Publications by authors named "Marc Lallemant"

90 Publications

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

Abacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).
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http://dx.doi.org/10.1128/AAC.01923-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179606PMC
April 2020

Acceptability and Feasibility of Using Raltegravir Oral Granules for the Treatment of Neonates in a Low-resource Setting.

Pediatr Infect Dis J 2020 01;39(1):57-60

Treatment and Care, Department of HIV/AIDS, World Health Organisation, Geneva, Switzerland.

Background: Raltegravir granules for oral suspension, now recommended by World Health Organization for use in neonates with HIV infection, may be challenging for caregivers because of the multistep preparation required.

Methods: We evaluated the acceptability and feasibility of preparing granules for oral suspension in a low-to-middle-income country setting. Thirty-four caregivers and 10 health-care workers were enrolled from an HIV clinic in Durban, South Africa. Health-care workers were provided with pictorial instruction booklet, demonstration kit and guidance on preparation of granules for oral suspension. The health-care workers then trained caregivers on the preparation of granules for oral suspension. Caregivers were evaluated during the preparation process and instructed to practice at home with a sample kit and return to the clinic for repeat evaluation 5-7 days later. Caregivers and health-care workers were interviewed and participated in a focus group discussion regarding their experiences.

Results: The median age of the caregivers was 31 years (interquartile range: 9.7); 70% had received secondary-level education, 37% were employed. The median preparation time was 7.95 minutes (interquartile range: 5.08 minutes) and 7.48 minutes (3.55 minutes) at initial and repeated observation, respectively. Major errors were insufficient mixing time and incorrect suspension volume. The average number of errors between the 2 observation time points was significantly reduced at the repeat session (2.5 vs. 0.87, P = 0.023). Most participants found the preparation difficult at first but gained confidence over time.

Conclusion: Despite the complexity involved in the preparation of the granules for oral suspension, with practice, this formulation was found to be acceptable and feasible to majority of participants in this low-resource setting. As a result, this formulation was included in the 2018 World Health Organization recommendations for first line in neonates living with HIV.
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http://dx.doi.org/10.1097/INF.0000000000002539DOI Listing
January 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

Understanding acceptance of and adherence to a new formulation of paediatric antiretroviral treatment in the form of pellets (LPV/r)-A realist evaluation.

PLoS One 2019 21;14(8):e0220408. Epub 2019 Aug 21.

Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.

Background: Improving access to paediatric HIV treatment requires large-scale antiretroviral treatment programmes and medication adapted to infants and children's needs. The World Health Organisation recommends lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors as first-line treatment for all HIV-infected children younger than three years, usually given as a syrup. A pellet formulation (i.e. tiny cylinders of compressed medication put in capsules) was developed to overcome the syrup formulation's disadvantages such as bitterness, toxicity and cold storage. This study assessed multi-level factors influencing caregivers' acceptance of and adherence to lopinavir/ritonavir pellets as well as their underlying mechanisms.

Methods: A realist evaluation (a theory-driven evaluation method considering the social context and mechanisms of change), embedded in a clinical trial was carried out in three hospital settings in Kenya. Data were collected through document review, observations (n = 34) in home and clinic settings and semi-structured interviews (n = 44) with caregivers and providers. Data analysis was based on realist principles.

Results: High levels of treatment initiation and adherence were observed. Taste masking, neutral packaging and easy storage made the new formulation highly acceptable. Caregivers developed individual strategies to deliver the treatment, particularly to overcome specific problems e.g. in case of just-weaned babies or food shortage. A refined program theory emerged from the triangulated findings showing that ease of administration combined with increased self-efficacy and competences of the caregivers, and effective provider support contributed to high levels of adherence.

Conclusions: Formulating combined antiretroviral treatment in the form of pellets is clearly a more acceptable solution for infants and children and their caregivers compared to the syrup. Further research in non-trial settings may shed light on factors related to providers, services and the health system that contribute to better adherence of such formulations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220408PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703671PMC
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

Long term renal function in Asian HIV-1 infected adults receiving tenofovir disoproxil fumarate without protease inhibitors.

J Infect 2019 11 8;79(5):454-461. Epub 2019 Aug 8.

