Hepatocellular carcinoma surveillance among people living with hepatitis B in Senegal (SEN-B): insights from a prospective cohort study.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in west Africa, yet data on the incidence of HBV-related hepatocellular carcinoma remain scarce. We aimed to describe the uptake and early outcomes of systematic ultrasound-based hepatocellular carcinoma screening in SEN-B, which is a prospective HBV cohort in Senegal. METHODS: In this prospective cohort study, we included treatment-naive, HBsAg-positive individuals who were referred to the two infectious diseases clinics (the Department of Tropical and Infectious Diseases and Ambulatory Treatment Center) at Fann University Hospital of Dakar, Senegal, between Oct 1, 2019, and Oct 31, 2022. All participants resided within the Dakar region. Participants underwent abdominal ultrasound, transient elastography, and clinical and virological assessments at inclusion and every 6 months. Liver lesions at least 1 cm in diameter on ultrasound were assessed using four-phase CT, MRI, or liver biopsy. Adherence to hepatocellular carcinoma surveillance was measured using the proportion of time covered, calculated by dividing the cumulative months covered by abdominal ultrasound examinations by the overall follow-up time, defined as the number of months from the date of cohort entry until the last recorded visit, hepatocellular carcinoma diagnosis, or death. Optimal adherence was defined as a proportion of time covered of 100%. FINDINGS: Overall, 755 (99·6%) of 758 participants had at least one abdominal ultrasound performed. The median age of the enrolled participants was 31 years (IQR 25-39), 355 (47·0%) of 755 participants were women, and 82 (10·9%) had a family history of hepatocellular carcinoma. 15 (2·0%) of 755 individuals were HBeAg positive, 206 (27·3%) of 755 individuals had HBV DNA of more than 2000 IU/mL, and 27 (3·6%) of 755 had elastography-defined liver cirrhosis. Of ten (1·3%) participants with a focal lesion at least 1 cm at initial assessment, CT or MRI ruled out hepatocellular carcinoma in nine, whereas imaging and subsequent liver biopsy confirmed one patient with hepatocellular carcinoma. Two further patients with hepatocellular carcinoma were diagnosed at study presentation due to the presence of portal thrombosis on ultrasound. Excluding the three participants with hepatocellular carcinoma identified at baseline, 752 participants were eligible for screening every 6 months. Median follow-up time was 12 months (IQR 6-18) and the median number of ultrasounds per patient was 3 (2-4). During 809·5 person-years of follow-up, one incident hepatocellular carcinoma was reported, resulting in an incidence rate of 1·24 cases per 1000 person-years (95% CI 0·18-8·80). Overall, 702 (93·0%) of 755 participants showed optimal hepatocellular carcinoma surveillance, but this proportion decreased to 77·8% (42 of 54 participants) after 24 months. INTERPRETATION: Hepatocellular carcinoma screening is feasible in HBV research cohorts in west Africa, but its longer-term acceptability needs to be evaluated. Long-term hepatocellular carcinoma incidence data are crucial for shaping tailored screening recommendations. FUNDING: Swiss National Science Foundation, the Swiss Cancer Research Foundation, the National Cancer Institute, and Roche Diagnostics. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Long-term hepatitis B and liver outcomes among adults taking tenofovir-containing antiretroviral therapy for HBV/HIV coinfection in Zambia.

