Comparison of Antiretroviral Therapies in Pregnant Women Living With Human Immunodeficiency Virus and Hepatitis B Virus

ObjectiveTo describe the anti-hepatitis B virus (HBV) efficacy, HBeAg serologic changes, HBV perinatal transmission, and safety in pregnant women who are living with human immunodeficiency virus (HIV) and HBV co-infection who were randomized to various antiretroviral therapy (ART) regimens.MethodsThe PROMISE (Promoting Maternal and Infant Survival Everywhere) trial was a multicenter randomized trial for ART-naive pregnant women with HIV infection. Women with HIV and HBV co-infection at 14 or more weeks of gestation were randomized to one of three ART arms: one without HBV treatment (group 1) and two HBV treatment arms with single (group 2) or dual anti-HBV activity (group 3). The primary HBV outcome was HBV viral load antepartum change from baseline (enrollment) to 8 weeks; safety assessments included alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, and anemia (hemoglobin less than 10 g/dL). Primary comparison was for the HBV-active treatment arms. Pairwise comparisons applied t test and the Fisher exact tests.ResultsOf 3,543 women, 3.9% were HBsAg-positive; 42 were randomized to group 1, 48 to group 2, and 48 to group 3. Median gestational age at enrollment was 27 weeks. Among HBV-viremic women, mean antepartum HBV viral load change at week 8 was -0.26 log 10 international units/mL in group 1, -1.86 in group 2, and -1.89 in group 3. In those who were HBeAg-positive, HBeAg loss occurred in 44.4% at delivery. Two perinatal HBV transmissions occurred in group 2. During the antepartum period, one woman (2.4%) in group 1 had grade 3 or 4 ALT or AST elevations, two women (4.2%) in group 2, and three women (6.3%) in group 3.ConclusionOver a short period of time, HBV DNA suppression was not different with one or two HBV-active agents. HbeAg loss occurred in a substantial proportion of participants. Perinatal transmission of HBV infection was low. Hepatitis B virus-active ART was well-tolerated in pregnancy, with few grade 3 or 4 ALT or AST elevations.Clinical trial registrationClinicalTrials.gov , NCT01061151

Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV

CITATION: Weinberg, A. et al. 2021. Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV. Clinical infectious diseases, 73(9): e3555–e3562. doi:10.1093/cid/ciaa1083The original publication is available at https://academic.oup.com/cid/Background Pregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity. Methods 944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. Results From entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum. Conclusions Decreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.https://academic.oup.com/cid/article/73/9/e3555/5877271?login=truePublishers versio

The cost‐effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa

Introduction Many HIV‐positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced‐prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 <100 cells/mm3. We investigated the cost‐effectiveness of this enhanced‐prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4 <200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. Methods The REALITY trial enrolled from June 2013 to April 2015. A decision‐analytic model was developed to estimate the cost‐effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard‐prophylaxis, enhanced‐prophylaxis, standard‐prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced‐prophylaxis (CrAg‐positive) or standard‐prophylaxis (CrAg‐negative), the second to enhanced‐prophylaxis (CrAg‐positive) or enhanced‐prophylaxis without fluconazole (CrAg‐negative) and the third to standard‐prophylaxis with fluconazole (CrAg‐positive) or without fluconazole (CrAg‐negative). The model estimated costs, life‐years and quality‐adjusted life‐years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results Enhanced‐prophylaxis was cost‐effective at cost‐effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost‐effectiveness ratio (ICER) of US$157 per QALY in the CD4 <200 cells/mm3 population providing enhanced‐prophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4 <100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US$722 per QALY). Results were sensitive to prices of the enhanced‐prophylaxis components. Enhanced‐prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced‐prophylaxis still conveyed health gains in CrAg‐negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost‐effective unless the price of CrAg testing fell below US$2.30. Conclusions The REALITY enhanced‐prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost‐effective. Efforts should continue to ensure that components are accessed at lowest available prices

Late presentation with HIV in Africa : phenotypes, risk, and risk stratification in the REALITY trial

REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development, the Wellcome Trust, and Medical Research Council (MRC) (grant number G1100693). Additional funding support was provided by the PENTA Foundation and core support to the MRC Clinical Trials Unit at University College London (grant numbers MC_UU_12023/23 and MC_UU_12023/26). Cipla Ltd, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, and Merck Sharp & Dohme donated drugs for REALITY, and ready-to-use supplementary food was purchased from Valid International. A. J. P. is funded by the Wellcome Trust (grant number 108065/Z/15/Z). J. A. B. is funded by the JGHTS (grant number MR/M007367/1). The Malawi-Liverpool–Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine (grant number 101113/Z/13/Z) and the Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi (grant number 203077/Z/16/Z) are supported by strategic awards from the Wellcome Trust, United Kingdom. Permission to publish was granted by the Director of KEMRI. This supplement was supported by funds from the Bill & Melinda Gates Foundation.Background. Severely immunocompromised human immunodefciency virus (HIV)-infected individuals have high mortality shortly afer starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods. Te Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children =5 years of age with CD4 counts .1). Results. Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P <.04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P =.02). Of fve late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/μL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/μL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/μL), but low symptom burden and maintained fat mass. Te remaining groups had 4%-6% mortality. Conclusions. Clinical and laboratory features identifed groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up.Peer reviewe