Institut de Recherche pour le Développement (IRD) Unit 174-PHPT, Kaew Nawarat Rd, Tambon Wat Ket, Amphoe Mueang Chiang Mai, Chiang Mai, Thailand; Harvard T.H. Chan School of Public Health, Boston, MA, USA; Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand. Electronic address:

Objectives: The risk of kidney dysfunction on the WHO recommended first line regimens containing tenofovir disoproxil fumarate (TDF) without protease inhibitors (PI) remains unclear in Asian patients, especially those with low body weight.

Methods: Using data collected in a multicenter clinical trial in Thailand and proportional hazard regression models, we compared the risk of a >25% estimated glomerular filtration rate (eGFR) reduction in HIV naïve patients initiating TDF or zidovudine (AZT) containing non-PI regimen.

Results: Of 640 patients included in the analysis, 461 (72%) received a TDF-containing regimen for a median 6.7 years and 179 (28%) an AZT-containing regimen for 6.5 years. The risk of a >25% eGFR reduction was not associated with treatment (HR 1.11, 95% CI 0.84-1.47, P = 0.46). In multivariate analysis, the risk of >25% eGFR reduction form baseline was associated with body weight at baseline (HR 2.12, 95% CI 1.48-3.02 for <48 kg patients and HR 1.64, 95% CI 1.20-2.25 for 48-59.9 kg patients, compared to those with >60 kg, P < 0.001) and hypertension (HR 4.03, 95% CI 2.0-8.0, P < 0.001). The effect of baseline weight on >25% eGFR reduction did not significantly vary with treatment (P = 0.27).

Conclusions: The risk of eGFR reduction was not higher on TDF- versus AZT-based non-PI regimens. Although the risk of eGFR reduction was greater for patients of lower body weight, this risk was not significantly increased by TDF.
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http://dx.doi.org/10.1016/j.jinf.2019.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825894PMC
November 2019

Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study.

Lancet HIV 2018 Dec 6. Epub 2018 Dec 6.

Drugs for Neglected Diseases Initiative, Geneva, Switzerland.

Background: Rifampicin reduces lopinavir concentrations in HIV and tuberculosis co-treated patients. We hypothesised that adding ritonavir to co-formulated lopinavir-ritonavir (4:1) to achieve a one-to-one ratio would overcome this drug-drug interaction in young children.

Methods: We did a prospective, open-label, one-group, one-sequence study at five sites in three South African provinces. We included HIV-infected children with tuberculosis, a bodyweight of 3-15 kg, and a post-conceptional age of more than 42 weeks. Children received the standard four-to-one ratio of lopinavir-ritonavir in the absence of rifampicin-based anti-tuberculosis treatment, whereas super-boosting of lopinavir-ritonavir with additional ritonavir was given orally twice a day to achieve a one-to-one ratio during rifampicin treatment. The primary outcome was the comparison of the proportion of children with predicted lopinavir morning minimum concentrations (C) of more than 1·0 mg/L during super-boosting with the proportion of more than 1·0 mg/L during standard lopinavir-ritonavir treatment without rifampicin. Lopinavir concentrations were determined before and at 1, 2, 4, 6, and 10 h after the morning dose during the second and the last month of tuberculosis co-treatment, and 4-6 weeks after stopping rifampicin. A non-linear mixed-effects model was implemented to interpret the data and Monte Carlo simulations were used to compare the percentage of lopinavir with morning C values of less than 1·0 mg/L for the two dosing schemes. A non-inferiority margin of 10% was used. This study is registered with ClinicalTrials.gov, number NCT02348177.

Findings: Between Jan 30, 2013, and Nov 9, 2015, 96 children with a median age of 18·2 months (IQR 9·6-26·8) were enrolled. Of these 96 children, 80 (83%) completed the first three pharmacokinetic evaluations. Tuberculosis therapy was started before antiretrovirals in 70 (73%) children. The model-predicted percentage of morning C of less than 1·0 mg/L after tuberculosis treatment without super-boosting was 8·8% (95% CI 0·6-19·8) versus 7·6% (0·4-16·2) during super-boosting and tuberculosis treatment. The difference of -1·1% (95% CI -6·9 to 3·2), at a non-inferiority margin of 10%, confirmed the non-inferiority of lopinavir trough concentrations during rifampicin co-treatment. 19 serious adverse events were reported in 12 participants. Three deaths and a temporary treatment interruption due to jaundice were unrelated to study treatment.

