Twice-Daily Dolutegravir Based Antiretroviral Therapy with One Month of Daily Rifapentine and Isoniazid (1HP) for TB Prevention.

BACKGROUND: One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for TB prevention in people with HIV (PWH). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. ACTG A5372 evaluated the effect of 1HP on the pharmacokinetics of twice daily dolutegravir. METHODS: A5372 was a multicenter, pharmacokinetic study in PWH (≥18 years) already on dolutegravir-containing antiretroviral therapy with HIV RNA < 50 copies/mL. Participants received daily rifapentine/isoniazid (600mg/300mg) for 28 days as part of 1HP. Dolutegravir was increased to 50mg twice daily during 1HP and intensive pharmacokinetic sampling was performed on day 0 (before 1HP) and on the final day of 1HP treatment. RESULTS: Thirty-two participants (41% female; 66% Black/African; median (Q1, Q3) age 42 (34, 49) years) were included in the pharmacokinetic analysis. Thirty-one of 32 had HIV RNA levels <50 copies/mL at the end of 1HP dosing. One participant had an HIV RNA of 160 copies/mL at day 28, with HIV RNA <50 copies/mL upon repeat testing on day 42. The median (Q1, Q3) dolutegravir trough concentration was 1751 ng/mL (1195, 2542) on day 0 vs. 1987ng/mL (1331, 2278) on day 28 (day 28:day 0 GMR 1.05, [90% CI 0.93-1.2]; p = 0.43). No serious adverse events were reported. CONCLUSION: Dolutegravir trough concentrations with 50mg twice daily dosing during 1HP treatment were greater than those with standard dose dolutegravir once daily without 1HP. These pharmacokinetic, virologic, and safety data provide support for twice daily dolutegravir use in combination with 1HP for TB prevention.

The plasma kynurenine-to-tryptophan ratio as a biomarker of tuberculosis disease in people living with HIV on antiretroviral therapy: an exploratory nested case-control study.

BACKGROUND: Non-sputum-based tests are needed to predict or diagnose tuberculosis (TB) disease in people living with HIV (PWH). The enzyme indoleamine 2, 3-dioxygenase-1 (IDO1) is expressed in tuberculoid granuloma and catabolizes tryptophan (Trp) to kynurenine (Kyn). IDO1 activity compromises innate and adaptive immune responses, promoting mycobacterial survival. The plasma Kyn-to-Trp (K/T) ratio is a potential TB diagnostic and/or predictive biomarker in PWH on long-term antiretroviral therapy (ART). METHODS: We compared plasma K/T ratios in samples from PWH, who were followed up prospectively and developed TB disease after ART initiation. Controls were matched for age and duration of ART. Kyn and Trp were measured at 3 timepoints; at TB diagnosis, 6 months before TB diagnosis and 6 months after TB diagnosis, using ultra performance liquid chromatography combined with mass spectrometry. RESULTS: The K/T ratios were higher for patients with TB disease at time of diagnosis (median, 0.086; IQR, 0.069-0.123) compared to controls (0.055; IQR 0.045-0.064; p = 0.006), but not before or after TB diagnosis. K/T ratios significantly declined after successful TB treatment, but increased upon treatment failure. The K/T ratios showed a parabolic correlation with CD4 cell counts in participants with TB (p = 0.005), but there was no correlation in controls. CONCLUSIONS: The plasma K/T ratio helped identify TB disease and may serve as an adjunctive biomarker for for monitoring TB treatment in PWH. Validation studies to ascertain these findings and evaluate the optimum cut-off for diagnosis of TB disease in PWH should be undertaken in well-designed prospective cohorts. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00411983.

Predictors of liver disease progression in people living with HIV-HBV co-infection on antiretroviral therapy.

