Summary and Discussion

Overview of Main Findings

We identified 12 studies—including 6 RCTs and 6 cohort studies—that addressed the comparative effectiveness of adherence interventions on health outcomes, intermediate markers, and patient adherence in hepatitis-C patients treated with the standard dual combination viral therapy. This existing body of literature, however, had substantial methodological and clinical heterogeneity.

The six included RCTs were rated as primarily poor quality, and all included small sample sizes (21–250). While two good-quality cohort studies^91,93 included a relatively large number of patients (674 and 1560) and reported effect estimates that adjusted for the influence of potential risk factors, the remaining cohort studies had serious methodological limitations and generally had small sample sizes. We also found important variations in patient populations in all of the included studies, such as including patients with differing genotypes, history of substance abuse, and history of antiviral treatment. These factors may represent potentially important risk factors for treatment response and/or adherence (see Table 1). Patient populations also differed in racial and ethnicity distribution, as well as patient comorbidities.

How these studies evaluated adherence interventions was another source of heterogeneity. While studies are grouped into four general categories, studies within a single category often investigated interventions that differed in their components and intensity. Interventions for managing adverse events, for example, included medications addressing different conditions (e.g. epoetin for preventing anemia vs. antidepressants for depression), the use of antidepressants to prevent or to manage depression once it occurred, and CBT to prevent depression. Similarly, the three system-level interventions had different approaches. One intervention evaluated the effect of specialty compared with standard pharmacy services and the other two evaluated direct observation treatments on QOL or intermediate outcomes. The most consistent grouping was the four patient-level interventions that enhanced patient education and/or support in order to improve adherence. Despite this, we were not able to identify the most successful intervention components given the lack of detailed descriptions, differences in intervention providers (e.g., nurses vs. physicians vs. psychologists), and differences in approaches in the various interventions.

The included studies rarely reported health outcomes, which hampered our ability to directly interpret the evidence. In addition, we were unable to pool the intermediate outcomes due to differing definitions and measurement methods for adherence. Although the completion of HCV treatment is a commonly used definition, studies used different thresholds for defining treatment completion. We encountered additional issues in cross-trial comparisons for these studies, including studies that may target the completion of different antiviral agents (i.e., ribavirin vs. pegIFN-α vs. both) or fail to clarify which antiviral agents they measured. The methods of measuring adherence included self-reported questionnaire, one-on-one interviews, pill counts, treatment administration records, or chart reviews. Several studies did not report this information. While SVR was commonly reported, this outcome was generally not comparable across studies due to diverse patient populations (with different likelihood of responding to treatment) across the body of evidence.

Outcomes of Adherence Interventions

There is a paucity of evidence assessing the effect of adherence interventions on health outcomes, particularly hepatitis C complications and mortality. Only two small poor-quality studies^61,64 reported data on QOL. Both studies suggested a tendency toward improved QOL in the adherence intervention groups compared with usual care, despite the interventions’ reflecting completely different approaches in very different patient populations: the use of epoetin to manage treatment-associated anemia in 67 patients⁶¹ and the use of DOT in methadone maintenance clinic attendees.⁶⁴ We cannot eliminate the possibility that these positive findings are affected by publication, reporting, or other biases. Nonetheless, the fact that the few studies that reported any health outcomes tended towards benefit and also did not indicate a decrement in intermediate measures of adherence and treatment response (i.e., SVR) should be encouraging to patients, clinicians, and researchers as this would be consistent with overall potential health benefit.

The association of adherence interventions with viral response, particularly SVR, was the most commonly investigated outcome in the available literature. In general, adherence interventions tended to result in greater proportions of patients achieving SVR (and EVR where reported), but few studies showed statistically significant differences between groups. When considered by intervention type, the evidence for increased SVR was most consistent for patient-level adherence interventions. Whether viewed by intervention type or considered as a whole, however, the available evidence is very weak in suggesting a clear improvement in SVR through adherence interventions.

