Neonatal HIV-1 infection is associated with rapidly progressive and frequently fatal immune deficiency if left untreated. Immediate institution of antiretroviral therapy (ART), ideally within hours after birth, may restrict irreversible damage to the developing neonatal immune system and possibly provide opportunities for facilitating drug-free viral control during subsequent treatment interruptions. However, the virological and immunological effects of ART initiation within hours after delivery have not been systematically investigated. We examined a unique cohort of neonates with HIV-1 infection from Botswana who started ART shortly after birth and were followed longitudinally for about 2 years in comparison to control infants started on treatment during the first year after birth. We demonstrate multiple clear benefits of rapid antiretroviral initiation, including an extremely small reservoir of intact proviral sequences, a reduction in abnormal T cell immune activation, a more polyfunctional HIV-1–specific T cell response, and an innate immune profile that displays distinct features of improved antiviral activity and is associated with intact proviral reservoir size. Together, these data offer rare insight into the evolutionary dynamics of viral reservoir establishment in neonates and provide strong empirical evidence supporting the immediate initiation of ART for neonates with HIV-1 infection.
Background HIV point-of-care (POC) testing allows for early infant HIV diagnosis and treatment, but POC accuracy at birth and in the setting of antiretroviral prophylaxis for the prevention of mother-to-child HIV transmission (MTCT) is unknown. Methods We evaluated the Cepheid Xpert® HIV-1 Qual POC test against the Roche Taqman HIV-1 PCR platform using dried blood spots from 15 HIV-infected and 75 HIV-exposed uninfected newborns. These infants were screened for HIV at <96 hours of life at 5 hospital maternity wards in Botswana; all infants received post-exposure antiretroviral prophylaxis (PEP) and most mothers received 3-drug antiretroviral therapy in pregnancy and at delivery. Results Fourteen of 15 PCR positive samples tested positive by Cepheid POC, yielding a sensitivity of 93.3% (95%CI: 68.1–99.8%). Baseline viral load among positive infants ranged from <40 to >10,000,000 copies/ml, with a median of 2,403 copies/mL. The HIV RNA for the infant with false negative POC testing was 1,661 copies/mL. Of note, two infants with low HIV RNA (< 40 copies/mL and 272 copies/ml) were correctly identified as HIV positive by Cepheid POC. All of the 75 PCR-negative samples tested negative by Cepheid POC, yielding a specificity of 100% (95% CI: 96.1 –100%). Discussion Our study demonstrates high sensitivity and specificity for the Cepheid POC assay in the first week of life despite early infection and antiretroviral prophylaxis. This platform may be a useful approach for adding early infant HIV diagnosis to current testing programs.
Background Early antiretroviral therapy (ART) is recommended for infants with human immunodeficiency virus (HIV) infection. However, few antiretroviral options are available for neonates. Methods The Early Infant Treatment Study in Botswana tested HIV-exposed infants within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6 mg/kg twice daily, zidovudine (ZDV), and lamivudine (3TC) at age < 7 days. NVP trough concentrations were tested at 1 and 2 weeks. NVP was switched to ritonavir-boosted lopinavir (LPV/r) at week 2, 3, 4, or 5 according to delivery gestational age. Results Forty HIV-infected infants started ART at median age 2 days (range, 1–5 days). NVP trough concentrations were highly variable and below therapeutic target (3000 ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only 1 unscheduled treatment modification was required. Within 4 weeks of transition to LPV/r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV/r palatability. At 12 weeks, 22 (55%) of 40 were <40 copies/mL (93% <400 copies/mL); by 24 weeks, 27 of 38 (71%) were < 40 copies/mL (84% < 400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA or other factors. Conclusions NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV/r, but by 12 and 24 weeks most children achieved and maintained viral suppression. Clinical Trials Registration U01AII4235.
Background The impact of very early infant treatment on HIV reservoir, and markers for treatment success, require study. Methods The Early Infant Treatment Study (EIT) enrolled 40 children living with HIV started on antiretroviral treatment (ART) at <7 days of age and 23 who had started treatment between 30-365 days to serve as controls. Quantitative HIV DNA was evaluated every 1-3 months in PBMCs. 84-week repeat qualitative whole blood DNA PCR and dual enzyme EIA were performed. Results Median quantitative cell-associated DNA after at least 84 weeks was significantly lower among the first 27 EIT children tested than among 10 controls (40.8 vs. 981.4 copies/million cells; p<0.001) and correlated with pre-ART DNA. Median DNA after 84 weeks did not differ significantly by negative or positive serostatus at 84 weeks (p=0.94), and appeared unaffected by periods of unsuppressed plasma RNA from 24-84 weeks (p=0.70). However, negative 84-week serostatus was 67% predictive for sustained RNA suppression and positive serostatus was 100% predictive for viremia. Loss of qualitative DNA positivity at 84 weeks was 73% predictive for sustained suppression and persistent positivity was 77% predictive for viremia. Conclusions Lower viral reservoir was associated with starting ART at <1 week. Negative serostatus and qualitative DNA were useful markers of sustained viral suppression from 24-84 weeks.