BACKGROUND: In people living with HIV-HBV, liver fibrosis progression can occur even with suppressive antiretroviral therapy (ART). We investigated the relationship between liver fibrosis and biomarkers of inflammation, apoptosis, and microbial translocation. METHODS: In this observational cohort study adults living with HIV-HBV already on effective ART were recruited in Australia and Thailand and followed for 3 years including 6 monthly clinical review and blood tests and annual transient elastography. Differences in clinical and laboratory predictors of liver fibrosis progression were tested followed by regression analysis adjusted for CD4+ T-cells at study entry. A linear mixed model was fitted to longitudinal data to explore changes over time. FINDINGS: 67 participants (85% male, median age 49 y) were followed for 175 person-years. Median duration of ART was 10 years (interquartile range (IQR) 8-16 years). We found 11/59 (19%) participants during 3-years follow-up (6/100 person-years) met the primary endpoint of liver disease progression, defined as increased Metavir stage from baseline to final scan. In regression analysis, progressors compared to non-progressors had higher levels of high mobility group box 1 protein (HGMB1), (median (IQR) 3.7 (2.6-5.0) and 2.4 ng/mL (1.5-3.4) respectively, adjusted relative risk 1.47, 95% CI [1.00, 2.17]) and lower nadir CD4+ T-cell percentage (median 4% (IQR 2-8) and 11% (4-15) respectively (relative risk 0.93, 95% CI [0.88, 0.98]). INTERPRETATION: Progression in liver fibrosis occurs in people with HIV-HBV on suppressive ART. Fibrosis progression was associated with higher HMGB1 and lower percentage nadir CD4+ T-cell count, highlighting the importance of early initiation of HBV-active ART. FUNDING: This work was supported by NHMRC project grant 1101836; NHMRC practitioner fellowship 1138581 and NHMRC program grant 1149990. The funder had no role in study design, data collection, data analysis, interpretation, writing of this manuscript or decision to submit for publication.

Framingham risk score based vascular outcomes in acute versus chronic HIV cohorts after 6 years of ART.

INTRODUCTION: Immune dysregulation persists in people with HIV (PWH) on antiretroviral therapy (ART) and may lead to accelerated vascular ageing and cardiovascular disease (CVD). While delayed time to initiation of ART has been linked to worse cardiovascular outcomes, the effect of ART initiation during acute infection on these outcomes is not well understood. METHODS: Participants were enrolled from the SEARCH010/RV254 acute HIV (AHI) and HIV-NAT chronic HIV (CHI) cohorts in Thailand. Participants with 6-year follow-up and viral suppression (viral load < 50 copies/µL) at follow-up were included. Both unmatched cohorts and age and gender-matched cohorts were analysed. Demographics, HIV laboratories, and cardiovascular risk factors from enrolment and 6-year follow-up were obtained from electronic records. Framingham Risk Score (FRS), vascular age (VA), vascular age deviation (VAD), and 10-year atherosclerotic cardiovascular disease (ASCVD) risk were calculated from previously published equations. Vascular outcomes in AHI and CHI cohorts were compared, and univariable and multivariable linear regression analyses were used to investigate risk factors associated with worse vascular scores. RESULTS: In all, 373 AHI participants and 608 CHI participants were identified. AHI participants were of younger age, had a higher prevalence of syphilis and a lower prevalence of prior hepatitis B, tuberculosis, diabetes, and hypertension. Higher CD4 T-cell and lower CD8 T-cell counts were seen in the AHI cohort at enrolment and 6-year follow-up. In all participants, the AHI cohort had a lower median FRS (p < 0.001) and VA (p < 0.001), but higher VAD (p < 0.001). However, in matched cohorts, no differences were found in FRS-based outcomes. In all participants, higher VAD after 6 years of ART was associated with higher body mass index (p < 0.001) and higher CD4 count (p < 0.001), which persisted in multivariable analysis. When FRS components were analysed individually, CD4 count was associated only with male sex and cholesterol. CONCLUSIONS: We did not identify differences in FRS-based vascular outcomes at 6 years in matched cohorts of participants who started ART during AHI versus CHI. We identified a correlation between higher CD4 count and worse FRS-based vascular outcomes, which may be driven by underlying metabolic risk factors. Further study is needed to confirm these findings and evaluate underlying mechanisms.

