Enhancing Current Human Immunodeficiency Virus/Hepatitis B and Human Immunodeficiency Virus/Hepatitis C Virus Co-Infection Management
Human immunodeficiency virus (HIV) co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) remains a significant global health challenge, particularly in regions with high prevalence rates and overlapping transmission pathways. Chronic HBV infection affects approximately 7.4% of people living with HIV (PLWH) worldwide, with the highest burden observed in sub-Saharan Africa and Asia. Horizontal and perinatal transmission drives HBV co-infection in these regions, whereas men who have sex with men and injecting drug users are disproportionately affected in developed countries. Similarly, HCV co-infection is prevalent among PLWH, with 6.2% (approximately 2.3 million individuals) showing serological evidence of past or present HCV exposure. These co-infections accelerate liver disease progression, increasing risks of fibrosis, cirrhosis, end-stage liver disease (ESLD), hepatocellular carcinoma, and all-cause mortality. Despite advancements in antiretroviral therapy (ART) and direct-acting antiviral agents (DAAs), morbidity and mortality gaps persist between co-infected and HIV-monoinfected individuals, necessitating optimized management strategies.
Epidemiology and Clinical Implications of Co-Infection
The overlapping transmission routes of HIV, HBV, and HCV underscore the importance of routine co-infection screening. HBV and HCV co-infections are systematically evaluated in PLWH before initiating ART. However, HIV screening is often neglected in HBV- or HCV-monoinfected patients, creating a critical gap in care. For instance, entecavir, a nucleoside analog used for HBV treatment, exhibits weak anti-HIV activity. Administering entecavir without recognizing HIV co-infection risks exposing HIV to suboptimal monotherapy, fostering nucleos(t)ide reverse transcriptase inhibitor (NRTI) resistance. Thus, universal HIV testing in HBV/HCV-diagnosed individuals is essential to prevent treatment mismanagement and enable early HIV diagnosis.
Co-infected patients face accelerated liver injury due to synergistic viral effects and immune dysregulation. HIV impairs CD4+ T-cell function, weakening control of HBV and HCV replication. This results in higher HBV DNA and HCV RNA levels, rapid fibrosis progression, and increased ESLD incidence. Even with effective HBV suppression via tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)-based ART, and HCV cure through DAAs, co-infected individuals experience higher non-liver-related mortality compared to monoinfected populations. Chronic inflammation, residual immune dysfunction, and high-risk behaviors (e.g., smoking, alcohol use) contribute to persistent morbidity gaps.
Advancements in Antiretroviral Therapy for HIV/HBV Co-Infection
ART regimens containing HBV-active NRTIs, such as lamivudine (3TC), emtricitabine (FTC), TDF, and TAF, form the cornerstone of HIV/HBV co-infection management. TAF, a tenofovir prodrug, delivers tenofovir-diphosphate (TFV-DP) more efficiently to hepatocytes and peripheral blood mononuclear cells than TDF. This targeted delivery reduces plasma TFV-DP concentrations, minimizing renal and bone toxicity while maintaining potent HBV suppression. Studies demonstrate that switching from TDF to TAF in stable HIV/HBV co-infected patients preserves virological control and improves safety profiles, suggesting long-term benefits in reducing drug-related complications.
Optimal ART selection requires balancing efficacy, toxicity, and drug interactions. A mathematical model by Nampala et al. compared NRTI backbones (FTC, 3TC, TDF) combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs). The FTC-TDF-efavirenz (EFV) combination emerged as the optimal regimen, maximizing viral suppression while minimizing adverse effects. In contrast, PI-based regimens, though effective, pose higher risks of hepatotoxicity and metabolic complications, particularly in advanced liver disease.
Direct-Acting Antivirals Revolutionize HIV/HCV Co-Infection Outcomes
The advent of DAAs has transformed HCV management, achieving sustained virologic response (SVR) rates exceeding 95% in HIV/HCV co-infected patients. Unlike interferon-based therapies, DAAs demonstrate comparable efficacy in co-infected and HCV-monoinfected populations, even in advanced cirrhosis. Modern guidelines no longer classify HIV/HCV co-infection as a special population, recommending identical treatment algorithms. However, clinicians must navigate drug-drug interactions (DDIs) between DAAs and ART. For example, certain DAAs (e.g., glecaprevir/pibrentasvir) interact with HIV PIs and NNRTIs, necessitating dose adjustments or alternative regimens.
Post-DAA era studies reveal persistent disparities in long-term outcomes. Chalouni et al. reported similar SVR rates and liver-related event risks between co-infected and monoinfected cohorts. However, HIV/HCV co-infected individuals faced higher all-cause mortality, driven by non-liver-related cancers and comorbidities. Chronic immune activation, residual HIV-related inflammation, and lifestyle factors likely underpin these findings, highlighting the need for comprehensive post-cure monitoring.
Hepatotoxicity and ART Regimen Selection
ART-associated hepatotoxicity remains a concern in co-infected patients, particularly those with advanced liver disease. NNRTIs (e.g., nevirapine, efavirenz) and PIs are associated with higher rates of liver enzyme elevation compared to integrase strand transfer inhibitors (INSTIs). Raltegravir (RAL), an INSTI, demonstrates favorable hepatic safety profiles in HCV co-infected patients, with lower hepatotoxicity incidence than NNRTI- or PI-based regimens. However, immune reconstitution inflammatory syndrome (IRIS) can trigger liver enzyme flares during early ART initiation, especially in untreated HBV co-infection. The SAILING study noted elevated transaminase levels in 24% of co-infected patients at week 24, emphasizing the importance of concurrent HBV therapy during ART initiation.
INSTI-based regimens are preferred in decompensated cirrhosis due to their minimal metabolic and hepatic risks. However, clinical data in this population remain limited, warranting cautious monitoring.
Persistent Challenges and Future Directions
Despite therapeutic advancements, ESLD rates in co-infected patients have not declined significantly over 15 years. Delayed HBV/HCV diagnosis, poor treatment access, and residual liver injury despite viral suppression contribute to sustained ESLD risk. Expanding tenofovir-based ART and DAA access, particularly in resource-limited settings, is critical to reducing global disparities.
Future strategies should prioritize:
- Universal Screening and Early Intervention: Implementing bidirectional HIV and HBV/HCV screening programs to prevent monotherapy-related resistance and late-stage presentations.
- Tailored ART Regimens: Optimizing NRTI and INSTI use to maximize efficacy and safety in advanced liver disease.
- Post-Treatment Surveillance: Monitoring for non-liver-related complications, including cardiovascular disease and malignancies, in cured co-infected populations.
- Research Gaps: Investigating INSTI safety in decompensated cirrhosis, long-term DAA outcomes, and interventions targeting residual inflammation.
In conclusion, the integration of HBV-active ART, DAAs, and comprehensive care models can narrow mortality gaps between co-infected and HIV-monoinfected patients. Sustained efforts in screening, treatment access, and multidisciplinary follow-up are essential to mitigating the dual burden of HIV and viral hepatitis.
doi.org/10.1097/CM9.0000000000001149
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