This Review presents current epidemiological trends of the most common liver diseases in Asia–Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia–Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care. Liver diseases exert a substantial disease burden across the Asia–Pacific region. In this Review, the authors explore the epidemiological trends in the most common liver diseases in the region, including HBV infection, HCV infection and nonalcoholic fatty liver disease, and discuss implications for preventive measures.

The changing epidemiology of liver diseases in the Asia-Pacific region.

HIV infection has a significant impact on the natural history of chronic hepatitis B virus (HBV) infection, with increased levels of HBV DNA, accelerated progression of liver disease and increased liver-associated mortality compared with HBV monoinfection. Widespread uptake and early initiation of HBV-active antiretroviral therapy has substantially improved the natural history of HIV-HBV coinfection but the prevalence of liver disease remains elevated in this population. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease and seroconversion in HIV-HBV coinfection in the era of HBV-active antiretroviral therapy and the effects of HIV directly on liver disease. We also review novel therapeutics for the management of HBV with a particular emphasis on clinical strategies being developed for an HBV cure and an HIV cure and their impact on HIV-HBV coinfected individuals.

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HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment.

The morbidity and mortality of HIV type-1 (HIV-1)-related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV-1 replication and gradual recovery of CD4+ T-cell counts. However, ∼10-40% of HIV-1-infected individuals fail to achieve normalization of CD4+ T-cell counts despite persistent virological suppression. These patients are referred to as "inadequate immunological responders," "immunodiscordant responders," or "immunological non-responders (INRs)" who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non-AIDS events and present higher rates of mortality than HIV-1-infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV-1-infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1002/JLB.4MR1019-189R

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders.

Background 
We assessed the effects of hepatitis B (HBV) or hepatitis C (HCV) co-infection on outcomes of antiretroviral therapy (ART) in HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD), a multi-center cohort of HIV-infected patients in the Asia-Pacific region.


Methods 
Patients testing HBs antigen (Ag) or HCV antibody (Ab) positive within enrollment into TAHOD were considered HBV or HCV co-infected. Factors associated with HBV and/or HCV co-infection were assessed by logistic regression models. Factors associated with post-ART HIV immunological response (CD4 change after six months) and virological response (HIV RNA <400 copies/ml after 12 months) were also determined. Survival was assessed by the Kaplan-Meier method and log rank test.


Results 
A total of 7,455 subjects were recruited by December 2012. Of patients tested, 591/5656 (10.4%) were HBsAg positive, 794/5215 (15.2%) were HCVAb positive, and 88/4966 (1.8%) were positive for both markers. In multivariate analysis, HCV co-infection, age, route of HIV infection, baseline CD4 count, baseline HIV RNA, and HIV-1 subtype were associated with immunological recovery. Age, route of HIV infection, baseline CD4 count, baseline HIV RNA, ART regimen, prior ART and HIV-1 subtype, but not HBV or HCV co-infection, affected HIV RNA suppression. Risk factors affecting mortality included HCV co-infection, age, CDC stage, baseline CD4 count, baseline HIV RNA and prior mono/dual ART. Shortest survival was seen in subjects who were both HBV- and HCV-positive.


Conclusion 
In this Asian cohort of HIV-infected patients, HCV co-infection, but not HBV co-infection, was associated with lower CD4 cell recovery after ART and increased mortality.

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Hepatitis B and C Co-Infection in HIV Patients from the TREAT Asia HIV Observational Database: Analysis of Risk Factors and Survival

Background. Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection has emerged as an important cause of morbidity and mortality. We determined the response to Truvada-based first-line combination antiretroviral therapy (cART) in HIV/HBV-coinfected verus HIV-monoinfected patients in Botswana.

Methods. Hepatitis B virus surface antigen (HBsAg), HBV e antigen (HBeAg), and HBV deoxyribonucleic acid (DNA) load were determined from baseline and follow-up visits in a longitudinal cART cohort of Truvada-based regimen. We assessed predictors of HBV serostatus and viral suppression (undetectable HBV DNA) using logistic regression techniques.

Results. Of 300 participants, 28 were HBsAg positive, giving an HIV/HBV prevalence of 9.3% (95% confidence interval [CI], 6.3–13.2), and 5 of these, 17.9% (95% CI, 6.1–36.9), were HBeAg positive. There was a reduced CD4+ T-cell gain in HIV/HBV-coinfected compared with HIV-monoinfected patients. Hepatitis B virus surface antigen and HBeAg loss was 38% and 60%, respectively, at 24 months post-cART initiation. The HBV DNA suppression rates increased with time on cART from 54% to 75% in 6 and 24 months, respectively.

Conclusions. Human immunodeficiency virus/HBV coinfection negatively affected immunologic recovery compared with HIV-1C monoinfection. Hepatitis B virus screening before cART initiation could help improve HBV/HIV treatment outcomes and help determine treatment options when there is a need to switch regimens.

Slow CD4+ T-Cell Recovery in Human Immunodeficiency Virus/Hepatitis B Virus-Coinfected Patients Initiating Truvada-Based Combination Antiretroviral Therapy in Botswana.

Background 
Despite the high burden, there is a dearth of (long-term) outcome data of hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infected patients receiving antiretroviral treatment (ART) in a clinical setting in resource-constrained settings, particularly from Asia.
Methods 
We conducted a retrospective cohort study including all adults initiating standard ART (non-tenofovir-based) between 03/2003 and 09/2012. HBV infection was diagnosed by HBV surface antigen detection. HCV diagnosis relied on antibody detection. The independent effect of HBV and HCV on long-term (≥5 years) ART response in terms of mortality (using Cox regression), severe livertoxicity (using logistic regression) and CD4 count increase (using mixed-effects modelling) was determined.
Results 
A total of 3089 adults were included (median age: 35 years (interquartile range 30–41); 46% male), of whom 341 (11.0%) were co-infected with HBV and 163 (5.3%) with HCV. Over a median ART follow-up time of 4.3 years, 240 individuals died. Mortality was 1.6 higher for HBV co-infection in adjusted analysis (P = 0.010). After the first year of ART, the independent mortality risk was 3-fold increased in HCV co-infection (P = 0.002). A total of 180 (5.8%) individuals discontinued efavirenz or nevirapine due to severe livertoxicity, with an independently increased risk for HBV (hazard ratio (HR) 2.3; P<0.001) and HCV (HR 2.8; P<0.001). CD4 recovery was lower in both HBV and HCV co-infection but only statistically significant for HBV (P<0.001).
Discussion 
HBV and HCV co-infection was associated with worse ART outcomes. The effect of early ART initiation and providing effective treatment for hepatitis co-infection should be explored.

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Hepatitis B and C co-infection among HIV-infected adults while on antiretroviral treatment: long-term survival, CD4 cell count recovery and antiretroviral toxicity in Cambodia.

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Lay Phirum

Papers

Hepatitis B and C co-infection among HIV-infected adults while on antiretroviral treatment: long-term survival, CD4 cell count recovery and antiretroviral toxicity in Cambodia.

A clinical prediction score for targeted creatinine testing before initiating tenofovir-based antiretroviral treatment in Cambodia.