BACKGROUND: Long-term outcomes of tenofovir-containing antiretroviral therapy (ART) for HBV/HIV coinfection were evaluated in Zambia. METHODS: A prospective cohort of adults with HIV and hepatitis B surface antigen (HBsAg)-positivity was enrolled at ART (included tenofovir DF + lamivudine) initiation. On therapy, we ascertained HBV viral load (VL) non-suppression, ALT elevation, serologic end-points, progression of liver fibrosis, based on elastography, and hepatocellular carcinoma (HCC) incidence. We also described a subgroup (low HBV VL and no/minimal fibrosis at baseline) that, under current international guidelines, would not have been treated in the absence of their HIV infection. RESULTS: Among 289 participants, at ART start, median age was 34 years, 40·1% were women, median CD4 count was 191 cells/mm3, 44·2% were hepatitis B e antigen-positive, and 28·4% had liver fibrosis/cirrhosis. Over median 5.91 years of ART, 13·6% developed HBV viral non-suppression, which was associated with advanced HIV disease. ALT elevation on ART was linked with HBV VL non-suppression. Regression of fibrosis and cirrhosis were common, progression to cirrhosis was absent, and no cases of HCC were ascertained. HBsAg seroclearance was 9·4% at 2 and 15·4% at 5 years, with higher rates among patients with low baseline HBV replication markers. DISCUSSION: Reassuring long-term liver outcomes were ascertained during tenofovir-based ART for HBV/HIV coinfection in Zambia. Higher than expected HBsAg seroclearance during ART underscores the need to include people with HIV in HBV cure research.

Impact of Integrase Inhibitors on Cardiovascular Disease Events in People With Human Immunodeficiency Virus Starting Antiretroviral Therapy.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting INSTI-based antiretroviral therapy (ART) on CVD events among treatment-naïve people with human immunodeficiency virus using a target trial framework, which reduces the potential for confounding and selection bias. METHODS: We included Swiss HIV Cohort Study participants who were ART-naïve after May 2008, when INSTIs became available in Switzerland. Individuals were categorized according to their first ART regimen (INSTI vs other ART) and were followed from ART start until the first of CVD event (myocardial infarction, stroke, or invasive cardiovascular procedure), loss to follow-up, death, or last cohort visit. We calculated hazard ratios and risk differences using pooled logistic regression models with inverse probability of treatment and censoring weights. RESULTS: Of 5362 participants (median age 38 years, 21% women, 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART. Within 4.9 years (interquartile range, 2.4-7.4), 116 CVD events occurred. Starting INSTI-based ART was not associated with an increased risk for CVD events (adjusted hazard ratio, 0.80; 95% confidence interval [CI], .46-1.39). Adjusted risk differences between individuals who started INSTIs and those who started other ART were -0.17% (95% CI, -.37 to .19) after 1 year, -0.61% (-1.54 to 0.22) after 5 years, and -0.71% (-2.16 to 0.94) after 8 years. CONCLUSIONS: In this target trial emulation, we found no difference in short- or long-term risk for CVD events between treatment-naïve people with human immunodeficiency virus who started INSTI-based ART and those on other ART.

Association of a Polygenic Risk Score With Osteoporosis in People Living With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS: Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS: We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS: In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.

Hepatitis B in Africa Collaborative Network: cohort profile and analysis of baseline data.

Approximately 80 million people live with chronic hepatitis B virus (HBV) infection in the WHO Africa Region. The natural history of HBV infection in this population is poorly characterised, and may differ from patterns observed elsewhere due to differences in prevailing genotypes, environmental exposures, co-infections, and host genetics. Existing research is largely drawn from small, single-centre cohorts, with limited follow-up time. The Hepatitis B in Africa Collaborative Network (HEPSANET) was established in 2022 to harmonise the process of ongoing data collection, analysis, and dissemination from 13 collaborating HBV cohorts in eight African countries. Research priorities for the next 5 years were agreed upon through a modified Delphi survey prior to baseline data analysis being conducted. Baseline data on 4,173 participants with chronic HBV mono-infection were collected, of whom 38.3% were women and the median age was 34 years (interquartile range 28-42). In total, 81.3% of cases were identified through testing of asymptomatic individuals. HBeAg-positivity was seen in 9.6% of participants. Follow-up of HEPSANET participants will generate evidence to improve the diagnosis and management of HBV in this region.

Cryptococcal Meningitis and Clinical Outcomes in Persons With Human Immunodeficiency Virus: A Global View.