Monocyte to lymphocyte ratio and hemoglobin level to predict tuberculosis after antiretroviral therapy initiation.

OBJECTIVE: To determine the performance of the baseline monocyte to lymphocyte ratio (MLR), baseline anemia severity and combination of these biomarkers, to predict tuberculosis (TB) incidence in people with HIV (PWH) after antiretroviral therapy (ART) initiation. DESIGN: Multicenter, retrospective cohort study. METHODS: We utilized the data from study A5175 (Prospective Evaluation of Antiretroviral Therapy in Resource-limited Settings: PEARLS). We assessed the utility of MLR, anemia severity and in combination, for predicting TB in the first year after ART. Cox regression was used to assess associations of MLR and anemia with incident TB. Harrell's C index was used to describe single model discrimination. RESULTS: A total of 1455 participants with a median age of 34 [interquartile range (IQR) 29, 41] were included. Fifty-four participants were diagnosed with TB. The hazard ratio (HR) for incident TB was 1.77 [95% confidence interval (CI) 1.01-3.07]; P  = 0.04 for those with MLR ≥0.23. The HR for mild/mod anemia was 3.35 (95% CI 1.78-6.29; P  < 0.001) and 18.16 (95% CI 5.17-63.77; P  < 0.001) for severe anemia. After combining parameters, there were increases in adjusted HR (aHR) for MLR ≥0.23 to 1.83 (95% CI 1.05-3.18), and degrees of anemia to 3.38 (95% CI 1.80-6.35) for mild/mod anemia and 19.09 (95% CI 5.43-67.12) for severe anemia. CONCLUSIONS: MLR and hemoglobin levels which are available in routine HIV care can be used at ART initiation for identifying patients at high risk of developing TB disease to guide diagnostic and management decisions.

A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV.

OBJECTIVE: The objective of this study was to assess the pharmacokinetics, safety, and efficacy and confirm the dose of once-daily bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF; B/F/TAF) during pregnancy. DESIGN: An open-label, multicenter, single-arm, phase 1b study (NCT03960645) was conducted in 33 virologically suppressed pregnant women with HIV-1. METHODS: Participants received B/F/TAF (50/200/25 mg) from the second or third trimester through ∼16 weeks postpartum. Steady-state maternal plasma pharmacokinetic samples were collected at the second and third trimesters and 6 and 12 weeks postpartum for BIC, FTC, and TAF. Neonates ( n  = 29) were followed from birth to 4-8 weeks with sparse washout pharmacokinetic sampling for BIC and TAF. The proportion of participants with HIV-1 RNA less than 50 copies/ml at delivery (missing = excluded) was evaluated. RESULTS: Mean areas under the concentration-time curve over the dosing interval (AUC tau ) for BIC, FTC, and TAF were lower during pregnancy versus postpartum but were closer to AUC tau values for nonpregnant adults with HIV reported in other studies. Geometric least-squares mean ratios for BIC, FTC, and TAF AUC tau during pregnancy versus postpartum ranged from 41 to 45%, 64 to 69% and 57 to 78%, respectively. Mean BIC trough concentrations during pregnancy were more than 6.5-fold greater than the protein-adjusted 95% effective concentration. In neonates, the median BIC half-life was 43 h. Virologic suppression was maintained in all adult participants throughout the study, with no virologic failure or treatment-emergent resistance to HIV-1, no discontinuations because of adverse events, and no perinatal transmission. CONCLUSION: Exposures to BIC, FTC, and TAF were lower during pregnancy than postpartum. However, mean BIC trough concentrations were maintained at levels indicative of efficacious exposure, and FTC/TAF data were concordant with published literature in this population. Pharmacokinetic and safety data, combined with maintenance of robust virologic suppression, suggest that once-daily B/F/TAF without dose adjustment is appropriate during pregnancy.

