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Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose pediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates.The PETITE study is an ongoing phase I/II, open-label, single-arm, 2-stage trial conducted in South Africa. In stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine ± zidovudine) received single dose(s) of the 4-in-1 formulation, followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn after an observed dose at 1, 2, 4, 8, and 12 hours postdose. In this study, we have reported the planned interim pharmacokinetic and safety analysis after completion of the single-dose administration.Sixteen neonates, with a median (range) birth weight of 3130 g (2790-3590 g), completed 24 pharmacokinetic visits. The 4-in-1 formulation imposed relatively high doses of abacavir [8.6 mg/kg (6.6-11.4)] and lamivudine [4.3 mg/kg (3.3-5.7)] but lower doses of lopinavir [11.5 mg/kg (8.8-15.2)]. The geometric means (GM, 90% CI) AUC0-12 of abacavir, lamivudine, and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83), and 3.49 (2.13-5.72) µg.h/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.h/mL), and ritonavir concentrations were only detectable in 4 of the 120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1 formulation.The high doses of abacavir and lamivudine (in mg/kg) and AUCs were safe, and the formulation was well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates use in neonates. Alternative pediatric solid antiretroviral formulations must be studied in neonates.

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.

Contains fulltext : 249069.pdf (Publisher’s version ) (Open Access) AIMS: Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. METHODS: A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling. RESULTS: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. CONCLUSION: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.

Children, although at lower risk of poor outcomes from COVID-19 relative to adults, still stand to benefit from therapeutic interventions. Understanding of COVID-19 clinical presentation and prognosis in children is essential to optimize therapeutic trials design. This perspective illustrates how to collectively accelerate pediatric COVID-19 therapeutic research and development, based on the experience of the Global Accelerator for Paediatric Formulations.

Summary 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 (Cmin) 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 Cmin 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 Cmin 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.

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

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.

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.

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 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.

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

IntroductionThe 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.MethodsAll 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.ResultsOf 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 ConclusionAdolescence, 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.

BackgroundImproving 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.MethodsA 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.ResultsHigh 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.ConclusionsFormulating 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.

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 to 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 to 3.02 for 60kg, P25% 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.

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.

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 (6 months after ART initiation, median age at ART initiation was 6.4 years, CD4% 8.2%, and HIV-RNA load 5.1 log(10) 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

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.

International audience; 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(R)). 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/=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.

Item does not contain fulltext 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.

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 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.

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 randomised, 2-period crossover trial comparing syrup and pellets in HIV-infected infants (n=19, group A, aged 3-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%,13% at weeks 0,12,48 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

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.

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

Background. There are scarce data on the long-termsurvival of human immunodeficiency virus (HIV)—infected children receiving antiretroviral therapy (ART) in lower-middle income countries beyond 2 years of follow-up. Methods. Previously untreated children who initiated ART on meeting immunological and/or clinical criteria were followed in a prospective cohort in Thailand. The probability of survival up to 5 years from initiation was estimated using Kaplan-Meier methods, and factors associated with mortality were assessed using Cox regression analyses. Results. Five hundred seventy-eight children received ART; of these, 111 (19.2%) were followed since birth. At start of ART (baseline), the median age was 6.7 years, 128 children (22%) were aged

To evaluate the pharmacokinetics and HIV viral load response following initiation during the third trimester of pregnancy of zidovudine plus standard-dose lopinavir boosted with ritonavir (LPV/r), twice daily, until delivery for the prevention of mother-to-child transmission of HIV.Prospective study nested within a multicenter, three-arm, randomized, phase III prevention of mother-to-child transmission of HIV trial in Thailand (PHPT-5, ClinicalTrials.gov Identifier: NCT00409591).Women randomized to receive 300 mg zidovudine and 400/100 mg LPV/r twice daily from 28 weeks' gestation, or as soon as possible thereafter, until delivery had intensive steady-state 12-h blood sampling performed. LPV/r pharmacokinetic parameters were calculated using noncompartmental analysis. Rules were defined a priori for a LPV/r dose escalation based on the proportion of women with an LPV area under the concentration-time curve (AUC) below 52 microg h/ml (10th percentile for LPV AUC in nonpregnant adults). HIV-1 RNA response was assessed during the third trimester.Thirty-eight women were evaluable; at entry, median (range) gestational age was 29 (28-36) weeks, weight 59.5 (45.0-91.6) kg, CD4 cells count 442 (260-1327) cells/microl and HIV-1 RNA viral load 7818 (40-402 015) copies/ml. Geometric mean (90% confidence interval) LPV AUC, Cmax and Cmin were 64.6 (59.7-69.8) microg h/ml, 8.1 (7.5-8.7) microg/ml and 2.7 (2.4-3.0) microg/ml, respectively. Thirty-one of 38 (81%) women had an LPV AUC above the AUC target. All women had a HIV-1 viral load less than 400 copies/ml at the time of delivery.A short course of zidovudine plus standard-dose LPV/r initiated during the third trimester of pregnancy achieved adequate LPV exposure and virologic response.

