Metabolic causes of liver disease among adults living with HIV from low- and middle-income countries: a cross-sectional study.

INTRODUCTION: Liver disease is a leading cause of morbidity and mortality among persons living with HIV (PLHIV). While chronic viral hepatitis has been extensively studied in low- and middle-income countries (LMICs), there is limited information about the burden of metabolic disorders on liver disease in PLHIV. METHODS: We conducted a cross-sectional analysis of baseline data collected between October 2020 and July 2022 from the IeDEA-Sentinel Research Network, a prospective cohort enrolling PLHIV ≥40 years on antiretroviral treatment (ART) for ≥6 months from eight clinics in Asia, Americas, and central, East, southern and West Africa. Clinical assessments, laboratory testing on fasting blood samples and liver stiffness measurement (LSM)/controlled attenuation parameter (CAP) by vibration-controlled transient elastography were performed. Multivariable logistic regression models assessed factors associated with liver fibrosis (LSM ≥7.1 kPa) and steatosis (CAP ≥248 dB/m). Population attributable fraction (PAF) of each variable associated with significant liver fibrosis was estimated using Levin's formula. RESULTS: Overall, 2120 PLHIV (56% female, median age 50 [interquartile range: 45-56] years) were included. The prevalence of obesity was 19%, 12% had type 2 diabetes mellitus (T2DM), 29% had hypertension and 53% had dyslipidaemia. The overall prevalence of liver fibrosis and steatosis was 7.6% (95% confidence interval [CI] 6.1-8.4) and 28.4% (95% CI 26.5-30.7), respectively, with regional variability. Male sex at birth (odds ratio [OR] 1.62, CI 1.10-2.40), overweight/obesity (OR = 2.50, 95% CI 1.69-3.75), T2DM (OR 2.26, 95% CI 1.46-3.47) and prolonged exposure to didanosine (OR 3.13, 95% CI 1.46-6.49) were associated with liver fibrosis. Overweight/obesity and T2DM accounted for 42% and 11% of the PAF for liver fibrosis, while HBsAg and anti-HCV accounted for 3% and 1%, respectively. Factors associated with steatosis included overweight/obesity (OR 4.25, 95% CI 3.29-5.51), T2DM (OR 2.06, 95% CI 1.47-2.88), prolonged exposure to stavudine (OR 1.69, 95% CI 1.27-2.26) and dyslipidaemia (OR 1.68, 95% CI 1.31-2.16). CONCLUSIONS: Metabolic disorders were significant risk factors for liver disease among PLHIV in LMICs. Early recognition of metabolic disorders risk factors might be helpful to guide clinical and lifestyle interventions. Further prospective studies are needed to determine the causative natures of these findings.

The Tuberculosis Sentinel Research Network (TB-SRN) of the International epidemiology Databases to Evaluate AIDS (IeDEA): protocol for a prospective cohort study in Africa, Southeast Asia and Latin America.

INTRODUCTION: Tuberculosis (TB) is a leading infectious cause of death globally. It is the most common opportunistic infection in people living with HIV, and the most common cause of their morbidity and mortality. Following TB treatment, surviving individuals may be at risk for post-TB lung disease. The TB Sentinel Research Network (TB-SRN) provides a platform for coordinated observational TB research within the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS AND ANALYSIS: This prospective, observational cohort study will assess treatment and post-treatment outcomes of pulmonary TB (microbiologically confirmed or clinically diagnosed) among 2600 people aged ≥15 years, with and without HIV coinfection, consecutively enrolled at 16 sites in 11 countries, across 6 of IeDEA's global regions. Data regarding clinical and sociodemographic factors, mental health, health-related quality of life, pulmonary function, and laboratory and radiographic findings will be collected using standardised questionnaires and data collection tools, beginning from the initiation of TB treatment and through 12 months after the end of treatment. Data will be aggregated for proposed analyses. ETHICS AND DISSEMINATION: Ethics approval was obtained at all implementing study sites, including the Vanderbilt University Medical Center Human Research Protections Programme. Participants will provide informed consent; for minors, this includes both adolescent assent and the consent of their parent or primary caregiver. Protections for vulnerable groups are included, in alignment with local standards and considerations at sites. Procedures for requesting use and analysis of TB-SRN data are publicly available. Findings from TB-SRN analyses will be shared with national TB programmes to inform TB programming and policy, and disseminated at regional and global conferences and other venues.

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.

Lipid and glucose abnormalities and associated factors among children living with HIV in Asia.