Micronutrients and nutritional status among children living with HIV with and without severe acute malnutrition: IMPAACT P1092

Abstract Background Micronutrient deficiencies from malabsorption, gut infections, and altered gut barrier function are common in children living with the human immunodeficiency virus (CLHIV) and may worsen with severe acute malnutrition (SAM). Exploratory data of baseline zinc and selenium levels and changes over 48 weeks in children living with HIV by nutritional status are presented. Methods Zinc, selenium, serum protein and albumin levels measured at study entry and over 48 weeks were compared between children aged 6 to < 36 months who were living with HIV and had SAM or mild malnutrition-normal nutrition. Children with SAM were enrolled after 10–18 days of nutritional rehabilitation. Two-sided t-tests were used to compare levels and changes in levels of micronutrients and proteins by nutritional status. Results Fifty-two participants, 25 with and 27 without SAM, of median (Q1,Q3) age 19 (13,25) and 18 (12,25) months respectively, were enrolled. Zinc deficiency was present at entry in 2/25 (8%) of those who had SAM. Mean (SD) baseline zinc levels were [52.2(15.3) and 54.7(12.0) µg/dL] for the SAM and non-SAM cohorts respectively while selenium levels were similar [92.9(25.0), 84.3(29.2) µg/L]. Mean changes of zinc and selenium from study entry to week 48 were similar between the children with and without SAM. There was no significant difference between baseline protein levels [75.2(13.2), 77.3(9.4) g/L] and the mean change from study entry to 48 weeks was also similar between the two groups; with a mean difference of 4.6 g/L [95% CI, (-2.4,11.6)]. Children with SAM compared to those without had significantly lower serum albumin levels at study entry with similar levels at 48 weeks. Conclusions Children with severe malnutrition who were initiated/switched to zidovudine/lamivudine/boosted lopinavir following 10 to 18 days of nutritional rehabilitation showed normal baseline levels of selenium and zinc, and had comparable selenium levels after 48 weeks. There was a strong positive correlation in entry and week 48 selenium levels within each cohort and for zinc in the non-SAM cohort. These data support the current WHO recommended approach to management of severe malnutrition in CLHIV who are initiated on combination antiretroviral treatment. Trial registration Registered with ClinicalTrials.gov Identifier NCT01818258 26/03/2013

1387. Women Living with HIV (WLWH) Lose IFNγ Responses Diagnostic of Latent TB Infection (LTBI) during Pregnancy and after INH Prophylactic Treatment (IPT)

Abstract Background TB is the most common opportunistic infection in PLWH. IPT is recommended for PLWH in endemic areas and for those with LTBI diagnosed by Quantiferon gold-in-tube (QGIT) or tuberculin skin test (TST) in other areas. We report on the performance of QGIT and TST in pregnant WLWH who received IPT antepartum (AP) or postpartum (PP). Methods WLWH participating in IMPAACT P1078, a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT AP vs. PP, were tested by QGIT at entry (14–34 weeks gestation) and by QGIT and TST at delivery (L&D) and 44 weeks PP. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. Results Among 944 women with study entry mean (SD) of 29 (6) years of age, 521 (245) CD4+ cells/µL, on ART, including 63% with undetectable HIV plasma RNA, 284/944 (30%) were QGIT+ AP, 215/862 (25%) at L&D and 246/764 (32%) PP (P < 0.001), while 127 (15%) were TST+ at L&D and 126 (17%) PP. QGIT was more likely positive than TST at L&D (Odds ratio = 4.3; 95% CI = 2.8–6.8) and PP (6.4; 3.9–10.7; P < 0.001). QGIT and TST agreement coefficients (95% CI) were 0.4 (0.3–0.5) at L&D and 0.5 (0.4–0.5) PP. Among women QGIT+ AP, 59 (24%) reverted to QGIT- or indeterminate at L&D. However, 37 (63%) reverters recovered QGIT+ results PP, suggesting transient suppression of IFNg responses during pregnancy. Responses to the mitogen-positive QGIT kit control were absent in 60 (7%) women AP, 116 (16%) at L&D, but only 3 (0.4%) PP (P < 0.01), supporting the notion of transient immune suppression during pregnancy. Among women QGIT- AP, 33 (7%) converted to QGIT+ PP. Among AP QGIT+ women, 24 (11%) reverted to QGIT- PP after finishing IPT. None of the results differed between treatment arms (P ≥ 0.13). Conclusion In WLWH on ART, the loss of IFNγ responses to TB antigen and mitogen in pregnancy decreased the diagnostic value of QGIT. TST was similar at L&D and PP but was less sensitive than QGIT. QGIT conversions likely resulted from a combination of PP immune reconstitution and new TB infections. QGIT reversions might represent a change in TB-specific immunity in response to IPT. Reversions have been reported in adults without HIV after treatment of active TB. The clinical significance of QGIT reversions in PLWH needs further investigation. Disclosures All authors: No reported disclosures