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

Tim R Cressey Author for correspondence: Program for HIV Prevention & Treatment (PHPT), Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, 110 Inthawaroros Road, Chiang Mai 50200, Thailand, Tel: +66 5389 4431 Fax: +66 5389 4220 tim@phpt.org and Harvard School of Public Health, Boston, MA, USA and Institut de Recherche pour le Developpement (IRD), Bangkok, Thailand

Objective: Each year, intrauterine growth retardation (IUGR) affects 20-30 million neonates worldwide, mostly in resource-limited settings. Increased perinatal and infant mortality has been associated with IUGR. Some studies have suggested that HIV infection could increase the risk of IUGR. To confirm this hypothesis, we examined the association between HIV-related factors and the risk of IUGR in Thailand. Patients and Methods: Data from a cohort of 1436 HIV-infected pregnant women enrolled in the "Perinatal HIV Prevention Trial-1", a clinical trial conducted from 1997 to 1999 in Thailand, were analyzed using a logistic regression, adjusting for risk factors usually associated with IUGR. Results: The rate of IUGR was 7.6%. Adjusting for a short maternal height, low body mass index, small weight gain during pregnancy, and infant female sex, a low maternal CD4 percentage was independently associated with IUGR (odds ratio 0.96, per 1% increment, 95% confidence interval 0.93 to 0.99, P = 0.03). Conclusions: The current World Health Organization recommendation to initiate combination antiretroviral therapy for immunocompromised women as early as possible during pregnancy for their own health and for the prevention of HIV mother-to-child transmission is likely to also decrease the incidence of IUGR. Encouraging immunocompromised HIV-infected women who plan to become pregnant to wait until immune restoration has been achieved may help to reduce the risk of IUGR.

Aim: Several studies have shown that preterm delivery, a primary cause of perinatal mortality and morbidity, is more frequent in HIV-positive women. This study aimed to determine factors associated with prematurity in HIV-infected women and identify risks for which specific interventions could be targeted. Methods: Data were prospectively collected in a clinical trial assessing the efficacy of different zidovudine prophylaxis durations for the prevention of perinatal HIV transmission in Thailand. Characteristics associated with prematurity – delivery before 37 weeks – were assessed using univariate and multivariate logistic regression and were subsequently used to identify subgroups of women at risk. Results: Among 979 women, independent prematurity risk factors were: viral load 4.5 log copies/mL; hemoglobin >11.5 g/dL; weight gain

Evaluation of: Lockman S, Shapiro RL, Smeaton LM et al.: Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N. Engl. J. Med. 356(2), 135–147 (2007). Although single-dose nevirapine given to HIV-infected pregnant women during labor is highly efficacious in preventing intrapartum mother-to-child transmission of HIV, it is associated with the selection of HIV nevirapine resistance mutations, which can compromise the efficacy of subsequent non-nucleosidic reverse transcriptase inhibitor-based regimens. In the context of a perinatal HIV prevention trial where pregnant women were randomized to receive intrapartum nevirapine or placebo, the authors assessed the impact of nevirapine exposure on virologic and immunologic response to nevirapine-based therapy in mothers who initiated therapy in the postpartum period and in their infected infants. Exposure to nevirapine was associated with an increased risk of virologic failure by the 6-month visit after treatment initiation in both women and infants. However, in the subgroup of women who initiated therapy more than 6 months after delivery, this association was not statistically significant. While the increase in CD4+ cell count by the 6-month visit was significantly different according to previous exposure to nevirapine in infants, this was not observed in the women.

