Patient-reported Outcomes in Chronic Hepatitis C

Alimentary Pharmacology & Therapeutics

Systematic Review

The Impact of Liver Disease and New Treatment Regimens

Z. Younossi, L. Henry

Aliment Pharmacol Ther. 2015;41(6):497-520.

Abstract and Introduction

Abstract

Background Treatment for chronic hepatitis C (CH-C) is rapidly changing and moving away from an interferon and ribavirin-based therapy to interferon-free ribavirin-free all oral regimens. These regimens are simpler and shorter to administer with very high efficacy rates and better side effect profiles. As advances in the treatment of CH-C occur, it is imperative to capture both clinical outcomes (efficacy and safety) as well as patient-reported outcomes (PROs). In fact, PROs assesses and quantifies the impact of these regimens on patient experience. PROs assess patients' health-related quality of life (HRQOL) especially in the realms of fatigue and neuropsychiatric issues such as depression which can affect treatment adherence and work productivity.

Aim To review the literature related to PRO's in HCV patients and summarise the impact of CH-C and its treatment on PROs.

Methods Databases Ovid MEDLINE and PubMed were searched from 1990 to October 2014 using a combination of MEsh, thesaurus terms and relevant text words: hepatitis C, CH-C, treatment, quality of life, health-related quality of life, fatigue, work productivity, adherence, patient-reported outcomes, direct acting anti-viral agents and second generation direct acting anti-viral agents. Each manuscript was assessed for pertinence to the issue of PROs in CH-C as well as the quality of study design and publications.

Results From the literature, it is evident that CH-C patients have baseline PRO impairment. Furthermore, treatment with interferon with or without ribavirin and first generation DAAs causes additional PRO burden which can negatively impact treatment adherence and indirectly, treatment efficacy and work productivity. The new treatment regimens with interferon- and ribavirin-free regimens not only have very high efficacy, but also result in the improvement of PRO scores as early as 2 weeks into treatment as well as possibly better adherence to treatment regimens.

Conclusions CH-C and its treatment have been associated with patient-reported outcome impairment. The new IF-free and RBV-free regimens are associated with high efficacy and substantial improvement of patient-reported outcomes in clinical trial setting. Although very encouraging, more data are needed to assess patient-reported outcomes, adherence and work productivity of CH-C patients in the real world setting of clinical practice.

Introduction

The new treatment of chronic hepatitis C (CH-C), a prominent and potentially devastating liver disease worldwide, is evolving and promises higher cure rates with fewer side effects and shorter treatment duration.^[1–5] To better understand the total impact of these regimens on CH-C patients' life and quality of life, the data on the efficacy and safety of these regimens must be combined with the data related to patient-reported outcomes (PROs). Patient reported outcomes are defined as measurements based on reports that come directly from the patient about the status of their health condition without amendment or interpretation by a clinician or anyone else.^[6] In clinical research and clinical practice, capturing PRO data in addition to efficacy and safety data provides a complete assessment of the impact of the disease as well as a comprehensive net benefit that chronic disease treatment may provide to CH-C patients.^[6]

One may argue that for CH-C patients, sustained virologic response (SVR) is a surrogate for clinical outcomes (such as improved survival). In contrast, PROs are surrogates for estimating patients' experience with the disease and its treatment. This is especially true for patients with CH-C who have historically been treated with regimens that have low efficacy and numerous side effects (anaemia, fatigue, depression and thrombocytopenia).^[7–14] The newer regimens are free of interferon and some free of ribavirin, have the advantage of high SVR and a better PRO profile. By combining both clinical and PRO outcomes, the true value of these regimens can be appreciated.^[15–23]

Although a number of PROs measurement tools and concepts provide important insight about patients' experience, in this manuscript, we will focus on the PRO's of health-related quality of life (HRQOL), fatigue and work productivity.^[24–30] Therefore, the purpose of this article was to briefly describe the PRO literature as it pertains to CH-C, the historical treatment with interferon-based regimens, the new treatment regimens free of interferon and to discuss the implications of these findings in relation to treatment adherence and patient reported outcomes.

