Long-Term Hepatitis B Virus (HBV) Response to Lamivudine-Containing Highly Active Antiretroviral Therapy in HIV-HBV Co-Infected Patients in Thailand

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 $log_{10}$ IU/mL and 4.47 $log_{10}$ 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

Early infant HIV diagnosis and entry to HIV care cascade in Thailand: an observational study

Background: Early infant diagnosis of HIV is crucial for timely initiation of antiretroviral therapy (ART) in infected children who are at high risk of mortality. Early infant diagnosis with dried blood spot testing was provided by the National AIDS Programme in Thailand from 2007. We report ART initiation and vital status in children with HIV after 7 years of rollout in Thailand. / Methods: Dried blood spot samples were collected from HIV-exposed children in hospitals in Thailand and mailed to the Faculty of Associated Medical Sciences, Chiang Mai University, where HIV DNA was assessed with real-time PCR to establish HIV infection. We linked data from children with an HIV infection to the National AIDS Programme database to ascertain ART and vital status. / Findings: Between April 5, 2007, and Oct 1, 2014, 16 046 dried blood spot samples were sent from 8859 children in 364 hospitals in Thailand. Median age at first dried blood spot test was 2·1 (IQR 1·8–2·5) months. Of 7174 (81%) children with two or more samples, 223 (3%) were HIV positive (including five unconfirmed). Of 1685 (19%) children with one sample, 70 (4%) were unconfirmed positive. Of 293 (3%) children who were HIV positive, 220 (75%) registered for HIV care and 170 (58%) initiated ART. Median age at ART initiation decreased from 14·2 months (IQR 10·2–25·6) in 2007 to 6·1 months (4·2–9·2) in 2013, and the number of children initiating ART aged younger than 1 year increased from five (33%) of 15 children initiating ART in 2007 to ten (83%) of 12 initiating ART in 2013. 15 (9%) of 170 children who initiated ART died and 16 (32%) of 50 who had no ART record died. / Interpretation: Early infant diagnosis with dried blood spot testing had high uptake in primary care settings. Further improvement of linkage to HIV care is needed to ensure timely treatment of all children with an HIV infection

Discordant retention of HIV-infected mothers and children

It is often assumed that children and their caregivers either stay in care together or discontinue together, but data is lacking on caregiver-child retention concordance. We sought to describe the pattern of care among a cohort of human immunodeficiency virus (HIV) infected children and mothers enrolled in care at the Manhiça District Hospital (MDH).This was a retrospective review of routine HIV clinical data collected under a larger prospective HIV cohort study at MDH. Children enrolling HIV care from January 2013 to November 2016 were identified and matched to their mother's HIV clinical data. Retention in care for mothers and children was assessed at 24 months after the child's enrolment. Multinomial logistic regression was performed to evaluate variables associated with retention discordance.For the 351 mother-child pairs included in the study, only 39% of mothers had concordant care status at baseline (23% already active in care, 16% initiated care concurrently with their children). At 24-months follow up, a total of 108 (31%) mother-child pairs were concordantly retained in care, 88 (26%) pairs were concordantly lost to follow up (LTFU), and 149 (43%) had discordant retention. Pairs with concurrent registration had a higher probability of being concordantly retained in care. Children who presented with advanced clinical or immunological stage had increased probability of being concordantly LTFU.High rates of LTFU as well as high proportions of discordant retention among mother-child pairs were found. Prioritization of a family-based care model that has the potential to improve retention for children and caregivers is recommended

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

A Survey of Adolescents Born with HIV: The TEEWA project in Thailand

Thailand is one of the Asian countries hardest hit by the HIV/AIDS epidemic. Before the widespread implementation, beginning in 1999, of programmes to prevent mother-to-child HIV transmission, many children were born with HIV in Thailand. They now reach adolescence thanks to antiretroviral treatments. While some qualitative studies have documented the family situation and the living conditions of these adolescents, the TEEWA (Teens Living With ARV) project has, for the first time, conducted a national quantitative survey among 10% of adolescents aged 12-19 infected with HIV at birth, under antiretroviral treatment, in order to assess their situation and compare it with that of adolescents in the general population. This article presents an original survey approach that takes into account the methodological and ethical issues specific to the situation of a population rendered doubly vulnerable by age and HIV

Une enquête auprès d'adolescents nés avec le VIH : le projet TEEWA en Thaïlande

La Thaïlande a été l’un des pays d’Asie les plus durement touchés par l’épidémie de VIH/sida. Avant que ne soit mise en place la généralisation de la prévention de la transmission mère-enfant (à partir de 1999), un grand nombre d’enfants sont nés infectés par le VIH et atteignent maintenant l’âge de l’adolescence grâce aux traitements. Si quelques études qualitatives ont permis d’étudier la situation familiale et les conditions de vie de ces adolescents, pour la première fois le projet TEEWA (TEEns Living With ARV) propose une enquête quantitative nationale, effectuée entre 2010 et 2012, auprès de 10 % des adolescents de 12 à 19 ans infectés à la naissance et sous traitement antirétroviral. Elle permet de faire le point sur leur situation et de la comparer à celle d’adolescents en population générale. L’article présente le dispositif d’enquête original tenant compte des enjeux méthodologiques et éthiques particuliers à la situation d’enquête auprès d’une population doublement vulnérable, par son âge et son statut VIH

Clinical Manifestations of Human Immunodeficiency Virus-Induced Uveitis

Purpose: To describe the clinical manifestations of patients with human immunodeficiency virus (HIV)-induced uveitis in Thailand. Design: Prospective cohort study of 6 patients with HIV-induced uveitis. Participants: Six patients (8 eyes) with HIV-induced uveitis who had an extremely high intraocular: plasma HIV-1 RNA ratio. Methods: The clinical manifestations and laboratory findings are reported of 6 consecutive patients with HIV-induced uveitis who had an extremely high intraocular-to-plasma HIV-1 RNA ratio and were diagnosed between July 2009 and May 2011. Main Outcome Measures: Clinical manifestations and laboratory findings. Results: Human immunodeficiency virus-induced uveitis was diagnosed in 4 men and 2 women with an average age of 41 years at presentation. None of the patients were receiving highly active anti-retroviral therapy (HAART) or had clinical or laboratory evidence, or both, of opportunistic infections. The mean plasma load was 218 688 copies/ml (median, 137 500 copies/ml; range, 24 900-540 000 copies/ml), and the mean intraocular HIV load was 20 937 755 copies/ml (median, 7 499 000 copies/ml; range, 2 Conclusions: Human immunodeficiency virus-induced uveitis should be suspected in HAART-naive, HIV-positive patients or in those in whom this treatment fails and who have anterior uveitis without any retinal lesions and exhibit no response to topical corticosteroids. The concurrent determination of HIV load in the intraocular fluids and plasma may clarify the cause of HIV-associated uveitis. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:1455-1459 (c) 2012 by the American Academy of Ophthalmology