BackgroundAntiretroviral 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.MethodsWe 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.ResultsMedian 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 (ConclusionThese 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 registrationThis analysis is based on secondary data obtained from three clinical trials. ClinicalTrials.gov. NCT00386230, NCT00398684, NCT00409591.

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. Keywords: antiretrovirals; treatment; children; ART; optimization; formulations; HIV. (Published: 2 December 2015) Citation: Penazzato M et al. Journal of the International AIDS Society 2015, 18(Suppl 6) :20270 http://www.jiasociety.org/index.php/jias/article/view/20270 | http://dx.doi.org/10.7448/IAS.18.7.20270

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.

Host genetics of drug transporters located in the renal tubule may contribute towards tenofovir disoproxil fumarate (TDF)-associated kidney disease susceptibility1, 2. Genetic variants in the ATP-binding cassette (ABC) transporters ABCC2 (1249 G>A) and ABCC4 (3463A>G) have been associated with a greater decline in creatinine clearance (CrCL) over 96 weeks of TDF-based treatment3. High plasma tenofovir (TFV) trough concentrations have been correlated with a decrease in glomerular filtration rate4. A recent study in Thailand reported that tenofovir ‘mid-dose’ plasma concentrations were significantly lower in ABCC2 -24 CT/TT carriers compared to CC carriers after 24 weeks of TDF/3TC/EFV treatment and independently associated with decreased glomerular rate after 48 weeks5. We investigated the association between drug transporter genetic polymorphisms implicated in tenofovir excretion and/or associated nephrotoxicity with TFV plasma concentrations and changes in kidney glomerular filtration rate in antiretroviral naive HIV-infected adults initiating TDF as part of a NNRTI-based regimen. This was a retrospective analysis of adults enrolled in an observational cohort study in Thailand [NCT00433030]. Criteria for treatment initiation were: CDC clinical stage B/C or CD4 T (rs717620), 1249G>A (rs2273697), 3563 T>A (rs8187694), 3972C>T (rs3740066) and 4544 G>A (rs8187710); ABCC4: 3463 A>G (rs1751034); ABCC10: G>A (rs9349256), 2843 T>C (rs2125739) and SLC22A2: -1604 T>C (rs3127573), G>A, (rs316009). Primers/probes were designed by the TaqMan® “Assays-by-Design®” SNP Genotyping Assay Service (Applied Biosystems, CA, USA) and SNPs identified using Real-time PCR. Plasma TFV concentrations were measured using a validated reversed-phase high-performance liquid chromatography assay6. This assay was internally validated and the average accuracy was 99–102% and precision (inter/intra-assay) was

Objective : To compare different methods of gestational age (GA) measurement for ensuring effective zidovudine (ZDV) prophylaxis to prevent mother-to-child transmission of HIV. Methods : For 1398 HIV-infected women enrolled in a perinatal prevention trial, gestation durations were calculated based on GA estimated using ultrasound (US), date of last menstruation period (LMP), first fundal height (FH 1 ), and a specific algorithm was developed to provide a “reference” GA. The performance of each GA estimate was evaluated by the percentage of women who would have received ≥ 8 weeks ZDV, if prophylaxis was initiated at 28 weeks. Results : The performances of the algorithm, US, LMP, and FH 1 were 95.5%, 94.8%, 88.4%, and 83.7%, respectively. US and FH 1 were significantly better when estimated before and after 24 weeks, respectively. Conclusion : In situations where no US is available and LMP is not or imprecisely known, FH 1 can be used after 24 weeks to schedule ZDV initiation date.

The emergence of drug-resistant human immunodeficiency virus (HIV) type 1 in the setting of antiretroviral therapy failure limits the number of drugs available for use in subsequent therapy regimens. To quantify the relative HIV-1-resistance costs associated with various antiretroviral therapy strategies, we developed 2 related measures of future drug options (FDOs) by use of rule-based genotype-interpretation systems. The FDO1 metric assesses the number of drug classes that remain useful; the FDO2 metric assesses the number of drug classes that remain useful and the number of active drugs within each class. Application of these methods is illustrated with data from a randomized study of 3 therapy regimens in nucleoside analog-experienced patients. Each therapy regimen resulted in a unique pattern of drug-resistance (and cross-resistance) mutations. The regimen with the highest virologic failure rate preserved greater future drug options. Quantification of future drug options as an outcome of antiretroviral therapy trials may complement traditional clinical, virologic, and immunologic end points, thereby providing novel insights.