Treatment Outcomes After Switching to Second-Line Anti-Retroviral Therapy: Results From the Thai National Treatment Program.

This study aimed to assess second-line antiretroviral therapy (ART) outcomes in a National HIV Treatment program. People living with HIV aged ≥18 years initiating first-line ART who switched to second-line protease inhibitor-based regimens from January 2008 to May 2019, with a minimum of 1-year follow-up were studied. The primary outcome was second-line treatment failure (two consecutive virological failure episodes (viral load ≥1000 copies/mL)). Of 318,506 PLH initiating ART, 29,015 (9.1%) switched to second-line regimens after a median (IQR) ART duration of 1.63 (0.60-3.59) years. Lost to follow-up (LTFU) occurred in 5316 (18.3%) of whom 1376 (5%) remained LTFU and alive; 4606 (15.9%) died. Cumulative second-line failure incidence was 9.8% at 6 years, more common in females, younger PLH those with lower switch CD4 cell counts. Multidisciplinary, innovative support systems are needed to improve second-line treatment outcomes, particularly those relating to modifiable risk factors.

Outcomes after switching to second line antiretroviral regimens in the Thai National Treatment programWe assessed the rates of virological failure, losses to follow-up and death in 29,015 people who switched to second line antiretroviral therapy in Thailand. The cumulative rate of virological failure was a 9.8% at 6 years, loss to follow-up occurred in 18.3% (5% who remained alive) and 15.9% died. Women and those with lower CD4 counts at switch had the highest risk of virological failure.

Impact of steatotic liver disease and non-alcoholic steatohepatitis on cognitive impairment in people living with HIV: A cross-sectional study.

INTRODUCTION: The link between fatty liver diseases and cognitive impairment among people living with HIV (PLWH) remains unclear. We investigated the association of steatotic liver disease (SLD), advanced liver fibrosis and non-alcoholic steatohepatitis (NASH) with significant activity and liver fibrosis with cognitive impairment in PLWH. METHODS: Cognitive performance was assessed for PLWH aged ≥50 years on stable antiretroviral therapy (ART) with the Thai-validated version of the Montreal Cognitive Assessment (MoCA), and a cut-off of <25/30 was used to define cognitive impairment. SLD and NASH with significant activity and liver fibrosis were defined as having a controlled attenuation parameter value ≥248 dB/m and a FibroScan-AST (FAST) score ≥0.67, respectively. Multivariable logistic regression was employed to investigate the association of cognitive impairment with SLD or NASH. RESULTS: Of the 319 PLWH (63.3% male and 98% had HIV-1 RNA ≤50 copies/mL) included, 74 (38%) had SLD. NASH with significant activity and liver fibrosis was present in 66 (20.1%) participants. Some 192 (60.2%) participants had cognitive impairment. In a multivariable analysis, NASH with significant activity and liver fibrosis was significantly associated with cognitive impairment (adjusted odds ratio [aOR] 2.01, 95% CI 1.02-3.98, p = 0.04), after adjusting for HIV-related parameters, age, sex, body mass index, employment status, education, income level, smoking, alcohol use, diabetes mellitus, hypertension and HIV-related parameters. The association of a lone diagnosis of SLD and cognitive impairment was not statistically significant. CONCLUSIONS: NASH with significant activity and liver fibrosis was associated with lower cognitive performance, even after controlling for demographics and HIV disease parameters. Additional research is needed to better understand the underlying mechanisms.

Long-term benefit of DAAs on gut dysbiosis and microbial translocation in HCV-infected patients with and without HIV coinfection.