Methods

Databases Ovid MEDLINE and PubMed were searched from 1990 to October 2014 using a combination of MEsh, thesaurus terms and relevant text words: hepatitis C, CH-C, treatment, quality of life, health-related quality of life, fatigue, work productivity, adherence, patient reported outcomes, direct acting anti-viral agents and second generation direct acting anti-viral agents. If there were no published full length manuscripts available, presentations from scientific meetings were obtained. Bibliographies from all identified studies were searched for relevant studies. The material used was written in English. Each manuscript was assessed for pertinence to the issue of PROs in CH-C as well as quality of study design and publications. Manuscripts only describing published reviews were not included but used for background information.

Health Related Quality of Life Defined

Although the terms HRQOL and patient-reported outcomes (PRO's) have been used interchangeably, PROs include other outcomes reported by and important to patients. HRQOL usually encompass the patient's perspective (self- report) of their physical, mental and social functioning to include health status and well-being.^[24–27]

It is important to note that HRQOL falls under the broader category of quality-of-life (QOL). QOL accounts for the influences of environment, freedom and economy, as well as aspects of a culture, values and spirituality on patients' well-being.^[28–31] Under this umbrella concept, HRQOL specifically deals with the impact of health (or lack thereof) on patients' well-being. HRQOL is succulently defined as a broad multidimensional concept that includes self-reported measures of physical and mental health as well as the ability to be socially active (social well-being).^[24–31]

In general, HRQOL tools or instruments are divided into General Measures (Generic Instruments) and disease-specific instruments.^[6,28–36] Health utility is another type of assessment used which determines a patient's preference for a state of health.^[37,38] Health utilities are also used to potentially compare the preferences of different stakeholders (patients and providers) for the same state of health. Additionally, health utilities are used in cost effectiveness analysis to quality adjust outcomes and provide quality adjusted years of life (QALYs) to compare different interventions.^{[38,39,37,36,40–42]} Health utilities can be assessed indirectly (example: Health Utility Index Mark 1 and 2) or directly (Standard gamble, Time-Trade-Off).

Work Productivity Defined

Work productivity has been defined as the economic productivity of a workplace in which worker productivity is a central part to the overall productivity of the workplace.^[43] Worker productivity is measured through two key concepts– presenteeism and absenteeism. Presenteeism is best defined as the amount of work that is completed when a person is at work whereas absenteeism is defined as the amount of work not completed due to the worker being absent or away from the workplace.^[44] For a long time, work productivity was only measured through absenteeism, but investigators realised that being present and not being attentive at work is just as important when measuring worker productivity. Therefore, a number of tools have been developed to measure both of these concepts (EWPS, HLQ, HRPDQ-D, LFQ, OST, SPS13, WHI, WHO-HPQ, WPAI-GH, WPSI);^[29,44,45] however, at a recent working conference researchers gathered to discuss the development of a global question that would measure these presenteeism concepts instead of having a number of tools. Four global measures of presenteeism were put forth for a plenary vote. The three measures that were supported as global measures included: (i) the presenteeism global from the Work Productivity and Activity Impairment Questionnaire (72% support), (ii) Rheumatoid Arthritis-specific Work Productivity Survey (71% support) and (iii) the central item from the Work Ability Index was endorsed (70%) by conference participants. Neither the presenteeism global item from the Health and Work Performance Questionnaire nor the Quantity and Quality method achieved endorsement at the conference. Work will continue on this initiative, but being able to measure worker productivity using less burdensome tools will be important as more therapies for HCV come to market.^[45,46]

PRO Instruments Used for Patients With CH-C

A large number of HRQOL instruments (SF-36, CLDQ-HCV, EQ-5D, sickness impact profile, Hepatitis Quality of Life Questionnaire, Liver Disease Quality of Life Index), Utility instruments (Health utility Index Mark 2 and 3, SF6D) and fatigue questionnaires (Fatigue screening score, Chronic Fatigue Screener, FACIT-F) have been used to assess PROs in CH-C patients, however, we will focus on the most widely used and validated instruments (Table 1).^[24–45] These include the Short Form-36 version 2 (SF-36v2), the chronic liver disease questionnaire for Hepatitis C (CLDQ-HCV), the functional assessment of chronic illness (FACIT-F), the work productivity and activity impairment questionnaire: specific health problem (WPAI:SHP) and SF6D utility scores.^[24–27]