Almost all included studies that measured adherence showed that interventions tended to improve adherence, despite the varying quality, interventions, definitions, and measurements. Additionally, the magnitude of the association remained consistent (or increased) over time (12 vs. 24 vs. 48 weeks) in those studies reporting adherence data in multiple followup time points.^90,91,93 The two fair-quality studies – one evaluating the effect of specialized pharmacy care⁶⁵ and the other evaluating the effect of CBT⁹⁷ – that showed no impact on adherence (and suggested a possible increase in nonadherence) after the interventions were imprecise in their estimates and relatively small. The existing body of literature offers little data about the harms associated with adherence interventions.

Strength of Evidence

We present the strength of the evidence for health outcomes for all studies by intervention group in Table 12. The strength of the evidence for intermediate outcomes for all studies by intervention group is presented in Table 13. We summarize this information by outcome and intervention group in narrative below.

Findings in Relationship to What Is Already Known

To our knowledge, there are no published systematic reviews that specifically examine the effectiveness or comparative effectiveness of adherence interventions for antiviral therapy of hepatitis C. However, AHRQ recently published a systematic review that examined the comparative effectiveness of adherence interventions in patients with chronic diseases with self-administered medication.⁸⁷ This review has important differences with our study. For example, it excluded patients with infectious conditions and conditions for which medications are administered in hospitals or health care offices, while these are the target population of our study. Similar to our study, the published review identified significant heterogeneity in the methods for measuring adherence, types and characterization of adherence interventions, as well as suggested low strength of evidence for a number of adherence interventions. In summary, our study provides supplementary and useful evidence in relation to the published AHRQ review. In particular, our study addressed a disease condition that was not assessed in the published review. Both studies identified similar patterns of evidence and research gaps.

Applicability of the Evidence to the United States Health Care System

The findings from included studies have generally good applicability to HCV patients in the United States receiving standard (dual) combination therapy of pegIFN-α and ribavirin. However, given the recent recommendation for adding protease inhibitors to the existing combination therapy for patients with genotype 1 HCV, which represents the preponderance of HCV infections in the United States,¹⁷ the available evidence is unlikely to be directly applicable to the present patients with genotype 1 HCV.³¹ In general, patient adherence to medication regimens often decreases as the complexity of the treatment regimen increases. It is plausible that the addition of a third agent administered multiple times per day is likely to further impact patients’ ability and likelihood of complying to treatment. In June 2012, the CDC called for universal HCV screening of the “baby boomer” population (i.e., individuals born between 1945 and 1965).⁴ Such screening could result in a rapid increase in the number of individuals being treated for HCV and subsequently struggling with adherence.

Seven of the 12 included studies were conducted in the United States. The remaining trials were conducted in France (k=2) or Italy (k=2). Two studies enrolled patients from a primary care setting,^96,97 two from specialized hepatology units,^61,65 three from addiction management centers,^64,92,98 and four from multiple clinics.^90,91,94,95 The other trial did not specify study setting. These studies included both academic and nonacademic centers.

Most studies had wide inclusion criteria, although a number of studies excluded those presumed to be less responsive to therapy (i.e., with coexisting infections or previous history of HCV treatment) or those at risk for poor adherence (i.e., with psychological illnesses or current or previous substance abuse). Patients coinfected with HBV, HIV, and/or hepatitis D virus (HDV) were excluded in five studies,^{61,64,65,90,94} those with ongoing depression were excluded in two,^94,96 and patients having a history of and/or active substance use were excluded in two studies.^95,96 Across all studies, there were a larger proportion of males than females and the majority of patients were Caucasian. Patients with HCV genotypes 1 or 4 were the primarily studied population, and the majority of patients had genotype 1 HCV in seven of the 12 included studies. Four studies^64,92,97,98 exclusively enrolled patients currently abstinent from drugs and other substances, but seeking treatment for drug abuse in methadone maintenance or other addiction centers. These data, although limited, suggest that patients at risk for poorer adherence may be appropriate candidates for HCV therapy coupled with effective adherence interventions. Generally, patients included in those studies were representative of the prevalent HCV population in the United States.

