Centre for the AIDS Programme of Research in South Africa (original) (raw)
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Dolutegravir Use at Conception — Additional Surveillance Data from Botswana
, an unscheduled analysis from the Botswana-Harvard AIDS Institute Partnership Tsepamo birth-outcomes surveillance study showed a higher prevalence of neuraltube defects among infants born to women who were using dolutegravir-based antiretroviral treatment (ART) regimens at the time of conception relative to infants born to women taking other types of ART. 1 In response to this safety signal, the Botswana Ministry of Health and Wellness expanded surveillance for neural-tube defects in selected non-Tsepamo health facilities. The Ministry of Health and Wellness surveillance system followed a protocol that had been approved by the institutional review boards of the Botswana Health Research Development Committee, the Centers for Disease Control and Prevention, and the University of Maryland, Baltimore, and included all pregnancies in which live-born or stillborn infants were delivered at more than 24 weeks of gestation at 22 non-Tsepamo facilities from October 2018 through March 2019. The end date of March 31, 2019, was chosen in light of the anticipated change in practice associated with the 2018 data release from the Tsepamo study, which was expected to result in a decrease in the number of pregnancies with periconceptional exposure to dolutegravir. Midwives conducted systematic surface examinations of all live-born and stillborn infants. Information regarding maternal human immunodeficiency virus (HIV) infection status, ART exposure at conception, and infant examination findings was collected. Data on the use of folate supplements and other medications, including antiepileptic medications, were abstracted only in cases in which a neural-tube defect was found. Data on folate use before pregnancy were not * Information on the type of antiretroviral treatment (ART) was unavailable for 11 women. HIV denotes human immunodeficiency virus. † Exact confidence intervals (CIs) are shown. ‡ Newcombe-Wilson hybrid score confidence intervals are shown. The difference in prevalence between deliveries among HIV-negative mothers and deliveries among mothers who had been taking dolutegravir at conception from our sensitivity analysis, which included the "possible" neural-tube defect, was 0.53 percentage points (95% CI, −0.07 to 3.50).
PLOS Medicine
Background The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). Methods and findings In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9 th March 2017 and 16 th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log 10 copies/mL both arms) and CD4 count (343 vs 466
The Lancet HIV, 2020
Background Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. Methods In this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0-14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181. Findings Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) or efavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33-77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1•64, 95% CI 1•31-2•06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0•013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16•4% vs 3•3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions. Interpretation Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential. Funding Unitaid.
The Lancet Global Health, 2018
Background-Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana. Methods-In this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofoviremtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes This is an Open Access article under the CC BY-NC-ND 4.0 license.
Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV
AIDS (London, England), 2018
To evaluate dolutegravir pharmacokinetics during pregnancy compared to postpartum and in infant washout samples after delivery. Ongoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants. Intensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum (PP). Infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005mcg/mL. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-subject comparisons. Twenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (PP) women. Median dolutegravir AUC0-24, Cmax and C24 were 25-51% lower in the 2T and 3T compared to PP. The median cord blood/maternal plasma conc...
The Lancet HIV
Background Late initiation of antiretrovirals in pregnancy is associated with increased risk of perinatal transmission and higher infant mortality. We report the final 72-week postpartum results for efficacy and safety of dolutegravir-based compared with efavirenz-based regimens in mothers and infants. Methods DolPHIN-2 was a randomised, open-label trial. Pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating antiretroviral therapy in third trimester were eligible for inclusion. Eligible women were randomly assigned (1:1) to receive either dolutegravir-based (50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda) or efavirenz-based (fixed dose combination 600 mg tenofovir disoproxil fumarate plus either emtricitabine in South Africa or lamivudine in Uganda) therapy. The primary efficacy outcome was the time to a viral load of less than 50 copies per mL measured at 6, 12, 24, 48, and 72 weeks postpartum with a Cox model adjusting for viral load and CD4 cell count. Safety endpoints were summarised by the number of women and infants with events. This trial is registered with ClinicalTrials.gov, NCT03249181. Findings Between Jan 23 and Aug 15, 2018, 280 women were screened for inclusion, of whom 268 (96%) women were randomly assigned: 133 (50%) to the efavirenz group and 135 (50%) to the dolutegravir group. 250 (93%; 125 [50%] in the efavirenz group and 125 [50%] in the dolutegravir group) women were included in the intention-to-treat analysis of efficacy. Median time to viral load of less than 50 copies per mL was 4•1 weeks (IQR 4•0-5•1) in the dolutegravir group compared with 12•1 weeks (10•7-13•3) in the efavirenz group (adjusted hazard ratio [HR] 1•93 [95% CI 1•5-2•5]). At 72 weeks postpartum, 116 (93%) mothers in the dolutegravir group and 114 (91%) in the efavirenz group had a viral load of less than 50 copies per mL. Of 57 (21%) mothers with a severe adverse event, three (2%) in the dolutegravir group and five (4%) in the efavirenz group were related to the drug (dolutegravir drug-related events were one woman each with suicidal ideation, suicide attempt, herpes zoster meningitis; efavirenz drug-related events were one woman each with suicide attempt and liver cirrhosis, and three people with drug-induced liver injury). Of 136 (56%) infants in whom severe adverse events were recorded, none were related to the study drugs. In addition to the three infant HIV infections detected at birth in the dolutegravir group that have been previously reported, an additional transmission in the efavirenz group occurred during breastfeeding despite optimal maternal viral suppression and serial negative infant tests in the first year of life. Interpretation Dolutegravir was safe and well tolerated, supporting updated WHO treatment recommendations in pregnant and breastfeeding women. Infant HIV transmissions can occur during breastfeeding despite persistently undetectable maternal viral load highlighting the need for continued infant testing. Funding Unitaid.