The SF-36v2 is a widely used generic instrument for HRQOL evaluation.^[24] The SF-36v2 assesses eight HRQOL scales (scores range from 0–100 with higher values corresponding to a better health status): physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE) and mental health (MH) along with two summary scores which summarise the physical [physical component summary score (PCS)] and mental health [mental component summary score (MCS)] components of SF-36. Scores can be compared to established U.S. population norms.^[24]

The CLDQ-HCV is another widely used and validated HRQOL instrument developed specifically for the assessment of HRQOL in HCV patients.^[32] CLDQ-HCV includes four HRQOL domains: activity and energy (AE), emotional (EM), worry (WO), and systemic (SY). There are domain scores and total CLDQ-HCV score which ranges 1–7 with higher values representing better HRQOL.^[24,32]

The FACIT-F is a 40-item PRO questionnaire which evaluates fatigue and its impact upon daily activities.^[26] The scoring scheme includes physical (PWB), emotional (EWB), social (SWB) and functional (FWB) well-being domains as well as the fatigue subscale domain (FS). These five scales together add up to the total FACIT-F score which range from 0 to 160 with higher values representing better well-being.^[26]

Finally, the WPAI:SHP questionnaire is a validated PRO instrument where participants are asked to evaluate impairment in their daily activities and work productivity associated with a specific health problem.^[27] Patients with HCV are specifically asked about the impact their HCV infection has on their work productivity and ability to perform daily activities other than work. Higher impairment scores indicate poorer health status: the minimum possible value of 0 represents no impairment in work productivity or daily activities while the value of 1 represents complete inability to work or perform those activities.^[27]

Health utilities are defined as cardinal values representing the strength of an individual's preferences for specific health-related outcomes–0 is death and 1 is perfect health. Measuring health utilities involves two main steps: defining a set of health states of interest and valuing those health states.^[37–39,36] Health utilities can be assessed indirectly (example: Health Utility Index Mark 1 and 2) or directly (Standard gamble, Time-Trade-Off). These measurements are typically used in cost effectiveness analysis to quality adjust outcomes and provide quality adjusted years of life (QALYs) to compare different interventions. One of the most commonly used tools is the SF-6D which was developed as a result of tying the economic impact of a disease process with a patients' quality of life (QALY's). The SF-6D is scored on a scale of 0–1 with 0 being death and 1 being perfect health. It is derived from the SF-36 where the SF-36 is revised into a six dimensional health state classification called the SF-6D. It is important to note that the algorithm used to score the SF-36 is country specific thus making the SF-6D country specific. To generalise study results across countries, the scores must be normalised. Currently, the SF-36 scores have been translated into 170 languages allowing for the normalisation of scores for multinational comparisons^[40–42] (http://www.optum.com/optum-outcomes/what-we-do/health-survey-translation.html).

The Concept of Minimal Clinically Important Difference in PRO Scores

Prior to discussing actual PRO data from clinical research of patients with CH-C, it is important to discuss the concept that may help explain the potential discrepancies reported between efficacy and effectiveness of some treatment regimens. This concept can be partially explained by the minimal clinically important differences (MCID).^[47,48] Changes in PRO scores can occur due to the natural history of the disease or due to treatment intervention. Although some of these score changes may reach statistical significance, these changes may be very small and not clinically relevant. The concept of MCID describes the changes in PRO scores that are clinically meaningful.^[47,48] Although there is no agreement on the best method, there are a number of techniques that are used to calculate the MCID: distribution-based methods, anchor-based methods and the Delphi method.^[47,48] In general, MCID for domain scores of some PRO questionnaires has been established between 5% and 10% changes in the score. In fact, through a very rigorous and systematic approach, the MCID for the Vitality Scale of SF-36 was established to be 4.2 (scale score ranges 0–100). Changes of this magnitude should signal to the treating physician that a change in treatment may be warranted.^[47,48]

Application of PRO Assessment in CH-C

Although there a number of important PROs for patients with CH-C, the most widely studied PROs are related to fatigue, HRQOL and Work Productivity (Figure 1). Patients with CH-C have substantial PRO impairment prior to the initiation of treatment which could worsen with treatment (Figure 1 and Table 1 and Table 2). This impairment not only affects patients' experience but also adherence to treatment regimen which in turn can negatively affect SVR rates in 'real world' clinical practice.^{[48–112,44,113–136]} The following paragraphs summarise the impact of CH-C and its treatment on PROs.