Brief Report: Impact of Antiretroviral Regimen on Pregnancy and Infant Outcomes in Women With HIV/ HBV Coinfection.

BackgroundThere are limited data on the impact of antenatal antiretroviral regimens (ARV) on pregnancy and infant outcomes in HIV/HBV coinfection. We compared outcomes among 3 antenatal antiretroviral regimens for pregnant women with HIV/HBV.MethodsThe PROMISE study enrolled ARV-naive pregnant women with HIV. Women with HBV were randomized to (no anti-HBV)-zidovudine (ZDV) + intrapartum nevirapine and 1 week of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC); (3TC)-3TC + ZDV + LPV/r; or (FTC-TDF)-FTC + TDF + LPV/r. Pairwise group comparisons were performed with Fisher exact, t , or log rank tests. Adverse pregnancy outcome (APO) was a composite of low birth weight, preterm delivery, spontaneous abortion, stillbirth, or congenital anomaly.ResultsOf 138 women with HIV/HBV, 42, 48, and 48 were analyzed in the no anti-HBV, 3TC, and FTC-TDF arms. Median age was 27 years. APOs trended lower in the no anti-HBV (26%) vs 3TC (38%), and FTC-TDF arms (35%), P ≥ 0.25). More infant deaths occurred among the FTC-TDF [6 (13%)] vs no anti-HBV [2 (5%)] and 3TC [3 (7%)] arms. There were no differences in time-to-death, HIV-free survival, birth or one-year WHO Z-score length-for-age, and head circumference. Hepatitis B e antigen (HBeAg) was associated with an increased risk of APO, 48% vs 27% (odds ratio 2.79, 95% confidence interval: 1.19 to 6.67, post hoc ).ConclusionWith HBV/HIV coinfection, the risk of an APO was increased with maternal ARV compared with ZDV alone, although the differences were not statistically significant. Maternal HBeAg was associated with a significantly increased risk of APO. Infant mortality was highest with FTC + TDF + LPV/r. Early assessment of HBeAg could assist in identifying high-risk pregnancies for close monitoring

1387. Women Living with HIV (WLWH) Lose IFNγ Responses Diagnostic of Latent TB Infection (LTBI) during Pregnancy and after INH Prophylactic Treatment (IPT)

Abstract Background TB is the most common opportunistic infection in PLWH. IPT is recommended for PLWH in endemic areas and for those with LTBI diagnosed by Quantiferon gold-in-tube (QGIT) or tuberculin skin test (TST) in other areas. We report on the performance of QGIT and TST in pregnant WLWH who received IPT antepartum (AP) or postpartum (PP). Methods WLWH participating in IMPAACT P1078, a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT AP vs. PP, were tested by QGIT at entry (14–34 weeks gestation) and by QGIT and TST at delivery (L&amp;D) and 44 weeks PP. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. Results Among 944 women with study entry mean (SD) of 29 (6) years of age, 521 (245) CD4+ cells/µL, on ART, including 63% with undetectable HIV plasma RNA, 284/944 (30%) were QGIT+ AP, 215/862 (25%) at L&amp;D and 246/764 (32%) PP (P &lt; 0.001), while 127 (15%) were TST+ at L&amp;D and 126 (17%) PP. QGIT was more likely positive than TST at L&amp;D (Odds ratio = 4.3; 95% CI = 2.8–6.8) and PP (6.4; 3.9–10.7; P &lt; 0.001). QGIT and TST agreement coefficients (95% CI) were 0.4 (0.3–0.5) at L&amp;D and 0.5 (0.4–0.5) PP. Among women QGIT+ AP, 59 (24%) reverted to QGIT- or indeterminate at L&amp;D. However, 37 (63%) reverters recovered QGIT+ results PP, suggesting transient suppression of IFNg responses during pregnancy. Responses to the mitogen-positive QGIT kit control were absent in 60 (7%) women AP, 116 (16%) at L&amp;D, but only 3 (0.4%) PP (P &lt; 0.01), supporting the notion of transient immune suppression during pregnancy. Among women QGIT- AP, 33 (7%) converted to QGIT+ PP. Among AP QGIT+ women, 24 (11%) reverted to QGIT- PP after finishing IPT. None of the results differed between treatment arms (P ≥ 0.13). Conclusion In WLWH on ART, the loss of IFNγ responses to TB antigen and mitogen in pregnancy decreased the diagnostic value of QGIT. TST was similar at L&amp;D and PP but was less sensitive than QGIT. QGIT conversions likely resulted from a combination of PP immune reconstitution and new TB infections. QGIT reversions might represent a change in TB-specific immunity in response to IPT. Reversions have been reported in adults without HIV after treatment of active TB. The clinical significance of QGIT reversions in PLWH needs further investigation. Disclosures All authors: No reported disclosures. </jats:sec