Background Improving access to paediatric HIV treatment requires both large-scale treatment programmes and medication that is adapted to infants and children9s 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 initiative9s (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.

Item does not contain fulltext BACKGROUND: Guidelines recommend lopinavir/ritonavir (LPV/r) as first- and second-line therapy for young and older HIV-infected children, respectively. Available formulations have limitations making their widespread use complex. METHODS: An open-label comparative bioavailability (randomized crossover) study compared a novel twice-daily minitab sprinkle formulation (40 mg/10 mg, Cipla Pharmaceuticals) versus innovator syrup in HIV-infected Ugandan infants aged 3 to

Background. With improvements in HIV antibody test (ELISA) performance, the win dow of time between infection and seroconversion becomes a major source of error in HIV screening. The authors examined its impact on the false-reassurance rate (FRR). Methods. Test sensitivity was modeled as the product of two factors: the in herent sensitivity (sensitivity when antibody is present) and the probability that antibody is present in infected blood. A model of HIV and AIDS incidence was used to derive an estimate of the probability of remaining in the seronegative window ( pw) among those who are infected. With plausible assumptions, this probability approaches 0.03. The FRR was then estimated as a function of the probability of remaining in the se ronegative window, the prevalence of HIV, and the inherent sensitivity of the ELISA test were estimated. Results. The FRRs for two blood donor groups, one with an HIV prevalence of 0.004 and a typical probability of remaining in the seronegative window ( pw = 0.03) and the other with a higher prevalence of 0.017 but fewer donors in the window ( pw = 0.003), are equal (140 per million donors) if the blood is negative on a single ELISA test. After two negative tests or a single test that can detect antibody more reliably, however, the FRR is much higher in the group with the higher pw (= 120 per million compared with 50 per million), because the greater numbers of donors in the window more than offsets the lower prevalence. Conclusions. With improvements in inherent sensitivity of ELISA by virtue of technical progress or retesting, the preva lence of HIV infection may no longer play the critical role in degrading the results of blood screening. As inherent test performance improves, tests are increasingly likely to miss infected blood because of the seronegative-window error rather than because of measurement error. Window error plays a proportionally greater role during the early stages of HIV dissemination in a population where the incidence of new HIV infection is high relative to the incidence of AIDS. These findings may explain, in part, the recent observation that cases of transfusion of contaminated blood often take place in areas where AIDS epidemics have started recently. They also suggest that the traditional strategy of soliciting blood donors from low-prevalence populations may not always be optimal, unless such populations are truly low-risk. Key words: HIV; AIDS; prevalence; incidence; sensitivity; ELISA; predicted values; protocols of screening; false-reassur ance rate. (Med Decis Making 1997;17:455-463)

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.

Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV in Thailand. Please see later in the article for the Editors' Summary, 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/mm3) 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 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.gov NCT00162682 Please see later in the article for the Editors' Summary, Editors' Summary Background About 34 million people (most of them living in low-and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV infection leads to the destruction of immune system cells (including CD4 cells, a type of white blood cell), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (HAART)—combined drugs regimens that suppress viral replication and allow restoration of the immune system—became available. For people living in affluent countries, HIV/AIDS became a chronic condition but, because HAART was expensive, HIV/AIDS remained a fatal illness for people living in resource-limited countries. In 2003, the international community declared HIV/AIDS a global health emergency and, in 2006, it set the target of achieving universal global access to HAART by 2010. By the end of 2011, 8 million of the estimated 14.8 million people in need of HAART in low- and middle-income countries were receiving treatment. Why Was This Study Done? At the time this trial was conceived, national and international recommendations were that HIV-positive individuals should start HAART when their CD4 count fell below 200 cells/mm3 and should have their CD4 count regularly monitored to optimize HAART. In 2013, the World Health Organization (WHO) recommendations were updated to promote expanded eligibility for HAART with a CD4 of 500 cells/mm3 or less for adults, adolescents, and older children although priority is given to individuals with CD4 count of 350 cells/mm3 or less. Because HIV often becomes resistant to first-line antiretroviral drugs, WHO also recommends that viral load—the amount of virus in the blood—should be monitored so that suspected treatment failures can be confirmed and patients switched to second-line drugs in a timely manner. This monitoring and switching strategy is widely used in resource-rich settings, but is still very difficult to implement for low- and middle-income countries where resources for monitoring are limited and access to costly second-line drugs is restricted. In this randomized non-inferiority trial, the researchers compare the performance of a CD4-based treatment monitoring and switching strategy with the standard viral load-based strategy among HIV-positive adults in Thailand. In a randomized trial, individuals are assigned different interventions by the play of chance and followed up to compare the effects of these interventions; a non-inferiority trial investigates whether one treatment is not worse than another. What Did the Researchers Do and Find? The researchers assigned about 700 HIV-positive adults who were beginning HAART for the first time to have their CD4 count (CD4 arm) or their CD4 count and viral load (VL arm) determined every 3 months. Participants were switched to a second-line therapy if their CD4 count declined by more than 30% from their peak CD4 count (CD4 arm) or if a viral load of more than 400 copies/ml was recorded (VL arm). The 3-year cumulative risk of clinical failure (defined as death, a new AIDS-defining event, or a CD4 count of less than 50 cells/mm3) was 8% in the VL arm and 7.4% in the CD4 arm. This difference in clinical failure risk met the researchers' predefined criterion for non-inferiority. The probability of a treatment switch was similar in the two arms, but the average time from treatment initiation to treatment switch and the average duration of a high viral load after treatment switch were both longer in the CD4 arm than in the VL arm. Finally, the future-drug-option score, a measure of viral drug resistance profiles, was similar in the two arms at the time of treatment switch. What Do These Findings Mean? These findings suggest that, in Thailand, a CD4 switching strategy is non-inferior in terms of clinical outcomes among HIV-positive adults 3 years after beginning HAART when compared to the recommended viral load-based switching strategy and that there is no difference between the strategies in terms of viral suppression and immune restoration after 3-years follow-up. Importantly, however, even though patients in the CD4 arm spent longer with a high viral load than patients in the VL arm, the emergence of HIV mutants resistant to antiretroviral drugs was similar in the two arms. Although these findings provide no information about the long-term outcomes of the two monitoring strategies and may not be generalizable to routine care settings, they nevertheless provide reassurance that using CD4 counts alone to monitor HAART in HIV treatment programs in resource-limited settings is an appropriate strategy to use as viral load measurement becomes more affordable and feasible in these settings. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001494. The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2010 recommendations for antiretroviral therapy for HIV infection in adults and adolescents are available as well as the June 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the global HIV/AIDS epidemic, on HIV and AIDS in Thailand, on universal access to AIDS treatment, and on starting, monitoring and switching HIV treatment (in English and Spanish) The UK National Health Service Choices website provides information (including personal stories) about HIV and AIDS More information about this trial (the PHPT-3 trial) is available Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about HIV treatment

Prevalence and risk factors for isolated antibody to hepatitis B core antigen (anti-HBc) and occult hepatitis B virus (HBV) infection are not well known in human immunodeficiency virus type 1 (HIV-1)-infected pregnant women. It is unclear if women with occult infections are at risk of transmitting HBV to their infants.HIV-1-infected and HBV surface antigen (HBsAg)-negative pregnant women were tested for antibody to HBsAg (anti-HBs) and anti-HBc using enzyme immunoassay. Women with isolated anti-HBc were assessed for occult HBV infection, defined as HBV DNA levels15 IU/mL, using the Abbott RealTime HBV DNA assay. Infants born to women with isolated anti-HBc and detectable HBV DNA were tested at 4 months of age for HBV DNA. Logistic regression analysis was used to identify factors associated with isolated anti-HBc and occult HBV infection.Among 1812 HIV-infected pregnant women, 1682 were HBsAg negative. Fourteen percent (95% confidence interval [CI], 12%-15%) of HBsAg-negative women had an isolated anti-HBc that was independently associated with low CD4 count, age35 years, birth in northern Thailand, and positive anti-hepatitis C virus serology. Occult HBV infection was identified in 24% (95% CI, 18%-30%) of women with isolated anti-HBc, representing 2.6% (95% CI, 1.9%-3.5%) of HIV-1-infected pregnant women, and was inversely associated with HIV RNA levels. None of the women with isolated anti-HBc and occult HBV infection transmitted HBV to their infants.HIV-1-infected pregnant women with isolated anti-HBc and occult HBV infection have very low HBV DNA levels and are thus at very low risk to transmit HBV to their infants.