Figure 1. Patient-reported outcomes in chronic hepatitis C.

Impact of CH-C on PRO Impairment Prior to the Treatment

A significant body of evidence also suggests that patients with CH-C infection who do not have advanced liver disease have diminished HRQOL.^[17,81–83] There is evidence to suggest that HRQOL impairment in patients with CH-C is driven by fatigue and psychological issues, namely depression and cognitive impairment. In fact, fatigue and depression are often assumed to be comorbid conditions that are highly prevalent in patients with CH-C or are consequences of chronic HCV infection.^[17,81–88] In recent studies of HRQOL in patients with CH-C, fatigue and depression were the most important independent predictors of PRO impairment.^{[18–23,89–92]} In fact, one can postulate that PRO impairment in CH-C with early liver disease may be primarily due to the extra hepatic manifestations related to HCV mainly fatigue and impaired cognitive functioning.^[91,92]

Another issue confounding the assessment of HRQOL is stigmatisation resulting from the HCV diagnosis. It is possible that stigmatisation creates the potential for a psychological impact with its negative influence on PROs and acts as a barrier to treatment. In studies assessing HRQOL after the initial diagnosis, the diagnosis of HCV itself has been found to negatively impact patients' HRQOL.^[48,70,71]

Strengthening the association between HCV and PRO impairment is the line of evidence suggesting that eradication of HCV improves PROs. In a systematic review, investigators reported that achieving a SVR with HCV treatment (i.e., being HCV RNA negative 6 months after completing therapy) was associated with an increase in HRQOL scores that met both statistical significant and MCID threshold.^[9] The improvement of PROs after SVR provides strong evidence for the association of HCV with PRO impairment.^[62,74–76]

Impact of dIsease Severity on PROs in Patients With CH-C

The severity of liver disease accounts for some impairment in patients' HRQOL. There are multiple publications suggesting that patients with compensated cirrhosis have more impairment than patients without significant hepatic fibrosis.^{[28,82–106,66]} Worsening hepatic dysfunction in patients with cirrhosis, as documented by higher model for end-stage liver disease (MELD) scores, and the development of complications, such as ascites and hepatic encephalopathy, account for severe impairment of HRQOL.^{[28,82–102]} However, treatment and correction of several potentially treatable variables such as ascites, hypoalbuminemia, minimal hepatic encephalopathy and anaemia, have been shown to positively alter patients' HRQOL (Table 2).^{[66,94–106]}

Impact of Interferon Treatment on PRO in Patients With CH-C

In the early 1990s, the FDA approved interferon for HCV treatment. In the late 1990s, ribavirin was approved in combination with interferon for the treatment of HCV. In the early 2000s, a pegylated form of interferon was developed to reduce the number of interferon injections required. In 2011, the first generation of protease inhibitors (BOC and TVR) were approved as the first direct acting antiviral agents (DAAs) to be used as triple combination with high efficacy reported from clinical trials.^[51,52] Despite gains in the efficacy of these regimens with increasingly better SVR rates, the side effect profile associated with interferon, ribavirin and first-generation DAAs caused debilitating symptoms and adversely affected patient-reported outcomes (Table 2).^[53,54,107]

In addition to the direct impact on PRO impairment during treatment, the side effect profile of IFN-based regimens (flu-like symptoms, fatigue, rash and depression) excluded many patients from receiving treatment leaving only a small number of HCV patients eligible for anti-HCV treatment.^[110] In addition, the presence of certain comorbid conditions (anaemia, autoimmune disorder, renal dysfunction, cardiovascular disease, psychiatric issues including severe depression, psychosis/bipolar disease, severe lung disease and substance abuse) contraindicated the use of IFN, RBV and first generation DAAs further decreasing the pool of eligible candidates for treatment.^[108–110] The lack of insurance coverage created another important barrier to receive treatment. In a study using the population database, only 35% of patients with HCV were candidates for the treatment and had adequate coverage.^[111] Furthermore, a number of patients with HCV who were otherwise eligible for treatment and had insurance coverage deterred treatment due to their fear of side effects.^[5,10] All of these reasons lead to only 10–15% of patients diagnosed with CH-C actually receiving treatment.^[110,111]

