Integrating hepatitis C care into human immunodeficiency virus clinics in the direct-acting antiviral era: From biological disadvantage to structural opportunity

Abstract

Direct-acting antivirals have rendered hepatitis C virus (HCV) infection a curable condition. As cure rates have become consistently high, the primary barrier to HCV elimination has shifted from pharmacologic efficacy to healthcare delivery, including access, timing, and continuity of care. Accumulating cohort evidence shows that, following sustained virologic response, liver-related outcomes in individuals living with human immunodeficiency virus (HIV)/HCV coinfection largely converge with those observed in HCV monoinfection. Notably, Park et al recently published a study in the World Journal of Gastroenterology demonstrated that, under optimized conditions, survival in HIV/HCV coinfected individuals may converge with that of those with HCV monoinfection, reinforcing the importance of timely, coordinated care delivery. Persistent variability in all-cause and non-liver-related outcomes across studies, however, highlights the need to shift attention from antiviral performance to structural models of care. HIV clinics, purpose-built for chronic disease management and sustained patient engagement, are uniquely positioned to incorporate HCV services. Embedding HCV screening, treatment, and post-sustained virologic response surveillance into routine HIV care allows antiviral therapy to function not only as curative treatment, but also as a platform for sustained risk reduction and prevention. Within this integrated framework, clinical decision-making is primarily driven by liver disease severity rather than infection status alone. In the era of highly effective direct-acting antivirals, integrated HIV-HCV care emerges as a practical necessity, not an optional enhancement.

Key Words: Integrated care; Liver disease severity; Direct-acting antivirals; Hepatitis C virus; Human immunodeficiency virus

Core Tip: In the interferon-based treatment era, human immunodeficiency virus (HIV) coinfection was associated with poorer hepatitis C virus (HCV) outcomes. In contrast, recent evidence from Park et al in the direct-acting antiviral era suggests that achieving sustained virologic response may substantially narrow survival differences between individuals living with HIV/HCV and those with HCV monoinfection. Residual adverse outcomes increasingly reflect attrition across the care cascade and post-cure metabolic and non-liver risks rather than ongoing viral effects alone. Accordingly, integrated care models within HIV clinics, coupled with structured post- sustained virologic response surveillance, are essential to translate virologic cure into durable long-term benefit.

This editorial refers to “Chrono-optimal treatments for human immunodeficiency virus/hepatitis C virus co-infection yield comparable survival outcomes with hepatitis C virus mono-infection” by Park et al, 2026; https://dx.doi.org/10.3748/wjg.v32.i3.114176.

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INTRODUCTION

For many years, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection represented a clear biological disadvantage. HIV-related immune dysfunction promotes HCV persistence and accelerates hepatic fibrosis, while chronic immune activation intensifies liver injury and increases the risk of cirrhosis and hepatocellular carcinoma (HCC)[1,2]. In the interferon-based treatment era, these interactions translated into lower virologic response rates, limited treatment eligibility, and higher liver-related mortality among coinfected individuals[3]. Consequently, infection status strongly influenced prognosis and clinical decision-making, with HIV coinfection regarded as a dominant adverse factor.

The advent of direct-acting antivirals (DAAs) has fundamentally altered this landscape. Sustained virologic response (SVR) rates now exceed 95% across HCV genotypes and patient populations, including individuals living with HIV/HCV coinfection[4-6]. As antiviral efficacy has become highly predictable, the central clinical question has shifted from whether cure is achievable to how cure can be delivered equitably and effectively. The primary challenges now lie in healthcare delivery, including timely access to treatment, continuity of care, and management of long-term risks.

Within this context, Park et al[6] recently published a study in the World Journal of Gastroenterology reported that under optimized DAA-based treatment conditions, long-term survival in individuals living with HIV/HCV coinfection converges with that observed in HCV monoinfection. These findings signal the need to reconsider how HCV services are organized within HIV care settings. This perspective draws on a selective narrative review of recent high-quality cohort studies and relevant clinical guidelines to highlight emerging trends in the management of HIV/HCV coinfection.

WHAT DOES “CLINICAL EQUIVALENCE” ACTUALLY MEAN?

Infection status no longer determines survival prognosis. Among individuals who achieve SVR, including those living with HIV/HCV coinfection and those with HCV monoinfection, essential questions remain regarding the residual risks that persist beneath apparently convergent survival curves. These remaining differences are explored below.