IntroductionMost African countries perform infant HIV testing at 6 weeks or later. The addition of targeted testing at birth may improve retention in care, treatment outcomes and survival for HIV‐infected infants.Methods HIV‐exposed infants were screened as part of the Early Infant Treatment (EIT) study in Botswana. Screened infants were ≥35 weeks gestational age and ≥2000 g at birth. Risk factors for mother‐to‐child transmission (MTCT) were assessed by maternal obstetric card or verbally. Risk factors included <8 weeks ART in pregnancy, last known CD4 <250 cells/mm3, last known HIV RNA >400 copies/mL, poor maternal ART adherence, lack of maternal zidovudine (ZDV) in labour, or lack of infant post‐exposure prophylaxis. Infants underwent dried blood spot testing by Roche Cobas Ampliprep/Cobas Taqman HIV‐1 qualitative PCR.ResultsFrom April 2015 to April 2016, 2303 HIV‐exposed infants were tested for HIV in the EIT study. Of these, 369 (16%) were identified as high risk for HIV infection by information available at birth, and 12 (0.5% overall, 3.25% of high risk) were identified as HIV positive at birth. All 12 positive infants were identified as high risk at the time of screening, and only 2 risk factors were required to identify all positive infants: either <8 weeks of maternal ART in pregnancy (75%) or lack of maternal HIV suppression at last test (25%).Conclusions In utero MTCT occurred only among infants identified as high risk at delivery, using information available from the mother or obstetric record. Birth testing that targets high‐risk infants based on maternal ART receipt is likely to identify the majority of in utero HIV transmissions, and allows early ART initiation for these infants.
Background: A large-scale evaluation of mother-to-child transmission (MTCT) with dolutegravir (DTG)-based antiretroviral treatment (ART) has not been conducted previously. Setting: Botswana was the first African country to change from efavirenz (EFV)/tenofovir (TDF)/emtricitabine (FTC) to DTG/TDF/FTC first-line ART. Methods: From April 2015 to July 2018, the Early Infant Treatment Study offered HIV DNA testing at <96 hours of life. Maternal ART regimen was available for screened infants who could be linked to the separate Tsepamo surveillance study database. We evaluated characteristics of HIV-positive infants, and compared MTCT rates by ART regimen for linked infants. Results: Of 10,622 HIV-exposed infants screened, 42 (0.40%) were HIV-positive. In total, 5064 screened infants could be linked to the surveillance database, including 1235 (24.4%) exposed to DTG/TDF/FTC and 2411 (47.6%) exposed to EFV/TDF/FTC. MTCT was rare when either regimen was started before conception: 0/213 [0.00%, 95% confidence interval (CI): 0.00% to 1.72%] on DTG, 1/1497 (0.07%, 95% CI: 0.00% to 0.37%) on EFV. MTCT was similar for women starting each ART regimen in pregnancy: 8/999 (0.80%, 95% CI: 0.35% to 1.57%) for DTG and 8/883 (0.91%, 95% CI: 0.39% to 1.78%) for EFV (risk difference 0.11%, 95% CI: −0.79% to 1.06%). Most MTCT events (4/8 with DTG, 6/9 with EFV) occurred when ART was started <90 days before delivery. Infants exposed to DTG in utero had lower baseline HIV RNA compared with other HIV-infected infants. Conclusion: In utero MTCT in Botswana remains rare in the DTG era. No significant MTCT differences were observed between DTG/TDF/FTC and EFV/TDF/FTC. Risk was highest for both groups when ART was started in the third trimester.
Background: Broadly neutralizing monoclonal antibodies (bNAbs) suppress HIV-1 RNA and may deplete residual viral reservoirs. We evaluated the safety and pharmacokinetics (PK) of dual intravenous VRC01LS and 10-1074 in very early-treated children with HIV-1 on suppressive antiretroviral treatment (ART).Setting: Botswana.Methods: Children with HIV-1 (median age 3.1 years) on ART from ,7 days old were enrolled. In phase A, 6 children received 10-1074 (30 mg/kg at day 0, 28, and 56) and 6 children received VRC01LS (30 mg/kg at day 0, 10 mg/kg at days 28 and 56) by intravenous infusion. In phase B, 6 children received the 2 bNAbs combined (with higher VRC01LS maintenance dose, 15 mg/kg) every 4 weeks for 32 weeks with PK evaluations over 8 weeks. Population PK models were developed to predict steadystate concentrations.Results: BNAb infusions were well tolerated. There were no infusion reactions nor any bNAb-related grade 3 or 4 events. The median (range) first dose Cmax and trough (day 28) combined from both phases were 1405 (876-1999) mg/mL and 133 (84-319) mg/mL for 10-1074 and 776 (559-846) mg/mL and 230 (158-294) mg/mL for VRC01LS. No large differences in bNAb clearances were observed when given in combination. The estimated VRC01LS half-life was shorter than in adults. Predicted steady-state troughs [median (90% prediction interval)] were 261 (95-565) and 266 (191-366) mg/mL for 10-1074 and VRC01LS, respectively, when given in combination.Conclusions: 10-1074 and VRC01LS were safe and well-tolerated among children receiving ART. Troughs exceeded minimal targets with every 4-week administration of 10-1074 at 30 mg/kg and VRC01LS at 15 mg/kg.
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