Predictors of PRO in Patients With CH-C

As described previously, all PRO studies have included multivariate analyses to determine the independent predictors associated with PRO impairment. The main independent predictors of PRO impairment prior to the initiation of treatment were identified as clinically overt fatigue, depression, insomnia, anaemia and anxiety. Furthermore, cirrhosis and HIV co-infection were predictors of PRO impairment in a sub-analysis. On the other hand, during treatment, in addition to these predictors, IFN and RBV were associated with PRO impairments. This was true regardless of the regimen, stage of liver disease or HCV genotypes (Figure 2).^{[19–23,112]}

Figure 2. Factors affecting patient-reported outcomes during treatment of chronic hepatitis C

Studies Assessing Work Productivity in CH-C

In the past decade, investigators have assessed the impact of the hepatitis C virus infection on worker productivity and found that the hepatitis C virus causes considerable disruption to work productivity.^{[44,113–116,63,75,117–120]} HCV-positive patients have been found to have 1.5 times higher rates of absenteeism levels (4.88% compared to non-HCV controls with levels of 3.03%), higher rates of presenteeism (16.69% vs. 13.50%), overall work impairment (19.40% vs. 15.35%) as well as activity impairment (25.01% vs. 21.78%) when measured over a 7 day period.^[113] Others have also performed similar studies and confirmed these initial findings that patients suffering with HCV have significant work impairment (Table 2).^{[114,118–120]}

In concert with this work, investigations were initiated to determine the effect treatment had on patients' work productivity. In 2001, one of the first studies investigating the role of HCV treatment (IFN a-2b and Ribavirin) on worker productivity was conducted. In this study, where one group received a placebo and the other the standard treatment of IFN and RBV, patients were followed over 48 weeks and asked to complete HRQL and work productivity questionnaires. During treatment, investigators found that work function and productivity decreased temporarily in 46% of patients who eventually reached SVR but decreased significantly more in the eventual nonresponder group (59%).^[63]

Another group studied the actual productivity of HCV-positive patients. They found that CH-C patients who were undergoing treatment actually missed more days of work (nontreatment mean of 0.75 days of work/month missed vs. those receiving treatment had an additional 0.52 absence days/month). In monetary terms, this was equivalent to $31.31 in additional monthly absence payments to patients receiving treatment. They also found that the treated patients processed 11.7% fewer units of work per hour and 17.4% fewer units of work per month than the untreated patients.^[115]

Another more recent study assessed the impact of successful treatment (SVR) on work productivity. In this study, treatment failures were more likely to have missed work or other commitments (such as volunteer activities and household activities) than those who achieved SVR (44% vs. 9%). The same trend was noted for presenteeism where patients who did not achieve SVR were twice as likely to experience presenteeism compared to those who obtained SVR (22% vs. 11%).^[75]

In summary, these studies found that the HCV virus significantly affected work productivity where patients missed more days of work or produced less when at work. Furthermore, these work place issues were worsened when patients were undergoing treatment with IFN/RBV based treatment. An interesting note was the patients who eventually obtained SVR encountered at the end of treatment only a temporary decrease in their work productivity compared to patients who did not achieve SVR. Patients not achieving SVR may have been due to treatment side effects which led to non-adherence which eventually impacted their ability to work. Following the impact of the new drug regimens on work productivity will be very important when assessing the effectiveness of treatment.