Patients in the included studies exclusively used standard doses of combination antiviral therapy of pegIFN-α and ribavirin. The intended duration of treatment in all studies was 48 weeks for patients with genotypes 1 or 4, and 24 weeks for those with genotype 2 or 3. Again, although the antiviral therapy was consistent with the current recommendations for patients with genotypes 2, 3, or 4, the currently recommended treatment for patients genotype 1 has shifted from the standard combination therapy to the triple therapy, in which a protease inhibitor is added to the combination of pegIFN-α plus ribavirin.¹²

A wide variety of adherence interventions were investigated in the included studies. These interventions included simplifying dosing, the use of medications or counseling for managing adverse events, patient education and support by various parties to motivate antiviral medication use or help manage adverse events, and provision of care within specialized care delivery systems (e.g., specialized pharmacies, methadone clinics). We found no studies that directly compared the effectiveness of one type of intervention with that of another type of intervention. In addition, very little detail was given in the majority of the studies regarding the specific intervention components, messages, frequency, and duration. Thus, it is unclear how feasible or effective these interventions would be in real-world settings.

Limitations

Implications for Clinical and Policy Decisionmaking

Available evidence does not provide a clear direction for clinical practice to improve adherence in hepatitis C treatment. The included studies suggest that adherence interventions tended towards improved adherence and/or SVR. In particular, three fair or good cohort studies with moderate sample sizes suggested that patient education and support program as patient-level interventions, as well as special drug packing (i.e. RibaPak) to reduce pill load improved patient adherence. While these findings look promising for clinical practice, the studies included various patient populations and used diverse interventions, and their impact on SVR and health outcomes are uncertain. Thus, we believe that readers should exercise caution when applying the evidence to practice.

Moreover, it continues to be uncertain which specific interventions are effective and what degree of improvement could be expected in current practice, particularly considering the recent updated recommendation for triple therapy in genotype-1 patients. Additionally, the research on the resources and methods for implementing adherence interventions was not within the scope of this systematic review. However, these are important considerations for those who consider implementing adherence interventions in practice,

In general, the available evidence on guiding efforts to improve adherence to recommended treatments of patients with chronic hepatitis C remains very limited. We did not find compelling evidence to suggest that adherence interventions were essential to increase adherence, surrogate and health outcomes. Nonetheless, general principles such as patient education and support and reducing pill burden that have been shown to increase patient adherence to treatment may be considered, since existing epidemiological studies suggest a consistency in the association between a higher level of adherence and an improved SVR.^44,73,76

Evidence Gaps

Substantial gaps exist for all types of adherence interventions. Across all trials, no trials investigated the impact of adherence interventions on long-term health outcomes, such as decompensated cirrhosis, HCC, and mortality. Nearly all studies included genotype-1 HCV patients that received the standard combination antiviral therapy. Therefore, the results may not be applicable to current clinical practice.

For system-level interventions, evidence was inconsistent regarding SVR and substantial uncertainty remains regarding adherence. While it appears that dose simplification is an effective regimen-related strategy to improve adherence, the evidence on SVR is lacking. While generally low, the evidence of patient-related interventions suggested a trend of improvement in SVR and adherence. The evidence for adverse events management is conflicting, although studies with fair-quality RCTs suggest a trend of improvement in SVR.

We identified no studies that evaluated the effect of an intervention that targeted two or more levels of influence (e.g., system-level changes plus patient counseling). It is likely that the most effective interventions would include a combination of changes made to the systems and settings in which HCV care is received, the packaging and delivery of medications and the support and education provided to HCV patients, including strategies to help patients manage side effects related to HCV treatment through medications or behavioral interventions. There is a need in the HCV literature to design and test such comprehensive approaches. Likewise, we identified no studies that evaluated the use of patient reminder systems to improve adherence. This type of intervention has been shown to improve medication adherence related to several other medical conditions.¹⁰⁰

Future Research

Future research should use more rigorous methods in the design and conduct of hepatitis C adherence intervention studies. Although various designs can assess the comparative effectiveness of adherence interventions, RCTs remain the optimal approach for hypothesis testing.¹⁰¹ While cohort studies may be used, they are susceptible to selection bias and are less able to account for unknown prognostic factors than RCTs,¹⁰² despite the use of novel approaches such as propensity scoring.¹⁰³ Future studies should have sufficient power for testing hypotheses, and ideally include longer followup periods to capture long-term health outcomes. As noted earlier, the quality and design of the available literature was a serious limitation in our review.