Brief Report: Impact of ART on Maternal Health After Cessation of Breastfeeding

IMPAACT PROMISE 1077BF/FF was a sequentially randomized study of pregnant and postpartum women living with HIV to investigate the efficacy and safety of antiretroviral therapy (ART). This Maternal Health Component investigated efficacy for the risk of developing AIDS or death; and safety among women randomized to continue ART (CTART: N = 289) or discontinue ART (N = 268) after cessation of breastfeeding or after confirmation of infant infection. No AIDS-defining illnesses were reported during follow-up in either arm. Adverse events of grade 3 or higher were more frequent in the CTART arm [hazard ratio = 1.78, 95% confidence interval: (1.05 to 3.02), P-value = 0.03]. The difference in adverse events in the 2 groups was mostly driven by moderate weight loss for women on the CTART arm

Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial.

BACKGROUND: No trials have investigated routine laboratory monitoring for children with HIV, nor four-drug induction strategies to increase durability of first-line antiretroviral therapy (ART). METHODS: In this open-label parallel-group trial, Ugandan and Zimbabwean children or adolescents with HIV, aged 3 months to 17 years and eligible for ART, were randomly assigned in a factorial design. Randomisation was to either clinically driven monitoring or routine laboratory and clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 cell counts; non-inferiority monitoring randomisation); and simultaneously to standard three-drug or to four-drug induction first-line ART, in three groups: three-drug treatment (non-nucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C; superiority ART-strategy randomisation). For patients assigned to routine laboratory monitoring, results were returned every 12 weeks to clinicians; for clinically driven monitoring, toxicity results were only returned for requested clinical reasons or if grade 4. Children switched to second-line ART for WHO stage 3 or 4 events or (routine laboratory monitoring only) age-dependent WHO CD4 criteria. Randomisation used computer-generated sequentially numbered tables incorporated securely within the database. Primary efficacy endpoints were new WHO stage 4 events or death for monitoring and change in CD4 percentage at 72 and 144 weeks for ART-strategy randomisations; the co-primary toxicity endpoint was grade 3 or 4 adverse events. Analysis was by intention to treat. This trial is registered, ISRCTN24791884. FINDINGS: 1206 children were randomly assigned to clinically driven (n=606) versus routine laboratory monitoring (n=600), and groups A (n=397), B (n=404), and C (n=405). 47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (hazard ratio [HR] 1·13, 95% CI 0·73-1·73, p=0·59; non-inferiority criterion met). However, in years 2-5, rates were higher in children on clinically driven monitoring (1·3 vs 0·4 per 100 child-years, difference 0·99, 0·37-1·60, p=0·002). One or more grade 3 or 4 adverse events occurred in 283 (47%) children on clinically driven versus 282 (47%) on routine laboratory monitoring (HR 0·98, 0·83-1·16, p=0·83). Mean CD4 percentage change did not differ between ART groups at week 72 (16·5% [SD 8·6] vs 17·1% [8·5] vs 17·3% [8·0], p=0·33) or week 144 (p=0·69), but four-drug groups (B, C) were superior to three-drug group A at week 36 (12·4% [7·2] vs 14·1% [7·1] vs 14·6% [7·3], p<0·0001). Excess grade 3 or 4 events in groups B (one or more events reported by 157 [40%] children in A, 190 [47%] in B; HR [B:A] 1·32, 1·07-1·63) and C (218 [54%] children in C; HR [C:A] 1·58, 1·29-1·94; global p=0·0001) were driven by asymptomatic neutropenia in zidovudine-containing groups (B, C; 86 group A, 133 group B, 184 group C), but resulted in drug substitutions in only zero versus two versus four children, respectively. INTERPRETATION: NNRTI plus NRTI-based three-drug or four-drug ART can be given across childhood without routine toxicity monitoring; CD4 monitoring provided clinical benefit after the first year on ART, but event rates were very low and long-term survival high, suggesting ART rollout should take priority. CD4 benefits from four-drug induction were not durable, but three-NRTI long-term maintenance was immunologically and clinically similar to NNRTI-based ART and could be valuable during tuberculosis co-treatment. FUNDING: UK Medical Research Council, the UK Department for International Development; drugs donated and viral load assays funded by ViiV Healthcare and GlaxoSmithKline