Interpretation: Lopinavir exposure with ritonavir super-boosting in a one-to-one ratio during rifampicin-based tuberculosis treatment was non-inferior to the exposure with lopinavir-ritonavir without rifampicin. Safe and effective, field application of super-boosting is limited by poor acceptability. Access to better adapted solid formulations will most likely facilitate public health implementation of this strategy.

Funding: DNDi, French Development Agency, UBS Optimus Foundation, and Unitaid.
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http://dx.doi.org/10.1016/S2352-3018(18)30293-5DOI Listing
December 2018

Optimizing Clinical Trial Design to Maximize Evidence Generation in Pediatric HIV.

J Acquir Immune Defic Syndr 2018 08;78 Suppl 1:S40-S48

MRC Clinical Trials Unit at UCL, University College London, London, United Kingdom.

For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.
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http://dx.doi.org/10.1097/QAI.0000000000001748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071856PMC
August 2018

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

Clin Infect Dis 2017 Jun;64(11):1597-1603

ICAP, Mailman School of Public Health.

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis.
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http://dx.doi.org/10.1093/cid/cix194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927327PMC
June 2017

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

Time to first positive HIV-1 DNA PCR may differ with antiretroviral regimen in infants infected with non-B subtype HIV-1.

AIDS 2017 11;31(18):2465-2474

aDepartment of Biostatistics and Epidemiology, University of Massachusetts-Amherst, Amherst, Massachusetts bDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland cDivision of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia dDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston eDepartment of Immunology and Infectious Diseases, Harvard University, T. H. Chan School of Public Health, Boston, Massachusetts, USA fBotswana Harvard AIDS Institute Partnership, Gaborone, Botswana gUniversity College Institute of Child Health, London, UK hInstitut de recherche pour le développement (IRD) UMI 174-PHPT, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand iDepartment of Biostatistics, Harvard University T. H. Chan School of Public Health, Boston, Massachusetts, USA jVirus Reference Department, National Infection Service, Public Health England, London, UK kDepartment of HIV/AIDS, World Health Organization, Geneva, Switzerland lDepartment of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand and National Institute for Communicable Diseases, Johannesburg, South Africa mSection of Infectious Diseases and International Health, Geisel School of Medicine at Dartmouth, 1 Medical Center Dr, Lebanon, New Hampshire nCenter for Biostatistics in AIDS Research, Harvard University T. H. Chan School of Public Health. Boston, Massachusetts, USA.

Objective: To evaluate the association of type and timing of prophylactic maternal and infant antiretroviral regimen with time to first positive HIV-1 DNA PCR test, in nonbreastfed HIV-infected infants, from populations infected predominantly with HIV-1 non-B subtype virus.

Design: Analysis of combined data on nonbreastfed HIV-infected infants from prospective cohorts in Botswana, Thailand, and the United Kingdom (N = 405).

Methods: Parametric models appropriate for interval-censored outcomes estimated the time to first positive PCR according to maternal or infant antiretroviral regimen category and timing of maternal antiretroviral initiation, with adjustment for covariates.

Results: Maternal antiretroviral regimens included: no antiretrovirals (n = 138), single-nucleoside analog reverse transcriptase inhibitor (n = 165), single-dose nevirapine with zidovudine (n = 66), and combination prophylaxis with 3 or more antiretrovirals [combination antiretroviral therapy (cART), n = 36]. Type of maternal/infant antiretroviral regimen and timing of maternal antiretroviral initiation were each significantly associated with time to first positive PCR (multivariate P < 0.0001). The probability of a positive test with no antiretrovirals compared with the other regimen/timing groups was significantly lower at 1 day after birth, but did not differ significantly after age 14 days. In a subgroup of 143 infants testing negative at birth, infant cART was significantly associated with longer time to first positive test (multivariate P = 0.04).

Conclusion: Time to first positive HIV-1 DNA PCR in HIV-1-infected nonbreastfed infants (non-B HIV subtype) may differ according to maternal/infant antiretroviral regimen and may be longer with infant cART, which may have implications for scheduling infant HIV PCR-diagnostic testing and confirming final infant HIV status.
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http://dx.doi.org/10.1097/QAD.0000000000001640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710822PMC
November 2017

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

Understanding the acceptability and adherence to paediatric antiretroviral treatment in the new formulation of pellets (LPV/r): the protocol of a realist evaluation.