The observation that long-term outcomes align between these groups marks a substantive shift in hepatology. In the study by Park et al[6], high cure rates were accompanied by comparable overall survival and HCC incidence after adjustment for baseline characteristics, indicating that HIV coinfection no longer confers an inherent disadvantage once HCV is eradicated under optimal care conditions. These findings are consistent with large European cohort studies demonstrating that, among individuals achieving SVR, HIV status does not independently predict liver-related mortality, particularly in those with advanced fibrosis[7]. However, this convergence warrants cautious interpretation given potential residual confounding and cohort selection bias. The observed equivalence pertains primarily to liver-related endpoints following SVR rather than to overall health outcomes.

Several methodological features of the Park et al[6] study further contextualize these findings. The retrospective design and recruitment from tertiary centers limit generalizability across diverse healthcare settings and populations. The HCV monoinfection group was drawn from only two centers, introducing potential selection bias that may not be fully addressed by inverse probability of treatment weighting. In addition, the co-infected cohort was small (n = 112), with very few events among SVR achievers, resulting in limited statistical power and wide confidence intervals. The inclusion of both interferon and DAA eras introduces temporal heterogeneity, and fibrosis assessment partly relied on the fibrosis-4 index, an indirect surrogate influenced by age-related and HIV-associated factors[8,9]. Taken together, these factors suggest that the observed clinical equivalence is context-dependent and should not be interpreted as evidence of complete risk normalization.

Although these data support a framework of clinical equivalence, comparable liver-specific outcomes do not imply identical long-term health trajectories. Observational studies from the DAA era consistently report higher all-cause mortality among individuals living with HIV compared with those with HCV monoinfection, even after successful HCV cure[10,11]. This excess mortality is mainly driven by non-liver-related causes, including cardiovascular disease, malignancies, and metabolic disorders, rather than by progressive liver disease or HCC[10].

These results underscore a critical distinction between viral eradication and full risk normalization. Achieving SVR removes the biological burden of chronic HCV infection and narrows disparities in liver-related outcomes under conditions of comprehensive care. However, residual risks persist, shaped by chronic immune activation, metabolic consequences of antiretroviral therapy, and broader social determinants of health. Clinical equivalence, therefore, reflects a redistribution of long-term risk rather than its elimination. Recognizing this distinction is essential to avoid treating SVR as the endpoint of HIV/HCV management. Moreover, these outcomes depend on timely and comprehensive care and may not fully generalize to resource-limited settings.

LIVER DISEASE SEVERITY RATHER THAN INFECTION LABELS AS THE AXIS OF DECISION-MAKING

The DAAs have catalyzed a paradigm shift in viral hepatitis care by reshaping the foundations of clinical decision-making. A central conceptual advance is the decoupling of management strategies from infection labels. In the interferon era, HIV coinfection directly determined treatment eligibility, anticipated response, and safety considerations, often relegating liver disease severity to a secondary role. Under this model, fibrosis staging had limited practical relevance - an imbalance that the DAA era has decisively corrected. With virologic disadvantage largely eliminated, prognosis now aligns more closely with the extent of pre-existing liver disease than with HIV status itself. Early evidence established the survival benefit of SVR, particularly in patients with advanced fibrosis[12], whereas subsequent cohort studies have consistently identified baseline liver disease severity as the principal determinant of post-cure outcomes[13]. Advanced fibrosis, cirrhosis, and portal hypertension have emerged as the principal drivers of liver-related morbidity and mortality after SVR[6,7]. Anchoring clinical decisions to liver disease severity, therefore, represents a pragmatic adaptation to contemporary antiviral therapy.

This shift rests on the availability of standardized, noninvasive tools for assessing hepatic fibrosis, including the fibrosis-4 index, the aspartate aminotransferase-to-platelet ratio index, and transient elastography[14]. These approaches support consistent risk stratification using validated thresholds, enabling clinicians to identify individuals who require specialist referral. Consequently, liver disease assessment can be integrated into HIV clinics, while hepatology expertise is focused on patients with advanced or complex disease.

This redistribution of responsibilities reflects a functional redefinition of specialist care rather than its dilution. Routine HCV treatment for individuals with mild to moderate fibrosis can be safely delivered within HIV services, whereas hepatologists remain essential for managing cirrhosis, portal hypertension, and HCC surveillance[7]. Decentralizing care in this manner aligns clinical oversight with actual risk, directing specialist resources to those most likely to benefit. By shifting the emphasis from infection status to liver disease severity, DAA implementation supports a scalable, rational care model capable of addressing both individual patient needs and broader public health goals (Figure 1). Within this framework, care is reoriented from virus-centered treatment to longitudinal risk management, such that this model not only optimizes specialist resource allocation but also extends the scope of care beyond viral eradication toward sustained risk management at the population level.

Figure 1 Conceptual shift in decision-making for human immunodeficiency virus/hepatitis C virus coinfection in the direct-acting antiviral era. Magnetic resonance elastography image adapted from Wu et al[34], see Supplementary material. HIV: Human immunodeficiency virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; CVD: Cardiovascular disease; DAA: Direct-acting antiviral; SVR: Sustained virologic response; AST: Aspartate aminotransferase; APRI: Aspartate aminotransferase to platelet ratio index.