Background Approximately 4 million of people are co-infected with HIV and Hepatitis B virus (HBV). In resource-limited settings, the majority of HIV-infected patients initiate first-line highly active antiretroviral therapy containing lamivudine (3TC-containing-HAART) and long-term virological response of HBV to lamivudine-containing HAART in co-infected patients is not well known. Methodology/Principal Finding HIV-HBV co-infected patients enrolled in the PHPT cohort (ClinicalTrials.gov NCT00433030) and initiating a 3TC-containing-HAART regimen were included. HBV-DNA, HIV-RNA, CD4+ T-cell counts and alanine transaminase were measured at baseline, 3 months, 12 months and then every 6 months up to 5 years. Kaplan-Meier analysis was used to estimate the cumulative rates of patients who achieved and maintained HBV-DNA suppression. Of 30 co-infected patients, 19 were positive for HBe antigen (HBeAg). At initiation of 3TC-containing-HAART, median HBV DNA and HIV RNA levels were 7.35 log10 IU/mL and 4.47 log10 copies/mL, respectively. At 12 months, 67% of patients achieved HBV DNA suppression: 100% of HBeAg-negative patients and 47% of HBeAg-positive. Seventy-three percent of patients had HIV RNA below 50 copies/mL. The cumulative rates of maintained HBV-DNA suppression among the 23 patients who achieved HBV-DNA suppression were 91%, 87%, and 80% at 1, 2, and 4 years respectively. Of 17 patients who maintained HBV-DNA suppression while still on 3TC, 4 (24%) lost HBsAg and 7 of 8 (88%) HBeAg-positive patients lost HBeAg at their last visit (median duration, 59 months). HBV breakthrough was observed only in HBeAg-positive patients and 6 of 7 patients presenting HBV breakthrough had the rtM204I/V mutations associated with 3TC resistance along with rtL180M and/or rtV173L. Conclusions All HBeAg-negative patients and 63% of HBeAg-positive HIV-HBV co-infected patients achieved long-term HBV DNA suppression while on 3TC-containing-HAART. This study provides information useful for the management of co-infected patients in resource-limited countries where the vast majority of co-infected patients are currently receiving 3TC.

Objective: To estimate the early and long-term mortalities and associated risk factors in adults receiving highly active antiretroviral therapy (HAART) in Thailand. Design: A prospective observational cohort study. Methods: Previously untreated adults starting HAART in 2002-2009 were followed-up in 43 public hospitals. Kaplan-Meier probability of survival was estimated up to 5 years of therapy. Factors associated with early (6 months) mortalities were assessed using Cox regression analyses. Results: A total of 1578 adults received HAART (74% women; median age, 33 years; CD4 cell count, 124/mL), with a median follow-up of 50 months (interquartile range, 41-66). Eighty-nine patients (6%) died (37 occurred 6 months) and 183 (12%) were lost to follow-up. Probability of survival [95% confidence interval (CI)] was 97.5% (96.7% to 98.2%) at 6 months, 96.6% (95.6% to 97.4%) at 1 year, and 93.5% (91.9% to 94.8%) at 5 years. Probability of being alive and on follow-up was 80.8% (78.5% to 82.8%) at 5 years. Early mortality was associated with anemia [adjusted hazard ratio (aHR) 3.6, 95% CI: 1.7 to 7.5] and low CD4 count (aHR 1.6, 95% CI: 1.1 to 2.2 per 50 cells decrease) at treatment initiation. Long-term mortality was associated with persistent anemia (aHR 4.9, 95% CI: 2.1 to 11.6), CD4 increase from baseline 1000 copies per milliliter (aHR 2.8, 95% CI: 1.3 to 6.1) at 6 months of HAART; male gender; and calendar year of enrollment. Conclusions: Early mortality was associated with anemia and severe immunosuppression at initiation of therapy. Long-term mortality was associated with persistent anemia, CD4 count increase, and virological response at 6 months of therapy over baseline characteristics, highlighting the importance of laboratory monitoring.