BMJ Open 2017 03 29;7(3):e014528. Epub 2017 Mar 29.

Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.

Background: Improving access to paediatric HIV treatment requires both large-scale treatment programmes and medication that is adapted to infants and children's needs. The WHO recommends lopinavir/ritonavir as first-line antiretroviral therapy for all HIV-infected children younger than 3 years. There is currently little evidence on the acceptability of, and adherence to, a formulation of this combination treatment if given in the form of pellets. This protocol presents how we will carry a realist evaluation to assess the factors that contribute to the acceptability and adherence to the new pellets formulation in 3 hospitals in Kenya.

Methods: We structured the protocol along the realist evaluation cycle following 4 steps: (1) the initial programme theory, (2) the study design, (3) the data collection methods and (4) the data analysis plan. Theories of behavioural sciences were reviewed for frames that could provide insights into how using such new formulations may contribute to better acceptability and adherence.

Ethics And Dissemination: This study was approved by the Institutional Review Board of the Institute of Tropical Medicine, the Ethical Committee of the University Hospital Antwerp and the Kenyatta National Hospital/University of Nairobi Ethics and Research Committee. We aim to disseminate the findings through international conferences and peer-reviewed journals and to share them with Drugs for Neglected Diseases initiative's (DNDi) programme managers and with the Kenyan healthcare providers.

Discussion: In developing this study, we encountered some challenges. First, methods to measure the acceptability of any formulation and adherence to it are not standardised. The second challenge is common in realist evaluation and relates to how to choose from different potentially interesting theoretical frameworks. We identified relevant and empirically tested theories from behavioural science that may be helpful in our study. We will test them in 3 settings by exploring the multilevel factors that influence acceptability and adherence of this new paediatric Antiretroviral (ARV) formulation.
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http://dx.doi.org/10.1136/bmjopen-2016-014528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372016PMC
March 2017

Antiretroviral treatment in HIV-infected children who require a rifamycin-containing regimen for tuberculosis.

Expert Opin Pharmacother 2017 Apr 27;18(6):589-598. Epub 2017 Mar 27.

a Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences , Stellenbosch University and Tygerberg Hospital , Cape Town , South Africa.

Introduction: In high prevalence settings, tuberculosis and HIV dual infection and co-treatment is frequent. Rifamycins, especially rifampicin, in combination with isoniazid, ethambutol and pyrazinamide are key components of short-course antituberculosis therapy. Areas covered: We reviewed available data, for which articles were identified by a Pubmed search, on rifamycin-antiretroviral interactions in HIV-infected children. Rifamycins have potent inducing effects on phase I and II drug metabolising enzymes and transporters. Antiretroviral medications are often metabolised by the enzymes induced by rifamycins or may suppress specific enzyme activity leading to drug-drug interactions with rifamycins. These may cause significant alterations in their phamacokinetic and pharmacodynamic properties, and sometimes that of the rifamycin. Recommended strategies to adapt to these interactions include avoidance and dose adjustment. Expert opinion: Despite the importance and frequency of tuberculosis as an opportunistic disease in HIV-infected children, current data on the management of co-treated children is based on few studies. We need new strategies to rapidly assess the use of rifamycins, new anti-tuberculosis drugs and antiretroviral drugs together as information on safety and dosing of individual drugs becomes available.
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http://dx.doi.org/10.1080/14656566.2017.1309023DOI Listing
April 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

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

Prevalence and effect of pre-treatment drug resistance on the virological response to antiretroviral treatment initiated in HIV-infected children - a EuroCoord-CHAIN-EPPICC joint project.

BMC Infect Dis 2016 11 8;16(1):654. Epub 2016 Nov 8.

IRD UMI 174 - PHPT-Faculty of Associated Medical Sciences, Chiang Mai University, 110, Intrawarorot Road, Sripoom, Muang, Chiang Mai, 50200, Thailand.

Background: Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.

Methods: HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.

Results: Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1-10.1), CD4 cell count 297 cells/mm (98-639), and HIV-RNA 5.2 logcopies/mL (4.7-5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5-10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4-23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2-54.8) versus 19.4 % (15.9-23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82-0.95; P < 0.001).

Conclusions: PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.
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http://dx.doi.org/10.1186/s12879-016-1968-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101717PMC
November 2016

Optimization of the strength of the efavirenz/lamivudine/abacavir fixed-dose combination for paediatric patients.