In addition to fibrosis severity, antiretroviral regimen composition and renal function may influence treatment selection in specific clinical contexts. Real-world data indicate that protease inhibitor- or cobicistat-based regimens, as well as impaired renal function, can limit DAA prescribing due to drug-drug interactions (DDI) and safety considerations[15]. In such cases, optimizing antiretroviral therapy and selection of renal-safe pangenotypic DAAs can facilitate treatment delivery.However, these factors primarily function as practical constraints on implementation rather than as core determinants of long-term prognosis. In contrast, liver disease severity remains the principal determinant guiding risk stratification and clinical decision-making in the DAA era.

WHO SHOULD DELIVER HCV CARE, AND WHY HIV CLINICS ARE UNIQUELY POSITIONED

Redefining the decision axis is only the first step; translating this risk-based framework into effective care delivery requires identifying the clinical setting best suited to implement it. We outline the strategic rationale for integrating HCV care into HIV clinics and describe how this patient-centered model can address gaps in care to expand treatment access and improve population-level outcomes. As therapeutic objectives have evolved, identifying the most appropriate setting for delivering HCV services to coinfected populations has become increasingly important. Concerns regarding non-specialist management typically center on treatment safety, diagnostic accuracy, and the adequacy of long-term follow-up. However, these reservations warrant re-evaluation in light of contemporary therapeutic approaches rather than assumptions rooted in earlier treatment eras.

HIV clinics possess distinct structural advantages that position them to deliver HCV care effectively. Longstanding experience in managing chronic viral infections, complex comorbidities, and polypharmacy equips HIV clinicians to prescribe and monitor standardized DAA regimens safely. In comparison, traditional referral-based pathways frequently fragment care at points where attrition along the HCV cascade is most pronounced[16,17]. Delays in referral, repeated diagnostic testing, and discontinuity in follow-up collectively blunt the real-world impact of highly effective antiviral therapies.

Integrated models that embed HCV screening and treatment directly within HIV services consistently achieve higher treatment uptake without compromising SVR rates[18-20]. Population-level data from Spain illustrate this effect, showing a reduction in active HCV infection among people living with HIV to near-elimination levels following widespread decentralization of care[21]. This “one-stop” approach reduces barriers associated with cross-specialty referrals and leverages established therapeutic relationships between patients and HIV providers. Such findings challenge the continued restriction of DAA prescribing to hepatology specialists, given pangenotypic regimens and simplified monitoring protocols[21]. This transition does not diminish the role of specialist expertise. Instead, it reflects a realignment of responsibilities, with hepatologists focusing on advanced disease and complications, while HIV clinicians deliver routine antiviral therapy at scale. This functional specialization is essential to translating the high efficacy observed in controlled settings into durable benefits across broader populations (Table 1).

Table 1 Evolution of clinical focus and care responsibilities in human immunodeficiency virus/hepatitis C virus coinfection across therapeutic eras.

Therapeutic era	Dominant clinical challenge	Primary decision axis	Main care responsibility
Interferon-based era	Limited antiviral efficacy and treatment-related toxicity	HIV coinfection status	Hepatology-centered care
Early DAA era	Access to and initiation of antiviral therapy	Treatment eligibility and availability	Specialist-led care
Contemporary DAA era	Risk stratification at treatment initiation	Liver disease severity	HIV clinic-based care
Post-SVR era	Long-term morbidity and competing health risks	Residual liver disease and metabolic comorbidities	Integrated HIV-centered care

HIV: Human immunodeficiency virus; DAA: Direct-acting antiviral; SVR: Sustained virologic response.

Quantifying these barriers helps clarify the magnitude of the integration imperative. National cascade data from England, along with recent international cohort analyses, indicate that substantial gaps in treatment uptake persist in real-world settings despite the availability of curative regimens. Multivariate analyses from these cohorts identified several modifiable factors associated with reduced prescribing, including a history of substance use, use of protease inhibitor - or cobicistat-based antiretroviral therapy, and impaired renal function[16,17]. Notably, a substantial proportion of untreated individuals maintained well-controlled HIV viremia, suggesting that the primary barrier is not patient-level adherence capacity but rather fragmentation in care delivery and provider-level constraints.

These findings reinforce the concept of a “fragmentation tax” imposed by siloed specialty systems and highlight the need for integrated care pathways that minimize referral delays, streamline treatment initiation, and coordinate the management of DDI within a single clinical setting. In this context, HIV clinics are uniquely positioned to operationalize simplified, standardized treatment models that translate therapeutic efficacy into real-world effectiveness at scale.