ObjectiveTo assess the risk of mother-to-child transmission of HIV-1 in a central African population and to study maternal factors associated with perinatal transmission.DesignProspective cohort study of infants born to HIV-1-positive women and controls born to HIV-1-negative women enrolled sequenti

Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity.

New data show earlier treatment of HIV vastly reduces transmission risk, but “test and treat” and “treatment as prevention” are well recognized notions in pediatric HIV care. Yet children with HIV in low- or middle-income countries remain a largely neglected population.

The evolution of hematological parameters in HIV-1-exposed uninfected infants according to various durations of perinatal zidovudine exposure was studied. We used data prospectively collected among 1122 HIV-uninfected formula-fed infants born to HIV-infected mothers who participated in a clinical trial to prevent perinatal transmission in Thailand (PHPT-1). Infants were exposed to different durations of zidovudine both in utero and after birth. Hemoglobin level and leukocyte, absolute neutrophil, and lymphocyte counts were measured at birth and at 6 weeks of age. The association between hematological parameters at birth and the duration of zidovudine exposure in utero was studied using a linear regression model, and changes between birth and 6 weeks of age and the duration of postnatal zidovudine exposure using mixed effects models. At birth, the hemoglobin level was lower in newborns exposed to zidovudine for more than 7.5 weeks in utero (adjusted regression coefficient: -0.6 g/dl; 95% confidence interval: -1.1 to -0.1). Six weeks after birth, the hemoglobin level had decreased faster in infants administered zidovudine for more than 4 weeks (adjusted regression coefficient: -0.1 g/dl; 95% confidence interval: -0.2 to -0.1). The duration of perinatal zidovudine exposure was not associated with the evolution of leukocyte, neutrophil, and lymphocyte counts. Despite the differences in hemoglobin levels, grade 3 or 4 anemia did not significantly differ by maternal or infant zidovudine duration. The clinical impact appeared modest, but longer exposure may warrant close monitoring.

BACKGROUND: Intrapartum single-dose nevirapine plus third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings. The persistence of nevirapine in the plasma for 3 weeks postpartum risks selection of resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We hypothesized that a 1-month zidovudine-didanosine course initiated at the same time as single-dose nevirapine (sdNVP) would prevent the selection of nevirapine-resistance mutations. METHODS: HIV-infected pregnant women in the PHPT-4 cohort with CD4 cell counts >250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, sdNVP during labor, and a 1-month zidovudine-didanosine course after delivery. These women were matched on the basis of baseline HIV load, CD4 cell count, and duration of antepartum zidovudine to women who received sdNVP in the PHPT-2 trial (control subjects). Consensus sequencing and the more sensitive oligonucleotide ligation assay were performed on samples obtained on postpartum days 7-10, 37-45, and 120 (if the HIV load was >500 copies/mL) to detect K103N/Y181C/G190A mutations. RESULTS: The 222 PHPT-4 subjects did not differ from matched control subjects in baseline characteristics except for age. The combined group median CD4 cell count was 421 cells/mm3 (interquartile range [IQR], 322-549 cells/mm3), the median HIV load was 3.45 log10 copies/mL (IQR, 2.79-4.00 log10 copies/mL), and the median duration of zidovudine prophylaxis was 10.4 weeks (IQR, 9.1-11.4 weeks). Using consensus sequencing, major NNRTI resistance mutations were detected after delivery in 0% of PHPT-4 subjects and 10.4% of PHPT-2 controls. The oligonucleotide ligation assay detected resistance in 1.8% of PHPT-4 subjects and 18.9% of controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects and 20.7% of controls (P < .001). CONCLUSIONS: A 1-month postpartum course of zidovudine plus didanosine prevented the selection of the vast majority of NNRTI resistance mutations.

Approximately half of the 33.4 million persons living with the human immunodeficiency virus (HIV) worldwide are women of reproductive age, and among the 2.1 million HIV-infected children, virtually all were infected during pregnancy, delivery, or breast-feeding.1 Since 2002, the number of newly infected children has declined, probably owing to increased implementation of interventions for the prevention of mother-to-child transmission of HIV and the global stabilization of HIV prevalence among women.2 With these advances, new challenges have surfaced. In 2008, almost half of HIV-infected pregnant women received antiretroviral medications for the prevention of mother-to-child transmission.1 In most cases, the simplest intervention, . . .