Long-term effect of Direct-acting antivirals (DAAs) on gut microbiota, short-chain fatty acids (SCFAs) and microbial translocation in patients with hepatitis C virus (HCV) infection who achieve sustained virological response (SVR) were limited. A longitudinal study of 50 patients with HCV monoinfection and 19 patients with HCV/HIV coinfection received DAAs were conducted. Fecal specimens collected at baseline and at week 72 after treatment completion (FUw72) were analyzed for 16S rRNA sequencing and the butyryl-CoA:acetateCoA transferase (BCoAT) gene expression using real-time PCR. Plasma lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) were quantified by ELISA assays. SVR rates in mono- and coinfected patients were comparable (94% vs. 100%). The improvement of gut dysbiosis and microbial translocation was found in responders but was not in non-responders. Among responders, significant restoration of alpha-diversity, BCoAT and LBP were observed in HCV patients with low-grade fibrosis (F0-F1), while HCV/HIV patients exhibited partial improvement at FUw72. I-FABP did not decline significantly in responders. Treatment induced microbiota changes with increasing abundance of SCFAs-producing bacteria, including Blautia, Fusicatenibacter, Subdoligranulum and Bifidobacterium. In conclusion, long-term effect of DAAs impacted the restoration of gut dysbiosis and microbial translocation. However, early initiation of DAAs required for an alteration of gut microbiota, enhanced SCFAs-producing bacteria, and could reduce HCV-related complications.

Adverse Pregnancy Outcomes among HIV-infected Women Taking Isoniazid Preventive Therapy During the First Trimester.

BACKGROUND: Tuberculosis prevention using isoniazid (IPT) is recommended for people with HIV, yet data on the safety of first-trimester pregnancy exposure are limited. METHODS: Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight <2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count and antiretroviral therapy (ART). RESULTS: 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (aRR 1.98; 95% CI 1.15, 3.41), but the effect was attenuated when adjusted for covariates at pregnancy outcome (aRR 1.47; 95% CI 0.84, 2.55); IPT was not associated with preterm delivery (RR 0.87; 95% CI 0.32-2.42) or low birth weight (RR 1.01; 95% CI 0.29, 3.56). CONCLUSION: First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome including ART use. Further study is needed to inform TB prevention guidelines.

High-Sensitivity Troponins and Subclinical Coronary Atherosclerosis Evaluated by Coronary Calcium Score Among Older Asians Living With Well-Controlled Human Immunodeficiency Virus.

Background: Elevated levels of high-sensitivity cardiac troponin (hs-cTn) are suggestive of myocardial cell injury and coronary artery disease. We explored the association between hs-cTn and subclinical arteriosclerosis using coronary artery calcification (CAC) scoring among 337 virally suppressed patients with human immunodeficiency virus (HIV) who were ≥50 years old and without evidence of known coronary artery disease. Methods: Noncontrast cardiac computed tomography and blood sampling for hs-cTn, both subunit I (hs-cTnI) and subunit T (hs-cTnT), were performed. The relationship between CAC (Agatston score) and serum hs-cTn levels was analyzed using Spearman correlation and logistic regression models. Results: The patients, of whom 62% were male, had a median age of 54 years and had been on antiretroviral therapy for a median of 16 years; the CAC score was >0 in 50% of patients and ≥100 in 16%. Both hs-cTn concentrations were positively correlated with the Agatston score, with correlation coefficients of 0.28 and 0.27 (P < .001) for hs-cTnI and hs-cTnT, respectively. hs-cTnI and hs-cTnT concentrations of ≥4 and ≥5.3 pg/mL, respectively, provided the best performance for discriminating patients with Agatston scores ≥100, with a sensitivity and specificity of 76% and 60%, respectively, for hs-cTnI and 70% and 50% for hs-cTnT. In multivariable logistic regression analysis, each log unit increase in hs-cTnI level was independently associated with increased odds of having an Agatston score ≥100 (odds ratio, 2.83 [95% confidence interval, 1.69-4.75]; P <.001). Although not an independent predictor, hs-cTnT was also associated with an increased odds of having an Agatston score ≥100 (odds ratio, 1.58 [95% confidence interval, .92-2.73]; P = .10). Conclusions: Among Asians aged ≥50 years with well-controlled HIV infection and without established cardiovascular disease, 50% had subclinical arteriosclerosis. Increasing hs-cTnI and hs-cTnT concentrations were associated with an increased risk of severe subclinical arteriosclerosis, and hs-cTn may be a potential biomarker to detect severe subclinical arteriosclerosis.

Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis With Liver Fibrosis as Predictors of New-Onset Diabetes Mellitus in People With HIV: A Longitudinal Cohort Study.

BACKGROUND: We investigated the association between nonalcoholic fatty liver disease (NAFLD) plus or minus a concurrent diagnosis of nonalcoholic steatohepatitis (NASH) and incident diabetes mellitus (DM) and the risk factors associated with NAFLD or NASH development. METHODS: In this prospective study, we analyzed people with human immunodeficiency virus (HIV; PWH) aged ≥18 years without excessive alcohol consumption or hepatitis coinfections. NAFLD was defined as controlled attenuation parameter ≥248 dB/m, whereas NASH with significant disease activity and liver fibrosis was defined as a FibroScan-AST score ≥0.67. Cox proportional hazard regression was used to investigate the association between NAFLD with or without NASH and new-onset DM. RESULTS: Of 847 PWH, the median age at baseline was 45 years (interquartile range, 38-51; 43% female). Baseline NAFLD was associated with 2.8-fold higher risk of new-onset DM after adjusting for age, sex, family history of DM, antiretroviral therapy duration, smoking, statin use, stavudine/didanosine/zidovudine exposure, time-updated body mass index, hypertension, and dyslipidemia. Combined NAFLD and NASH at baseline had 3.1-fold higher new-onset DM risk. In separate analyses, baseline DM did not predict progression to NAFLD or NASH, but tenofovir alafenamide use was associated with an increased risk of NAFLD (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.02-4.02) or NASH development (2.31; 95% CI, 1.12-5.11). CONCLUSIONS: NAFLD alone or combined with NASH strongly predicts new-onset DM. This highlights the need for systematic risk assessments and management of NAFLD/NASH, as it may contribute to metabolic complications such as DM and subsequent cardiovascular diseases in PWH.

Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial.

BACKGROUND: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. METHODS: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. FINDINGS: Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per µL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. INTERPRETATION: In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. FUNDING: Gilead Sciences.

Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 and hepatitis B coinfection (ALLIANCE): a double-blind, multicentre, randomised controlled, phase 3 non-inferiority trial.

BACKGROUND: For most adults with HIV-1 and hepatitis B virus (HBV) coinfection, initial recommended treatment is a tenofovir-containing antiretroviral regimen, but no randomised studies have compared tenofovir disoproxil fumarate with tenofovir alafenamide. We aimed to investigate whether bictegravir, emtricitabine, and tenofovir alafenamide is non-inferior to dolutegravir, emtricitabine, and tenofovir disoproxil fumarate for viral suppression in individuals with HIV-1 and HBV coinfection at 48 and 96 weeks. METHODS: We did this randomised, double-blind, active-controlled, phase 3, non-inferiority trial at 46 outpatient centres in China, Dominican Republic, Hong Kong, Japan, Malaysia, South Korea, Spain, Taiwan, Thailand, Turkey, and the USA. Eligible participants were treatment-naive adults (aged ≥18 years) with plasma HIV-1 RNA of at least 500 copies per mL and plasma HBV DNA of at least 2000 IU/mL. Participants were randomly assigned (1:1) to receive daily oral bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or dolutegravir 50 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg, each with corresponding matching placebo. Randomisation was stratified by hepatitis B e antigen (HBeAg) status (positive vs negative), HBV DNA (<8 vs ≥8 log10 IU/mL), and CD4 count (<50 vs ≥50 cells per µL) at screening. All investigators, participants, and staff providing treatment, assessing outcomes, and collecting data were masked to study treatment for 96 weeks. Coprimary endpoints were the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL (defined by the US Food and Drug Administration snapshot algorithm) and plasma HBV DNA less than 29 IU/mL (using the missing-equals-failure approach) at week 48, with a prespecified non-inferiority margin of -12%. Coprimary endpoints were assessed in the full analysis set, which included all randomly assigned participants who received at least one dose of study drug and had at least one post-baseline HIV-1 RNA or HBV DNA result while on study drug. Safety endpoints were assessed in all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03547908. FINDINGS: Between May 30, 2018 and March 16, 2021, 381 participants were screened, of whom 243 initiated treatment (121 in the receive bictegravir, emtricitabine, and tenofovir alafenamide group; 122 in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group). At week 48, both endpoints met the criteria for non-inferiority: 113 (95%) of 119 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group and 111 (91%) of 122 participants in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group had HIV-1 RNA less than 50 copies per mL (difference 4·1, 95% CI -2·5 to 10·8; p=0·21), and 75 (63%) of 119 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus 53 (43%) of 122 participants in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group had HBV DNA suppression (difference 16·6, 5·9 to 27·3; nominal p=0·0023). Drug-related adverse events up to week 96 occurred in 35 (29%) of 121 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group and 34 (28%) of 122 participants in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group. One (1%) of 121 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group reported a serious adverse event (cryptococcal meningitis attributed to immune reconstitution inflammatory syndrome) that was deemed to be treatment-related. INTERPRETATION: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is an effective therapy for adults with HIV-1 and HBV coinfection starting antiviral therapy. FUNDING: Gilead Sciences.

Trends in hepatitis C virus coinfection and its cascade of care among adults living with HIV in Asia between 2010 and 2020.

BACKGROUND: Chronic hepatitis C virus (HCV) infection contributes to substantial morbidity and mortality among adults living with HIV. Cascades of HCV care support monitoring of program performance, but data from Asia are limited. We assessed regional HCV coinfection and cascade outcomes among adults living with HIV in care from 2010-2020. METHODS: Patients ≥18 years old with confirmed HIV infection on antiretroviral therapy (ART) at 11 clinical sites in Cambodia, China, India, Indonesia, South Korea, Thailand and Vietnam were included. HCV- and HIV-related treatment and laboratory data were collected from those with a positive HCV antibody (anti-HCV) test after January 2010. An HCV cascade was evaluated, including proportions positive for anti-HCV, tested for HCV RNA or HCV core antigen (HCVcAg), initiated on HCV treatment, and achieved sustained virologic response (SVR). Factors associated with screening uptake, treatment initiation, and treatment response were analyzed using Fine and Gray's competing risk regression model. RESULTS: Of 24,421 patients, 9169 (38%) had an anti-HCV test, and 971 (11%) had a positive result. The proportion with positive anti-HCV was 12.1% in 2010-2014, 3.9% in 2015-2017, and 3.8% in 2018-2020. From 2010 to 2014, 34% with positive anti-HCV had subsequent HCV RNA or HCVcAg testing, 66% initiated HCV treatment, and 83% achieved SVR. From 2015 to 2017, 69% with positive anti-HCV had subsequent HCV RNA or HCVcAg testing, 59% initiated HCV treatment, and 88% achieved SVR. From 2018 to 2020, 80% had subsequent HCV RNA or HCVcAg testing, 61% initiated HCV treatment, and 96% achieved SVR. Having chronic HCV in later calendar years and in high-income countries were associated with increased screening, treatment initiation or achieving SVR. Older age, injecting drug use HIV exposure, lower CD4 and higher HIV RNA were associated with reduced HCV screening or treatment initiation. CONCLUSIONS: Our analysis identified persistent gaps in the HCV cascade of care, highlighting the need for focused efforts to strengthen chronic HCV screening, treatment initiation, and monitoring among adult PLHIV in the Asia region.

Metabolic-Associated Fatty Liver Disease (MAFLD) is associated with immune activation, increased epicardial fat volume, and steatohepatitis among people with HIV in a Thai cohort.