The Lancet, 2021
SH implemented interventions and collected data. All co-authors helped oversee study conduct and reviewed and commented on the report. SSB, LZ, BJ, and CK accessed and verified the data; SSB and LZ analyzed data. SL wrote the first version of the report. SL, SSB, LC, and JC finalized the report. Declaration of interests JDM has received research support from Gilead, paid to his institution. NKT is an employee of ViiV Healthcare. JFR is an employee and stockholder of Gilead Sciences. KRA has received fees from Gilead Sciences for expert consultation. JC has received fees from Merck & Co. for service on a Scientific Advisory Board. PES has received research support, and fees for service on Scientific Advisory Boards, from Gilead Sciences and ViiV Healthcare. The other authors declare no competing interests. Data sharing statement This study's data cannot be made publicly available due to ethical restrictions in the study's informed consent documents and in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network's approved human subjects protection plan; public availability may compromise participant confidentiality. However, data, including participant data with partially identifying information, are available to interested researchers upon request to the IMPAACT Statistical and Data Management Center's Data Access Committee
AIDS, 2019
Use of dolutegravir-based first-line antiretroviral therapy (ART) in response to rising levels of pretreatment HIV drug resistance (PDR) to nonnucleoside reverse transcriptase inhibitors (NNRTIs) may be limited, given safety concerns for birth defects in women of child-bearing potential. Pooled data from 11 nationally representative surveys show that NNRTI PDR in women is nearly twice that in men, exceeding 10% in 8 of 11 countries monitored, suggesting the urgent need for a non-NNRTI-based ART regimen in this population.
The Lancet HIV, 2021
BACKGROUND: Dolutegravir (DTG) has been widely available in Brazil since 2017. Following the signal that infants born to women with DTG exposure at conception had a higher risk of neural tube defects (NTD), public health leaders initiated a national investigation. METHODS: All women with pregnancies and possible DTG exposure within 8 weeks of estimated date of conception (EDC) between January 1, 2015 and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz (EFV), were identified using the Brazilian ART database. Detailed chart reviews were performed for identified women. Primary outcomes were NTD, stillbirth, and/or abortion. NTD incidences were calculated with 95% Wilson confidence intervals (95%CI). The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1,427 included women, 382 were DTG-exposed within 8 weeks of EDC. During pregnancy, 48% of DTG-exposed and 45% EFV-exposed women received folic acid supplementation. There were 1,452 birth outcomes. There were no NTD in either DTG-exposed (0 [95%CI 0, 0•0010]) or EFV-exposed groups (0 [95%CI 0, 0•0036]). Twenty-five (6•5%) and 43 (4•0%) stillbirths/abortions occurred among DTG-exposed and EFV-exposed fetuses, respectively (p=0•05). Logistic regression models did not consistently indicate an association between DTG exposure and risk of stillbirths/abortions. After study closure, two confirmed NTD outcomes in fetuses with periconception DTG exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional DTG-exposed pregnancies through February 2019 is 0•0018 (95%CI 0•0005-0•0067). INTERPRETATION: Neither DTG or EFV exposure was associated with NTD in our national cohort; incidence of NTD is likely well under 1% among DTG-exposed HIV-positive women but still slightly above HIV-uninfected women (0.06%) in Brazil.
Ginekologia Polska, 2019
Objectives: The purpose of this study was to investigate dolutegravir (DTG) use among women and exposure to DTG during pregnancy in real world in Central and Eastern Europe and neighboring countries. Material and methods: Centres from 20 countries included in the Euroguidelines in Central and Eastern Europe (ECEE) Network and Finland were asked to complete an on-line questionnaire. Results: Seven centres from Czech Republic, Finland, Greece, Poland, Slovakia, and Turkey provided detailed information. DTG exposure was reported in 415 women, of which 26 were during pregnancy. Of those, 22 were on DTG at the time of conception and 4 had started DTG during pregnancy. Few women had conventional risk factors. The data on folic acid usage was unknown for eight women; 14 were using and four were not using folic acid. Four pregnancies were ongoing at the time of the study and of those with an outcome, 77.3% resulted with term, 13.6% preterm delivery, 4.5% spontaneous and 4.5% medical abortion. Conclusions: The DTG signal report indicates the importance of safety research for drug use in pregnancy and highlights the urgent need for systematic surveillance of pregnancy outcomes and neonatal surveillance. Countries with low-or moderate HIV prevalence should be included in studies reviewing pregnancy outcomes and in any surveillance system to ensure the accuracy of drug safety revision.