Summary of Historical Data Related to PRO Impairment in Patients With CH-C

The early pioneers of PRO work during this treatment period of time determined that patients reported a significant decrease in their HRQOL even prior to the treatment. One of the initial studies of HRQOL in CH-C reported that five of the eight domains of the SF-36 (RP, GH and SF) were significantly impaired before anti-HCV therapy even began.^[103] However, even more significant was that the investigators found patient scores fell even further during treatment. The vitality parameter of the SF-36 was identified as the area most affected. Following further studies, researchers have deemed vitality as the most comprehensive well-being measure for a patient who suffers from HCV (Table 2).^[64,84,87]

Other studies have investigated the impact of IFN/RBV induced anaemia and depression on HRQOL.^{[11,12,17,38,48,58,59]} In one such study, investigators found that treatment-induced depression which increased for the first 20 weeks of treatment as well as the presence of anaemia both negatively affected HRQOL scores. From the results of their multivariate analysis, the researchers found that the impact of depression on a patient's HRQOL was so strong that many variables that were initially found to be significant were no longer significant once depression was introduced into the multivariate model. Therefore, the authors concluded that treatment for depression and anaemia must be addressed carefully when treating patients with PEG/INF.^[58]

There have also been a number of studies investigating the impact of IFN/RBV therapy on health utilities. In one such study, investigators used several measures of health utilities (HUI2, HUI3, SF-6D and Time trade off) to assess patients' preferences. After adjusting for known confounders (age, sex, ethnicity, marital status, comorbidity and severity of impairment), the main utility outcome of HUI-3 (levels of functioning on vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain) was effected by viral factors not by the host factors.^[38] Using the same measurement tools, other investigators determined that CH-C patients who had developed sustained viral clearance had the highest utility scores while those with late advanced stage liver disease (cirrhosis and liver cancer) had the lowest utility scores.^[121] In contrast, these investigators found that host factors such as age, lower income, unattached marital status and high comorbidity were strongly associated with impairment in health utilities.^[121]

Despite the significant reduction in patient's HRQOL and worker productivity during IFN/RBV treatment, PRO scores and worker productivity both improved after treatment discontinuation. Furthermore, those who achieved SVR, had further improvement of their HRQOL, health utility scores and worker productivity.^{[55,74–76,44,113–116,63,117–120]}

The Impact of HIV/HCV Co-infection on Pros

Another important aspect of the new regimens is the tremendous gains for HIV/HCV co-infected patients. Clinical trials, PHOTON 1 and 2, studied the impact of HIV/HCV co-infection on PROs, and their tolerance of SOF + RBV. When comparing cohorts from PHOTON 1 and 2 to the appropriate mono-infected controls (FUSION and VALENCE), results indicated that HIV/HCV co-infected patients have more impairment of PROs prior to initiation of treatment. Nevertheless, during treatment with SOF + RBV, co-infected patients tolerated these regimens in a fashion similar to mono-infected patients without any additional PRO burden.^[112]

Comparing PRO scores for patients in PHOTON 1 and 2 to their own baseline showed a similar mild ribavirin-induced decline in PRO scores which recovered after 12 weeks of follow-up. Again, co-infected patients who achieved SVR-12 showed further gains in PRO scores. Furthermore, fatigue, anxiety/depression and anaemia were predictors of PRO impairment. These data support the recommendation that HIV/HCV co-infected patients experience the same benefits as those infected with HCV alone and should be a given the same consideration for treatment with the same regimens.^[112]

The Impact of Hepatic Fibrosis on Patient Reported Outcomes

The studies of SOF regimens also provided an opportunity to assess the impact of advanced fibrosis on PROs. As mentioned previously, patients with advanced fibrosis (cirrhosis) have been shown to have more impairment of their PROs. This impairment worsens with disease severity as indicated by complications of cirrhosis.^[66,89,94] Furthermore, in the era of IFN-based regimens, patients with advanced fibrosis were difficult to treat predominantly due to substantial side effects and low efficacy rates of these regimens.^[66,89]

In the era of IFN-free regimen, the interaction among stage of liver disease, treatment regimen and PROs must be revisited. Recently, a large study assessing PROs in cirrhotics, using multiple validated instruments, provided an opportunity to perform an in-depth analysis. In fact, this study showed that patients with advanced fibrosis do have significantly more PRO impairment prior to treatment than those with early fibrosis.^[15,18] During treatment with IFN-free regimens that contained RBV, minimal PRO decrements related to RBV were noted. Nevertheless, these impairments were similar between cirrhotic and noncirrhotic patients. Again, the short duration of treatment (12 weeks) provided an advantage to these patients as PRO scores returned to the baseline, shortly after the termination of therapy. Finally, cirrhotic patients who achieved SVR-12 after treatment, especially with the interferon-free regimens, enjoyed significant improvement of some of their PRO scores. From these data, one can conclude that patients with advanced fibrosis can tolerate interferon-free regimens in a similar fashion to those with early fibrosis. In fact, this occurred regardless of which IFN-free SOF regimen was used.^[18]