INTRODUCTION: A change in terminology from fatty liver disease to metabolic-associated fatty liver disease (MAFLD), along with modified diagnostic criteria, was proposed in 2020, and data regarding MAFLD burden in people living with HIV are limited. We investigated associations between MAFLD and immune activation, cardiovascular disease (CVD) risks including epicardial fat volume, and steatohepatitis in an Asian cohort. METHODS: We evaluated CVD risk (epicardial fat tissue, coronary artery calcium [CAC] score, and 10-year atherosclerotic CVD [ASCVD] score) in people living with HIV aged >50 years. Individuals with excessive alcohol consumption and viral hepatitis infections were excluded. MAFLD diagnosis was based on 2020 International Consensus criteria. Non-alcoholic steatohepatitis (NASH) with significant activity and liver fibrosis was defined as FibroScan-aspartate aminotransferase (FAST) score ≥0.67 and >0.35. Multivariate logistic regression models were used to investigate factors associated with MAFLD and NASH with significant activity and liver fibrosis. RESULTS: The median age was 54 years (interquartile range [IQR] 52-60) and current CD4 count was 613 (IQR 467-804) cells/mm3 . A total of 37% were female, and most (98%) people living with HIV were virally suppressed. The prevalence of MAFLD and non-alcoholic fatty liver disease was 35% and 38%, respectively. In multivariate analyses, higher body mass index, albumin, epicardial fat volume, and liver stiffness were significantly associated with MAFLD. A higher CD4/CD8 ratio was associated with a lower risk of MAFLD. People with HIV with MAFLD had higher odds of having NASH with significant activity and liver fibrosis (adjusted odds ratio 3.3; 95% confidence interval 1.6-6.6), and similar associations were also observed among different MAFLD categories. CONCLUSIONS: The complex relationship between MAFLD and immune activation, steatohepatitis, and epicardial fat tissue suggests an increased risk of advanced liver disease and CVDs beyond the traditional risk factors in people living with HIV with fatty liver disease.

Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS: Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Electrochemical capillary-driven microfluidic DNA sensor for HIV-1 and HCV coinfection analysis.

Electrochemical DNA sensors can be operated in either static or flow-based detection schemes. In static schemes, manual washing steps are still necessary, resulting in a tedious and time-consuming process. In contrast, in flow-based electrochemical sensors, the current response is collected when the solution flows through the electrode continuously. However, the drawback of such a flow system is the low sensitivity due to the limited time for the interaction between the capturing element and the target. Herein, we propose a novel electrochemical capillary-driven microfluidic DNA sensor to combine the advantages of static and flow-based electrochemical detection systems into a single device by incorporating burst valve technology. The microfluidic device with a two-electrode configuration was applied for the simultaneous detection of two different DNA markers, human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) cDNA, via the specific interaction between pyrrolidinyl peptide nucleic acids (PNA) probes and the DNA target. The integrated system, while requiring a small sample volume (7 µL for each sample loading port) and less analysis time, achieved good performance in terms of the limits of detection (LOD) (3SDblank/slope) and quantification (LOQ) (10SDblank/slope) at 1.45 nM and 4.79 nM for HIV and 1.20 nM and 3.96 nM for HCV, respectively. The simultaneous detection of HIV-1 and HCV cDNA prepared from human blood samples showed results that are in complete agreement with the RT‒PCR assay. The results qualify this platform as a promising alternative for the analysis of either HIV-1/HCV or coinfection that can be easily adapted for other clinically important nucleic acid-based markers.

Immunogenicity and Safety of Hepatitis B Virus (HBV) Vaccine With a Toll-Like Receptor 9 Agonist Adjuvant in HBV Vaccine-Naïve People With Human Immunodeficiency Virus.

In this international, multicenter open-label study (ACTG A5379) of HepB-CpG vaccine in people with human immunodeficiency virus (HIV) without prior hepatitis B virus (HBV) vaccination, all 68 participants achieved HBV seroprotective titers after the 3-dose series in the primary analysis. No unexpected safety issues were observed.

Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tanzania.

In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.