BACKGROUND: Cryptococcal meningitis (CM) is a major cause of morbidity and mortality in persons with human immunodeficiency virus (HIV; PWH). Little is known about CM outcomes and availability of diagnostic and treatment modalities globally. METHODS: In this retrospective cohort study, we investigated CM incidence and all-cause mortality in PWH in the International Epidemiology Databases to Evaluate AIDS cohort from 1996 to 2017. We estimated incidence using quasi-Poisson models adjusted for sex, age, calendar year, CD4 cell count (CD4), and antiretroviral therapy (ART) status. Mortality after CM diagnosis was examined using multivariable Cox models. A site survey from 2017 assessed availability of CM diagnostic and treatment modalities. RESULTS: Among 518 852 PWH, there were 3857 cases of CM with an estimated incidence of 1.54 per 1000 person-years. Mortality over a median of 2.6 years of post-CM diagnosis follow-up was 31.6%, with 29% lost to follow-up. In total, 2478 (64%) were diagnosed with CM after ART start with a median of 253 days from ART start to CM diagnosis. Older age (hazard [HR], 1.31 for 50 vs 35 years), lower CD4 (HR, 1.15 for 200 vs 350 cells/mm3), and earlier year of CM diagnosis (HR, 0.51 for 2015 vs 2000) were associated with higher mortality. Of 89 sites, 34% reported access to amphotericin B; 12% had access to flucytosine. CONCLUSIONS: Mortality after CM diagnosis was high. A substantial portion of CM cases occurred after ART start, though incidence and mortality may be higher than reported due to ascertainment bias. Many sites lacked access to recommended CM treatment.

External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection.

BACKGROUND & AIMS: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection. METHODS: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves. RESULTS: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10-17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03-3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61-1.25), and the pooled c-index was 0.77 (range 0.73-0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals. CONCLUSIONS: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. IMPACT AND IMPLICATIONS: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV.

Hepatitis delta infection among persons living with HIV in Europe.

BACKGROUND AND AIMS: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes. METHODS: All PLWH with a positive hepatitis B surface antigen (HBsAg) in the Swiss HIV Cohort Study and EuroSIDA between 1988 and 2019 were tested for anti-HDV antibodies and, if positive, for HDV RNA. Demographic and clinical characteristics at initiation of antiretroviral therapy were compared between HDV-positive and HDV-negative individuals using descriptive statistics. The associations between HDV infection and overall mortality, liver-related mortality as well as hepatocellular carcinoma (HCC) were assessed using cumulative incidence plots and cause-specific multivariable Cox regression. RESULTS: Of 2793 HBsAg-positive participants, 1556 (56%) had stored serum available and were included. The prevalence of HDV coinfection was 15.2% (237/1556, 95% confidence interval [CI]: 13.5%-17.1%) and 66% (132/200) of HDV-positive individuals had active HDV replication. Among persons who inject drugs (PWID), the prevalence of HDV coinfection was 50.5% (182/360, 95% CI: 45.3%-55.7%), with similar estimates across Europe, compared to 4.7% (52/1109, 95% CI: 3.5%-5.9%) among other participants. During a median follow-up of 10.8 years (interquartile range 5.6-17.8), 82 (34.6%) HDV-positive and 265 (20.1%) HDV-negative individuals died. 41.5% (34/82) of deaths were liver-related in HDV-positive individuals compared to 17.7% (47/265) in HDV-negative individuals. HDV infection was associated with overall mortality (adjusted hazard ratio 1.6; 95% CI 1.2-2.1), liver-related death (2.9, 1.6-5.0) and HCC (6.3, 2.5-16.0). CONCLUSION: We found a very high prevalence of hepatitis delta among PWID across Europe. Among PLWH who do not inject drugs, the prevalence was similar to that reported from populations without HIV. HDV coinfection was associated with liver-related mortality and HCC incidence.