J Antimicrob Chemother 2017 02 24;72(2):490-495. Epub 2016 Oct 24.

EA7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Background: Child-friendly, low-cost, solid, oral fixed-dose combinations (FDCs) of efavirenz with lamivudine and abacavir are urgently needed to improve clinical management and drug adherence for children.

Methods: Data were pooled from several clinical trials and therapeutic drug monitoring datasets from different countries. The number of children/observations was 505/3667 for efavirenz. Population pharmacokinetic analyses were performed using a non-linear mixed-effects approach. For abacavir and lamivudine, data from 187 and 920 subjects were available (population pharmacokinetic models previously published). Efavirenz/lamivudine/abacavir FDC strength options assessed were (I) 150/75/150, (II) 120/60/120 and (III) 200/100/200 mg. Monte Carlo simulations of the different FDC strengths were performed to determine the optimal dose within each of the WHO weight bands based on drug efficacy/safety targets.

Results: The probability of being within the target efavirenz concentration range 12 h post-dose (1-4 mg/L) varied between 56% and 60%, regardless of FDC option. Option I provided a best possible balance between efavirenz treatment failure and toxicity risks. For abacavir and lamivudine, simulations showed that for option I >75% of subjects were above the efficacy target.

Conclusions: According to simulations, a paediatric efavirenz/lamivudine/abacavir fixed-dose formulation of 150 mg efavirenz, 75 mg lamivudine and 150 mg abacavir provided the most effective and safe concentrations across WHO weight bands, with the flexibility of dosage required across the paediatric population.
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http://dx.doi.org/10.1093/jac/dkw444DOI Listing
February 2017

Acceptability of lopinavir/r pellets (minitabs), tablets and syrups in HIV-infected children.

Antivir Ther 2016 29;21(7):579-585. Epub 2016 Apr 29.

Medical Research Council Clinical Trials Unit, University College London, London, UK.

Background: Lopinavir/ritonavir 'pellets' were recently tentatively approved for licensing. We describe their acceptability for infants and children up to 48 weeks.

Methods: CHAPAS-2 was a randomized, two-period crossover trial comparing syrup and pellets in HIV-infected infants (n=19, group A, aged 3-<12 months) and children (n=26, group B, 1-<4 years) and tablets and pellets in older children (n=32, group C, 4-<13 years) from two clinics ('JCRC', 'PIDC') in Uganda. At week 8, all groups chose which formulation to continue. Acceptability data were collected at weeks 0, 4, 8, 12 and 48.

Results: For groups A and B overall, the proportion preferring pellets increased between week 0 and week 12 and decreased at week 48 (group A 37%, 72%, 44%; group B 12%, 64% and 36%, respectively), although there were marked differences between clinics. For group C, pellets were progressively less preferred to tablets over time: 41%, 19% and 13% at weeks 0, 12 and 48, respectively. During follow-up unpleasant taste was similarly reported among young children taking pellets and syrups (37%/43% group A; 29%/26% group B), whereas among older children, pellets tasted worse than tablets (40%/2%). No participants reported problems with storage/transportation for pellets (0%/0%) unlike syrups (23%/13%).

Conclusions: For children <4 years, pellets were more acceptable at week 12 but not week 48. Clinic differences could reflect bias among health-care workers for different formulations. Pellets taste similar to syrup, are easier to store and transport than syrup and represent an alternative formulation for young children unable to swallow tablets; improvements in taste and support for health-care workers may help sustain acceptability.
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http://dx.doi.org/10.3851/IMP3054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029664PMC
February 2018

An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012.

BMC Pediatr 2016 Mar 15;16:41. Epub 2016 Mar 15.

INSERM, UMR912 "Economics and Social Sciences Applied to Health & Analysis of Medical Information" (SESSTIM), 13006, Marseille, France.

Background: The pediatric antiretroviral (ARV) market is poorly described in the literature, resulting in gaps in understanding treatment access. We analyzed the pediatric ARV market from 2004 to 2012 and assessed pricing trends and associated factors.