BEYOND SVR: WHY LONG-TERM MONITORING INEVITABLY EXTENDS BEYOND THE LIVER

We examine the long-term risks that persist after SVR and explain why post-cure care must extend beyond liver-specific outcomes. Achieving SVR marks a major therapeutic milestone but should not be regarded as the endpoint of clinical management. Although viral clearance attenuates hepatic inflammation and often stabilizes or reverses fibrosis, accumulating evidence suggests that long-term risk in individuals with HIV/HCV coinfection shifts rather than disappears following cure.

Longitudinal studies demonstrate sustained improvements in liver stiffness after DAA-induced SVR, even among patients with advanced fibrosis[22,23]. Concurrently, adverse metabolic changes, including weight gain, dyslipidemia, and impaired glucose metabolism, have been reported[24], particularly in individuals with HIV, in whom antiretroviral therapy, chronic immune activation, and accelerated aging converge to amplify cardiometabolic risk. This pattern reflects a broader shift in disease burden. As virus-mediated liver injury recedes, metabolic and immune-mediated processes increasingly drive long-term outcomes. Although DAAs reduce systemic inflammation, residual immune activation remains more pronounced in HIV/HCV coinfection than in HCV monoinfection[25,26], with non-liver comorbidities emerging as major contributors to morbidity and mortality.

These shifts have important implications for post-SVR care. Continued surveillance for HCC remains essential in patients with cirrhosis, as viral eradication does not abolish oncogenic risk[27,28]. Beyond this population, follow-up strategies should be expanded to include structured monitoring of metabolic and cardiovascular health. Without such adaptation, the long-term benefits of viral cure may be undermined by preventable non-liver complications.

HIV clinics, already oriented toward comprehensive chronic disease management, are well positioned to deliver this expanded model of post-SVR care. The role of antiretroviral therapy extends into this phase as an additional determinant of management complexity. Persistent challenges related to DDI and metabolic effects underscore the need for coordinated, longitudinal care rather than isolated therapeutic adjustments. In this context, integrated HIV clinic infrastructure provides the continuity, multidisciplinary expertise, and routine monitoring necessary to translate viral eradication into sustained long-term health.

STRUCTURAL BARRIERS, NOT ANTIVIRAL FAILURE, DEFINE CURRENT OUTCOMES

The gap between outcomes achieved under ideal conditions and those observed in routine practice reflects deficiencies in healthcare delivery rather than limitations of antiviral therapy. Despite the broad availability of DAAs in many regions, substantial attrition persists along the HCV care continuum, from diagnosis to treatment initiation and post-treatment follow-up[16,17]. Target trial emulation studies further reveal clinically meaningful delays in DAA initiation even after HIV viral suppression, underscoring the impact of system-level barriers[29].

Within this context, the results reported by Park et al[6] illustrate what becomes possible when barriers to timely treatment and sustained engagement are reduced. Their cohort reflects the effect of optimized care delivery rather than typical real-world practice. Variation across studies reinforces that long-term outcomes in HIV/HCV coinfection are driven primarily by structural determinants, not antiviral efficacy. Confronting these barriers is therefore essential to convert therapeutic progress into durable, population-level benefits[30].

The next frontier of progress, therefore, shifts from achieving virologic cure to ensuring its accessibility, durability, and equity across diverse populations. Importantly, translating this potential into routine practice faces substantial real-world barriers. Outside specialized cohorts in high-income settings, primary care systems often lack essential diagnostic infrastructure, including standardized liver staging and DDI management, needed to integrate DAA and antiretroviral therapy regimens effectively. Similarly, health system constraints, such as fragmented referral pathways and inadequate reimbursement, continue to perpetuate disparities in care for high-risk populations, including people who inject drugs and men who have sex with men[31].

Important research gaps also persist. Although SVR is now readily achievable, the long-term consequences of metabolic rebound and residual immune activation remain incompletely understood, particularly in the context of contemporary antiretroviral classes such as integrase inhibitors[32]. Future investigations must extend beyond high-resource settings to encompass the diverse genetic backgrounds and viral genotypes (e.g., GT3 and GT6) prevalent in developing regions. By aligning integrated care models with the World Health Organization’s 2030 elimination targets[33] and UNAIDS’s “95-95-95” goals, the success of DAA therapy can be measured not merely by the feasibility of cure, but by its sustained and equitable delivery to every patient.

CONCLUSION

In conclusion, DAAs have shifted HIV/HCV coinfection from a condition defined by biological disadvantage to one shaped by the organization and delivery of care. Evidence from cohorts such as Park et al[6] suggests that, under optimized and timely care, HIV coinfection may no longer be associated with inferior long-term survival.