Studies should also strive to use direct health-related outcomes such as HCV-morbidity, mortality, and QOL, in addition to the surrogate outcomes that are most often reported in the current literature. However, we acknowledge that these outcomes will require longer followup and may be challenging. While longer-term outcome data, such as cirrhosis and HCC, are less readily available in RCTs, it is possible to use cohort studies that rely on patient registries to address this issue. In the meantime, better designed and conducted studies should confirm the relationship between adherence to treatment and SVR, including the effect of adherence interventions on SVR.

The recommended treatment for genotype-1 patients has shifted from the standard combination therapy of pegIFN-α plus ribavirin to triple therapy including protease inhibitors.¹² As such, the available evidence is of very limited value to the treatment of genotype 1 HCV. Although the available literature base may provide indirect evidence regarding interventions for this population, it is unclear how adding new antiviral agent will affect patient adherence. In particular, the administration of the protease inhibitor is complex, and adding this agent to the standard combination therapy will further complicate the treatment. Studies that clearly delineate the risk factors affecting the adherence in this specific group of patients are thus warranted, and adequately powered RCTs testing adherence interventions that address the identified risk factors for the nonadherence to the new treatment regimen are needed.

There is also a strong need for standardizing the definitions of adherence in the context of chronic hepatitis C treatment. Multiple components—including treatment duration, dosing, timing, and intensity—are used in the varying definitions of adherence that we found, and treatment adherence can be associated with one or more antiviral agents in hepatitis C treatment. The multiplicity of domains and components may result in many variants in the definitions about adherence to hepatitis C treatment. In particular, future research should consider using consistent terms and clearly defining the terms in their studies. Emerging systems for defining adherence may help hepatitis C adherence interventions researchers appropriately use and interpret their research.¹⁰⁴ The “80/80/80” criterion is often used in hepatitis C literature but has two major limitations. First, this definition will no longer be applicable to the triple antiviral therapy for genotype 1 HCV patients. Second, there seems a continuous relationship between the level of adherence and the treatment response⁴⁴ so defining adherence vs. nonadherence based on an arbitrary threshold may thus be suboptimal.

Future studies should clearly distinguish physician-initiated dose-reduction or discontinuation from patient nonadherence to treatment. Although physician initiated dose-reduction or discontinuation seems related to adherence, this treatment change is typically due to vital adverse events associated with antiviral therapy, and is based on the treatment protocol. The nature of this change differs from patient nonadherence, in which patients fail to match agreed treatment plan probably because of difficulties in remembering taking medications or following the complex treatments, unwillingness to continue the treatment, and reduced QOL.

In our exploration of risk factors associated with treatment response, we have found a number of potentially important factors associated with treatment response and patient nonadherence (Table 1). Future studies, particularly observational studies, should consider the issue about patient comparability in exposure and nonexposure groups. Efforts are needed to adequately adjust for the influence of those factors.

Finally, as noted earlier, many of the studies we found were of poor quality, with inadequate reporting of study design and intervention details. Future studies should include clearer and more detailed reporting of study design and conduct. Studies need to provide sufficient information about how adherence interventions are undertaken, including the parties of undertaking intervention, such details of interventions such as intervention components, intensity, and duration. Studies should also describe methodological characteristics in more details. RCTs should report details on patient selection, allocation, and followup. In the results, the data on loss to followup should be clearly reported. Cohort studies should provide detail on collected variables, sources of data, accuracy of measurements, and approaches that are used to minimize bias. In addition, studies should be more explicit and clear in defining and measuring adherence. Ideally, study reports should include a section to describe the definition and measurement of adherence. Due to space limitations in most peer-reviewed journals, authors and journal editors should be encouraged to publish these details as appendices, supplementary material, or as separate design-specific papers, at the very least published online.