Hepatitis B Virus (HBV) Replication During Tenofovir Therapy Is Frequent in Human Immunodeficiency Virus/HBV Coinfection.

In the Swiss HIV Cohort Study, 61 of 222 (27%) HIV-suppressed persons with chronic hepatitis B virus (HBV) infection had HBV replication after 2 years on tenofovir, of whom 77% were suppressed thereafter. Self-reported adherence to therapy and HBV viral load at tenofovir initiation were predictors of persistent replication.

Medication Adherence Evaluated Through Electronic Monitors During the 2020 COVID-19 Pandemic Lockdown in Switzerland: A Longitudinal Analysis.

Background: During the 2020 COVID-19 lockdown, patients included in the Interprofessional Medication Adherence Program (IMAP) in Switzerland continued to use electronic monitors (EMs) that registered daily drug-dose intake. We aimed to understand to what extent patients' medication implementation (ie, the extent to which the patient took the prescribed medicine), measured with EMs, was impacted by the lockdown. Methods: Patients participating in the IMAP were diagnosed with diabetic kidney disease (DKD), solid cancer, human immunodeficiency virus (HIV) and miscellaneous long-term diseases (MLTD). Patient implementation was defined through a proxy: if all patient EMs were opened at least once daily, implementation was considered active (=1), and no implementation was considered (=0) otherwise. Implementation before (from December 2019 to March 2020), during (March to June 2020) and after (June to September 2020) the lockdown was compared. Subanalyses were performed according to the patients' diseases. Subanalyses were performed in patients who used at least one EM in 2018-2019 during the same periods (defined as winter, spring and summer). The logistic regression models used to estimate medication implementation according to the period were fitted using generalized estimating equations. Results: In 2020, patient implementation (n = 118) did not differ significantly before versus during (OR = 0.98, 95% CI: 0.84-1.15, p = 0.789) and before versus after (OR = 0.91, 95% CI: 0.79-1.06, p = 0.217) the lockdown. These findings remained stable when separately analyzing the implementation of patients with HIV (n = 61), DKD (n = 25) or MLTD (n = 22). Too few patients with cancer were included (n = 10) to interpret the results. In 2019, the implementation of 61/118 (51.7%) patients was significantly lower during summertime versus wintertime (OR = 0.73, 95% CI: 0.60-0.89, p = 0.002). Conclusion: Medication implementation remained steady before, during and after the lockdown in 2020. The IMAP before, during and after the lockdown may have supported the adherence of most patients, by ensuring continuity of care during periods of routine disturbances.

Prevalence and Predictors of Liver Fibrosis in People Living with Hepatitis B in Senegal.

Hepatitis B virus (HBV) infection is the first cause of liver cirrhosis and cancer in West Africa. Although the exposure to additional environmental and infectious risk factors may lead to the faster progression of liver disease, few large-scale studies have evaluated the determinants of HBV-related liver fibrosis in the region. We used transient elastography to evaluate the prevalence of liver fibrosis and assessed the association between HBV markers and significant liver fibrosis in a cohort of people living with HBV in Dakar, Senegal. The prevalence of significant liver fibrosis was 12.5% (95% confidence interval [CI] 9.6%−15.9%) among 471 people with HBV mono-infection (pwHBV) and 6.4% (95% CI 2.6%−12.7%) in 110 people with HIV/HBV co-infection (pwHIV/HBV) on tenofovir-containing antiretroviral therapy (p = 0.07). An HBV viral load > 2000 IU/mL was found in 133 (28.3%) pwHBV and 5 (4.7%) pwHIV/HBV, and was associated with significant liver fibrosis (adjusted odds ratio (aOR) 1.95, 95% CI 1.04−3.66). Male participants (aOR 4.32, 95% CI 2.01−8.96) and those with elevated ALT (aOR 4.32, 95% CI 2.01−8.96) were especially at risk of having significant liver fibrosis. Our study shows that people with an HBV viral load above 2000 IU/mL have a two-fold increase in the risk of liver fibrosis and may have to be considered for antiviral therapy, independent of other disease parameters.

Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal.

Chronic hepatitis B virus (HBV) infection affects >10% of the general population and is the leading cause of liver cirrhosis and cancer in West Africa. Despite current recommendations, HBV is often not tested for in clinical routine in the region. We included all people living with HIV (PLWH) in care between March and July 2019 at Fann University Hospital in Dakar (Senegal) and proposed hepatitis B surface antigen (HBsAg) test to those never tested. All HBsAg-positive underwent HIV and HBV viral load (VL) and liver stiffness measurement. We evaluated, using logistic regression, potential associations between patient characteristics and (a) HBV testing uptake; (b) HIV/HBV co-infection among individual HBsAg tested. We determined the proportion of co-infected who had HBV DNA >20 IU/ml on ART and sequenced HBV polymerase in those with HBV replication.of 1076 PLWH in care, 689 (64.0%) had never had an HBsAg test prior to our HBV testing intervention. Women and individuals >40 years old were less likely to have been previously tested. After HBV testing intervention,107/884 (12.1%) PLWH were HBsAg-positive. Seven of 58 (12.1%) individuals newly diagnosed with HIV/HBV co-infection had a detectable HBV VL, of whom five were HIV-suppressed. Two patients on ART including 3TC and AZT as backbone showed the presence of the triple resistance mutation 180M/204I/80V. In this Senegalese urban HIV clinic, the majority of patients on ART had never been tested for HBV infection. One in ten co-infected individuals had a detectable HBV VL despite HIV suppression, and 8% were not receiving a TDF-containing regimen.

The association between hepatitis B virus infection and nonliver malignancies in persons living with HIV: results from the EuroSIDA study.

OBJECTIVES: The aim of this study was to assess the impact of hepatitis B virus (HBV) infection on non-liver malignancies in people living with HIV (PLWH). METHODS: All persons aged ≥ 18 years with known hepatitis B virus (HBV) surface antigen (HBsAg) status after the latest of 1 January 2001 and enrolment in the EuroSIDA cohort (baseline) were included in the study; persons were categorized as HBV positive or negative using the latest HBsAg test and followed to their first diagnosis of nonliver malignancy or their last visit. RESULTS: Of 17 485 PLWH included in the study, 1269 (7.2%) were HBV positive at baseline. During 151 766 person-years of follow-up (PYFU), there were 1298 nonliver malignancies, 1199 in those currently HBV negative [incidence rate (IR) 8.42/1000 PYFU; 95% confidence interval (CI) 7.94-8.90/1000 PYFU] and 99 in those HBV positive (IR 10.54/1000 PYFU; 95% CI 8.47-12.62/1000 PYFU). After adjustment for baseline confounders, there was a significantly increased incidence of nonliver malignancies in HBV-positive versus HBV-negative individuals [adjusted incidence rate ratio (aIRR) 1.23; 95% CI 1.00-1.51]. Compared to HBV-negative individuals, HBsAg-positive/HBV-DNA-positive individuals had significantly increased incidences of nonliver malignancies (aIRR 1.37; 95% CI 1.00-1.89) and NHL (aIRR 2.57; 95% CI 1.16-5.68). There was no significant association between HBV and lung or anal cancer. CONCLUSIONS: We found increased rates of nonliver malignancies in HBsAg-positive participants, the increases being most pronounced in those who were HBV DNA positive and for NHL. If confirmed, these results may have implications for increased cancer screening in HIV-positive subjects with chronic HBV infection.

Alcohol reduction outcomes following brief counseling among adults with HIV in Zambia: A sequential mixed methods study.