Methods: Data on donor funded procurements of pediatric ARV formulations reported to the Global Price Reporting Mechanism database from 2004 to 2012 were analyzed. Outcomes of interest were the volume and mean price per patient-year ARV formulation based on WHO ARV dosing recommendations for a 10 kg child. Factors associated with the price of formulations were assessed using linear regression; potential predictors included: country income classification, geographical region, market segment (originator versus generic ARVs), and number of manufacturers per formulation. All analyses were adjusted for type of formulations (single, dual or triple fixed-dose combinations (FDCs))

Results: Data from 111 countries from 2004 to 2012 were included, with procurement of 33 formulations at a total value of USD 204 million. Use of dual and triple FDC formulations increased substantially over time, but with limited changes in price. Upon multivariate analysis, prices of originator formulations were found to be on average 72 % higher than generics (p < 0.001). A 10 % increase in procurement volume was associated with a 1 % decrease (p < 0.001) in both originator and generic prices. The entry of one additional manufacturer producing a formulation was associated with a decrease in prices of 2 % (p < 0.001) and 8 % (p < 0.001) for originator and generic formulations, respectively. The mean generic ARV price did not differ by country income level. Prices of originator ARVs were 48 % (p < 0.001) and 14 % (p < 0.001) higher in upper-middle income and lower-middle income countries compared to low income countries respectively, with the exception of South Africa, which had lower prices despite being an upper-middle income country.

Conclusions: The donor funded pediatric ARV market as represented by the GPRM database is small, and lacks price competition. It is dominated by generic drugs due to the lower prices offered and the practicality of FDC formulations. This market requires continued donor support and the current initiatives to protect it are important to ensure market viability, especially if new formulations are to be introduced in the future.
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http://dx.doi.org/10.1186/s12887-016-0578-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793558PMC
March 2016

Optimizing drugs to reach treatment targets for children and adolescents living with HIV.

J Int AIDS Soc 2015 2;18(Suppl 6):20270. Epub 2015 Dec 2.

Drugs for Neglected Diseases Initiative, Geneva, Switzerland.

Introduction: As the global community makes progress towards the 90-90-90 targets by 2020, a key challenge is ensuring that antiretroviral drugs for children and adolescents are suitable to the context of resource-limited settings. Drug optimization aims to support the expanded use of more simplified, less toxic drug regimens with high barriers to drug resistance that require minimal clinical monitoring while maintaining therapeutic efficacy. This manuscript summarizes the progress made and outlines further critical steps required to ensure that the right drugs are available to start children and adolescents on treatment and to keep them virologically suppressed.

Discussion: Building upon previous work in drug optimization, several important steps were taken in 2014 to ensure alignment between WHO dosing recommendations and the requirements of regulatory bodies, to accelerate drug development, to reduce intellectual property barriers to generic production of combined formulations and rationalize drug selection in countries. The priority for the future is to improve access to antiretroviral therapy (ART) at the two ends of the paediatric age spectrum--infants and adolescents--where the treatment gap is greatest, and optimize drug sequencing with better use of available medicines for second- and third-line ART. Future efforts in this area will require continuous collaboration and coordination, and the promotion of innovative approaches to accelerate access to new drugs and formulations.

Conclusions: While significant progress has been made, additional efforts are needed to ensure that treatment targets are reached by 2020.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670841PMC
http://dx.doi.org/10.7448/IAS.18.7.20270DOI Listing
August 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

How can we end paediatric AIDS?

Lancet HIV 2015 Mar 26;2(3):e80-1. Epub 2015 Feb 26.

Drugs for Neglected Diseases initiative, Geneva, Switzerland.

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http://dx.doi.org/10.1016/S2352-3018(15)00025-9DOI Listing
March 2015

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

Efavirenz Concentrations and Probability of HIV Replication in Children.

Pediatr Infect Dis J 2015 Nov;34(11):1214-7

From the *Institut de recherche pour le développement (IRD UMI 174-PHPT), Marseille, France; †Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; ‡Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand; §Ecole Doctorale de Santé Publique, Université Paris Saclay, Paris, France; ¶Harvard School of Public Health, Boston, Massachusetts; ‖Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris; **CIC1419, INSERM & APHP, EAU08 Université Paris Descartes Sorbonne Paris Cité, Paris, France; ††Chiangrai Prachanukroh Hospital, Chiangrai, Thailand; ‡‡Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; §§Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; ¶¶Samutsakhon Hospital, Samutsakhon, Thailand; and ‖‖Somdej Prapinklao Hospital, Bangkok, Thailand.

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.
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http://dx.doi.org/10.1097/INF.0000000000000854DOI Listing
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