BACKGROUND: Children living with HIV (CLHIV) on prolonged antiretroviral therapy (ART) are at risk for lipid and glucose abnormalities. Prevalence and associated factors were assessed in a multicentre, Asian longitudinal paediatric cohort. METHODS: CLHIV were considered to have lipid or glucose abnormalities if they had total cholesterol ≥200 mg/dL, high-density lipoprotein (HDL) ≤35 mg/dL, low-density lipoprotein (LDL) ≥100 mg/dL, triglycerides (TG) ≥110 mg/dL, or fasting glucose >110 mg/dL. Factors associated with lipid and glucose abnormalities were assessed by logistic regression. RESULTS: Of 951 CLHIV, 52% were male with a median age of 8.0 (interquartile range [IQR] 5.0-12.0) years at ART start and 15.0 (IQR 12.0-18.0) years at their last clinic visit. 89% acquired HIV perinatally, and 30% had ever used protease inhibitors (PIs). Overall, 225 (24%) had hypercholesterolemia, 105 (27%) low HDL, 213 (58%) high LDL, 369 (54%) hypertriglyceridemia, and 130 (17%) hyperglycemia. Hypercholesterolemia was more likely among females (versus males, aOR 1.93, 95% CI 1.40-2.67). Current PIs use was associated with hypercholesterolemia (current use: aOR 1.54, 95% CI 1.09-2.20); low HDL (current use: aOR 3.16, 95% CI 1.94-5.15; prior use: aOR 10.55, 95% CI 2.53-43.95); hypertriglyceridemia (current use: aOR 3.90, 95% CI 2.65-5.74; prior use: aOR 2.89, 95% CI 1.31-6.39); high LDL (current use: aOR 1.74, 95% CI 1.09-2.76); and hyperglycemia (prior use: aOR 2.43, 95% CI 1.42-4.18). CONCLUSION: More than half and one-fifth of CLHIV have dyslipidemia and hyperglycemia, respectively. Routine paediatric HIV care should include metabolic monitoring. The association between PIs use and dyslipidemia emphasizes the importance of rapidly transitioning to integrase inhibitor-containing regimens.

BMI as a predictor of high fasting blood glucose among people living with HIV in the Asia-Pacific region.

BACKGROUND: Non-Asian body mass index (BMI) classifications are commonly used as a risk factor for high fasting blood glucose (FBG). We investigated the incidence and factors associated with high FBG among people living with HIV in the Asia-Pacific region, using a World Health Organization BMI classification specific to Asian populations. METHODS: This study included people living with HIV enrolled in a longitudinal cohort study from 2003 to 2019, receiving antiretroviral therapy (ART), and without prior tuberculosis. BMI at ART initiation was categorized using Asian BMI classifications: underweight (<18.5 kg/m2 ), normal (18.5-22.9 kg/m2 ), overweight (23-24.9 kg/m2 ), and obese (≥25 kg/m2 ). High FBG was defined as a single post-ART FBG measurement ≥126 mg/dL. Factors associated with high FBG were analyzed using Cox regression models stratified by site. RESULTS: A total of 3939 people living with HIV (63% male) were included. In total, 50% had a BMI in the normal weight range, 23% were underweight, 13% were overweight, and 14% were obese. Median age at ART initiation was 34 years (interquartile range 29-41). Overall, 8% had a high FBG, with an incidence rate of 1.14 per 100 person-years. Factors associated with an increased hazard of high FBG included being obese (≥25 kg/m2 ) compared with normal weight (hazard ratio [HR] = 1.79; 95% confidence interval [CI] 1.31-2.44; p < 0.001) and older age compared with those aged ≤30 years (31-40 years: HR = 1.47; 95% CI 1.08-2.01; 41-50 years: HR = 2.03; 95% CI 1.42-2.90; ≥51 years: HR = 3.19; 95% CI 2.17-4.69; p < 0.001). CONCLUSION: People living with HIV with BMI >25 kg/m2 were at increased risk of high FBG. This indicates that regular assessments should be performed in those with high BMI, irrespective of the classification used.

Factors associated with high alanine aminotransferase (ALT) and cirrhosis in people living with HIV on combination antiretroviral treatment (cART) in the Asia-Pacific.

Liver disease is a growing burden among people living with HIV (PLHIV) in resource-limited settings. As an indicator of liver disease, risk factors of high alanine aminotransferase (ALT) and cirrhosis were assessed among PLHIV in the TREAT Asia HIV Observational Database (TAHOD). Patients on combination antiretroviral therapy (cART) with a pre-cART ALT measurement and at least one follow-up ALT measurement were included. Factors associated with high ALT (ALT levels > 5 times its upper limit of normal) were analyzed using repeated measure logistic regression over a 10-year follow-up period. Liver cirrhosis was defined as having an AST to Platelet Ratio Index score > 1.5, fibrosis-4 score > 3.25, or a clinical diagnosis of cirrhosis. Cox regression analysis stratified by site was used to analyze factors associated with cirrhosis among those in follow-up after 2015. Of 5182 patients, 101 patients (1.9%) had high ALT levels with hepatitis C virus (HCV) antibody positive (odds ratio [OR]: 4.98, 95% confidence interval [CI]: 2.82-8.77, p < 0.001) and ever high alcohol consumption (OR: 2.33, 95% CI: 1.00-5.46, p = 0.050) as likely factors. Among 6318 PLHIV in the liver cirrhosis analysis, 151 (2%) developed cirrhosis (incidence rate = 0.82 per 100 person-years). Those HCV-antibody positive (hazard ratio [HR]: 5.54, 95% CI: 3.75-8.18, p < 0.001) and had high alcohol consumption (HR: 2.06, 95% CI: 1.23-3.45, p = 0.006) were associated with liver cirrhosis. HCV-antibody positive and high alcohol consumption are factors associated with high ALT. With raised ALT levels as a known factor associated with liver cirrhosis, greater efforts are required in managing ALT levels and reducing the risk of developing liver cirrhosis among those positive for HCV-antibody and those who consume alcohol.