Data from sub-Saharan Africa on the impact of alcohol on the HIV epidemic in sub-Saharan Africa is limited. In this region, it is not well understood how people with HIV (PLWHA) respond to alcohol reduction counseling while they are linked to HIV clinical care. We conducted an explanatory sequential mixed-methods study to understand patterns of alcohol use among adults (18+ years) within a prospective HIV cohort at two urban public-sector clinics in Zambia. At antiretroviral therapy (ART) start and one year later, we measured alcohol use with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and those reporting any alcohol use were provided brief counseling. We conducted focus groups at 1 year with participants who had any alcohol use and 20 in-depth interviews among the subgroup with unhealthy use pre-ART and who either reduced or did not reduce their use by 1 year to moderate levels or abstinence. Focus group Discussions (FGDs) (n = 2) were also held with HIV clinic staff. Qualitative data were analyzed using thematic analysis. The data obtained from 693 participants was analyzed (median age 34 years, 45% men), it revealed that unhealthy alcohol use (AUDIT-C >3 for men; >2 for women) was reported among 280 (40.4%) at baseline and 205 (29.6%) at 1 year on ART. Reduction from unhealthy to moderate use or abstinence was more common with older age, female, non-smoking, and at Clinic B (all P<0.05). Qualitative data revealed ineffective alcohol support at clinics, social pressures in the community to consume alcohol, and unaddressed drivers of alcohol use including poverty, poor health status, depression, and HIV stigma. Healthcare workers reported a lack of training in alcohol screening and treatment, which led to mixed messages provided to patients ('reduce to safe levels' versus 'abstain'). In summary, interventions to reduce unhealthy alcohol use are needed within HIV clinics in Zambia as a substantial population have persistent unhealthy use despite current HIV clinical care. A better understanding is needed regarding the implementation challenges related to screening for unhealthy alcohol use integrated with HIV services.

Elimination of Viral Hepatitis in Low and Middle-Income Countries: Epidemiological Research Gaps.

PURPOSE OF REVIEW: The purpose of our review was to summarize current recommendations on testing strategies, antiviral therapy eligibility and monitoring, and prevention of mother-to-child transmission of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and to highlight major research gaps in low and middle-income countries (LMIC), with a particular focus on sub-Saharan Africa (SSA). RECENT FINDINGS: While data on the prevalence of HBV and HCV infections in LMIC are increasing, current knowledge on liver-related complications as well as on treatment outcomes remains limited. Furthermore, very little information is available on the feasibility and cost-effectiveness of large-scale testing and management strategies in high-prevalence settings. The availability of policy-relevant data is particularly scarce in SSA, which accounts for a significant part of the global burden of chronic viral hepatitis. SUMMARY: Current recommendations on the management and monitoring of chronic viral hepatitis rely mainly on data from high-income settings. The global elimination of viral hepatitis will only be achieved if prevention, testing, and treatment strategies tailored to specific LMIC are implemented. In order to inform scalable and cost-effective interventions, dedicated research initiatives have to be undertaken. Future studies will have to include the evaluation of innovative testing strategies, the validation of simplified methods to diagnose liver cirrhosis and hepatocellular carcinoma, and the monitoring of long-term treatment outcomes and toxicity. In addition, national plans to achieve the elimination of HBV mother-to-child transmission are urgently needed, including effective ways to test pregnant women, treat those who are eligible, and ensure birth dose vaccination is given to all newborns.

Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment-Experienced People Living With Human Immunodeficiency Virus.

BACKGROUND: Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. METHODS: Antiretroviral treatment-experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012-1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. RESULTS: Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7-24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8-38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5-8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9-6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72-1.19; P = .53). CONCLUSIONS: This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.

Prevalence of liver cirrhosis in individuals with hepatitis B virus infection in sub-Saharan Africa: Systematic review and meta-analysis.

BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection accounts for 30%-50% of cirrhosis related deaths in sub-Saharan Africa (SSA). Since HBV-related cirrhosis is an indication for immediate antiviral therapy and cancer surveillance, we aimed to estimate the prevalence of cirrhosis among treatment-naïve patients with chronic HBV infection in SSA. METHODS: We performed a systematic review of published articles which evaluated liver fibrosis stage among treatment-naïve HBV-infected individuals who presented to care in SSA. Our primary outcome was the prevalence of cirrhosis in HBsAg-positive persons, which was estimated using random-effects meta-analysis. Risk factors for cirrhosis were explored using subgroup-analyses and multivariable meta-regression. RESULTS: Of 2129 articles identified, 17 met our eligibility criteria. The studies described 22 cohorts from 13 countries, including 13 cohorts (3204 patients) with chronic HBV mono-infection and nine cohorts (688 patients) with HIV/HBV-coinfection. Liver fibrosis was assessed using transient elastography (10 cohorts), APRI score (11 cohorts), and Fibrotest (one cohort). The pooled prevalence of cirrhosis was 4.1% (95% confidence interval [CI] 2.6-6.4) among studies from primary care facilities or general population, compared to 12.7% (95% CI 8.6-18.3) in studies performed in referral or tertiary care facilities (adjusted odds ratio 0.29, 95% CI 0.15-0.56). We found no association between cirrhosis and age, gender, fibrosis test used or HIV-coinfection. CONCLUSIONS: Depending on the setting, between 4% and 13% of HBV-infected individuals in SSA have cirrhosis and need immediate antiviral therapy. These estimates should be considered when planning HBV treatment strategies and resource allocation.

Hepatosplenic schistosomiasis in Zambian adults is characterized by increased liver stiffness: A nested case-control study.

Cirrhosis commonly complicates portal hypertension worldwide but in Zambia hepatosplenic schistosomiasis (HSS) dominates as the cause of portal hypertension. We need easier and non-invasive ways to assess HSS. Transient elastography (TE), a measure of liver stiffness can diagnose liver cirrhosis. TE remains unexplored in HSS patients, who generally have normal liver parenchyma. We aimed to explore liver stiffness in HSS. This nested case control study was conducted at the University Teaching Hospital, Lusaka, Zambia between January 2015 and January 2016. We enrolled 48 adults with HSS and 22 healthy controls. We assessed liver stiffness using TE while plasma hyaluronan was used to assess liver fibrosis. Plasma tumor necrosis factor receptor 1 (TNFR1) and soluble cluster of differentiation 14 (sCD14) were used to assess inflammation. The median (interquartile range) liver stiffness was higher in patients, 9.5 kPa (7.8, 12.8) than in controls, 4.7 kPa (4.0, 5.4), P < 0.0001. We noted linear correlations of hyaluronan and TNFR1 with the liver stiffness, P = 0.0307 and P = 0.0003 respectively. HSS patients seem to have higher liver stiffness than healthy controls. TE may be useful in identifying fibrosis in HSS. The positive correlations of inflammatory markers with TE suggest that HSS has both periportal and parenchymal pathophysiology.

Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting.

BACKGROUND: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING: International multicohort collaboration. METHODS: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSIONS: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

Clinical Outcomes in Persons Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus: Impact of Hepatitis C Virus Treatment.

BACKGROUND: A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear. METHODS: People living with HIV from EuroSIDA with a known HCV status after January 2001 were classified into strata based on time-updated HCV RNA measurements and HCV treatment, as either HCV antibody-negative; spontaneously resolved HCV; chronic, untreated HCV; cured HCV (HCV RNA-negative); or HCV treatment failures (HCV RNA-positive). Poisson regression was used to compare incidence rates between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non-acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD). RESULTS: There were 16 618 persons included (median follow-up 8.3 years, interquartile range 3.1-13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0-6.9) for CVD, 6.5 (95% CI 6.1-6.9) for NADM, and 3.1 (95% CI 2.8-3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14-0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36-1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02-2.13) or treatment failure (aIRR 1.80, 95% CI 1.22-2.66) had significantly raised rates of ESLD, compared to those who were cured. CONCLUSIONS: Incidences of NADM or CVD were independent of HCV group, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD.