside reverse-transcriptase inhibitors (NNRTI) to/from protease inhibitor (PI)), and to salvage therapy (dual PI or PI and NNRTI). Antiretroviral drug costs were calculated in 6-month cycles (US$ 2009 prices). Predictors of high drug cost including characteristics at start of ART (baseline), initial regimen, treatment change, and duration on ART were assessed using mixed-effects regression models.

Results: Five hundred seven children initiated ART with a median 54 (interquartile range, 36-72) months of follow-up. Fifty-two percent had a drug substitution, 21% switched across class, and 2% to salvage therapy. When allowing for drug substitution, 78% remained on their initial regimen. Mean drug cost increased from $251 to $428 per child per year in the first and fifth year of therapy, respectively. PI-based and salvage regimens accounted for 16% and 2% of treatments prescribed and 33% and 5% of total costs, respectively. Predictors of high cost include baseline age ≥ 8 years, non nevirapine-based initial regimen, switch across drug class, and to salvage regimen (P < 0.005).

Conclusions: At 5 years, 21% of children switched across drug class and 2% received salvage therapy. The mean drug cost increased by 70%. Access to affordable second- and third-line drugs is essential for the sustainability of treatment programs.
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http://dx.doi.org/10.1097/QAI.0b013e318298a309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744770PMC
September 2013

Switching HIV treatment in adults based on CD4 count versus viral load monitoring: a randomized, non-inferiority trial in Thailand.

PLoS Med 2013 Aug 6;10(8):e1001494. Epub 2013 Aug 6.

Unité Mixte Internationale 174, Institut de Recherche pour le Développement (IRD)-Programs for HIV Prevention and Treatment (PHPT), Chiang Mai, Thailand.

Background: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.

Methods And Findings: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.

Conclusions: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.

Trial Registration: ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary.
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http://dx.doi.org/10.1371/journal.pmed.1001494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735458PMC
August 2013