Viral hepatitis and the cascade of care among people living with HIV in the Asia-Pacific.

BACKGROUND: Although the prevalence and mortality of hepatitis is high in the Asia-Pacific region, few studies are available on the diagnosis, treatment, and cure rates for viral hepatitis among people living with HIV in this area. This study aims to report the cascade of care (CoC) for hepatitis B (HBV) and C (HCV) among people living with HIV receiving combined antiretroviral therapy (ART). METHODS: Patients enrolled in the TREAT Asia HIV Observational Database Low Intensity Transfer (TAHOD-LITE) cohort, on ART, and with follow-up data from 2010 to 2019 were included. Patients were determined as positive for HCV or HBV co-infection if they ever tested positive for HCV antibody (anti-HCV) or HBV surface antigen (HBsAg), respectively. RESULTS: In total, 39% (8612/22 340) of the adult HIV cohort had undergone HBsAg testing, with 8% (672/8612) testing positive. HBV CoC demonstrated that 71% (474/672) of those with HBsAg positive results initiated treatment, 67% (318/474) of those on treatment had HBV DNA testing to evaluate treatment progression, and 18% (58/318) of those tested reached viral suppression. Of the cohort, 37% (8231/22 340) had anti-HCV testing, of whom 10% (779/8231) tested positive. The HCV CoC showed that 68% (526/779) of those with positive anti-HCV tests had HCV RNA tests, of whom 51% (267/526) had detectable HCV RNA. Among those with detectable HCV RNA, 65% (174/267) initiated HCV treatment. Of the 40% (69/174) who initiated HCV treatment, 90% (62/69) reached sustained virological response. CONCLUSION: Our findings identified less frequent testing in the healthcare system and limited access to treatment as gaps in the CoC for viral hepatitis. More routine HCV RNA and HBV DNA testing is required for patients with positive screening tests to identify those in need of treatment.

Trends in mortality among ART-treated HIV-infected adults in the Asia-Pacific region between 1999 and 2017: results from the TREAT Asia HIV Observational Database (TAHOD) and Australian HIV Observational Database (AHOD) of IeDEA Asia-Pacific.

INTRODUCTION: AIDS-related deaths in people living with HIV/AIDS have been decreasing in number since the introduction of combination antiretroviral treatment (cART). However, data on recent causes of death in the Asia-Pacific region are limited. Hence, we analysed and compared AIDS-related and non-AIDS-related mortality in high- and low-income settings in the region. METHODS: Patients from the TREAT Asia HIV Observational Database (TAHOD) and Australian HIV Observational Database (AHOD) receiving cART between 1999 and 2017 were included. Causes of death verification were based on review of the standardized Cause of Death (CoDe) form designed by the D:A:D group. Cohorts were grouped as AHOD (all high-income sites), TAHOD-high (high/upper-middle income countries) and TAHOD-low (lower-middle income countries). TAHOD sites were split into high/upper-middle income and lower-middle income country settings based on World Bank classifications. Competing risk regression was used to analyse factors associated with AIDS and non-AIDS-related mortality. RESULTS: Of 10,386 patients, 522 died; 187 from AIDS-related and 335 from non-AIDS-related causes. The overall incidence rate of deaths during follow-up was 0.28 per 100 person-years (/100 PYS) for AIDS and 0.51/100 PYS for non-AIDS. Analysis indicated that the incidence rate of non-AIDS mortality decreased from 0.78/100 PYS to 0.37/100 PYS from year groups 2003 to 2007 to 2013 to 2017 (p < 0.001). Similarly, incidence rates of AIDS-related deaths decreased from 0.51/100 PYS to 0.09/100 PYS from year groups 2003 to 2007 to 2013 to 2017 (p < 0.001). More recent years of follow-up were associated with reduced hazard for non-AIDS mortality (2008 to 2012: aSHR (adjusted sub-hazard ratio) 0.72, 95% confidence interval (CI) 0.54 to 0.96, p = 0.027; 2013 to 2017: aSHR 0.64, 95% CI 0.47 to 0.87, p = 0.004) compared to years 2003 to 2007. The AHOD cohort had almost twice the hazard of non-AIDS mortality compared to TAHOD-low (lower-middle income sites) (aSHR 1.72, 95% CI, 1.20 to 2.46, p = 0.003); there were no differences between cohorts for AIDS-related mortality (p = 0.834). CONCLUSION: AIDS and non-AIDS-related mortality rates have decreased over the past years in the Asia-Pacific region. There is a greater risk for non-AIDS-associated deaths in the AHOD cohort compared to lower-middle income settings in TAHOD.