Another related important question is whether patients with early fibrosis can experience substantial improvement of their HRQOL, fatigue and other PROs after achieving SVR. This is especially important in the current environment where stage of fibrosis has been used to make treatment decisions for CH-C patients. It is important to remember that fibrosis stage is a surrogate marker for liver-related mortality and possibly overall mortality. In contrast, fibrosis stage is not a surrogate marker for patient experience or their HRQOL. There are a substantial number of CH-C patients with significant fatigue and impairment of HRQOL who have very early stage liver disease. In this context, benefits of achieving SVR and improving PROs in a patient with early fibrosis can be extremely valuable from patients' perspective. In fact, the analyses of SOF regimens have shown that patients with early fibrosis gain substantial PRO benefits, similar to the gains achieved by those with advanced fibrosis. Therefore, using fibrosis stage to limit treatment with the newer anti-HCV regimens is not warranted based on PRO gains.^[122]

As noted previously, in addition to other PROs, health utilities in CH-C have also been assessed. In clinical trials of SOF regimens SF6D scores and EQ5D scores were derived from SF-36 scores. As expected, the overall results and predictors of utility score changes for CH-C patients during treatment and after achieving SVR-12 were similar to those reported for SF-36.^[121]

PRO Data From Wave 1 New Treatment Regimens Containing the Second Generation of Direct Acting Anti-virals- Sofosbuvir (SOF) and Ribavirin With or Without Interferon

Although SOF-containing regimen for HCV genotype 1 has substantially higher efficacy and shorter duration, it still includes IFN and RBV. The regimen which was assessed in Neutrino clinical trial included 12 weeks of SOF + IFN + RBV in treatment naïve patients with genotypes 1/4/5/6.^[3] The PRO data from this trial indicated that both the SF-36 physical and mental component summary scores (PCS and MCS) decreased during treatment (by the last day of treatment a decline of −5.93 ± 9.44 and −6.33 ± 9.70, P < 0.05, respectively). However, by the 12th week of follow-up, post-treatment scores were significantly better than the baseline scores (+0.28 ± 7.33 and +0.82 ± 9.43, P < 0.0001, respectively) as well as all other domains had significantly increased. These significant increases in PRO score are thought to be due to the high SVR rates (90%) in this clinical trial.^[3] In fact, in a separate analysis, PRO data from NEUTRINO was compared to those with PEG-IFN and RBV only. The decline in HRQOL was similar between the two regimens during treatment but because of shorter duration and high efficacy of triple combination of SOF + IFN + RBV, this regimen has significant PRO advantage at the end of follow-up (Figure 3 and Table 3).^[23]

Figure 3 Description of clinical trials using sofosbuvir regimens.^{3,19–23,112,122–127}

IFN-free SOF regimens were assessed in five recently completed clinical trials (POSITRON, FISSION, FUSION, PHOTON 1 and 2). These studies used a regimen consisting SOF + RBV for treatment naïve or treatment experienced patients with genotype 2/3 as well as those with HIV/HCV co-infection with varying lengths of treatment (Figure 3).^{[112,122–126]}

Since FISSION, compared 12 weeks SOF + RBV to 24 weeks of PEG-IFN + RBV, an opportunity was provided to assess the impact of removing IFN on PROs. In fact, the PRO data showed that patients who were treated with SOF + RBV in FISSION showed substantially better PROs than PEG-IFN + RBV.^[19,20,23] Independent predictors of PRO impairment were fatigue depression, anaemia and receiving IFN.

The impact of prolonging the duration of treatment with SOF + RBV from 12 weeks to 16 or 24 weeks was tested in FUSION (12 vs. 16 weeks) and VALENCE (12 vs. 24 weeks) studies. Both studies showed a minimal decline in PROs during treatment. This decline was primarily due to RBV and associated anaemia. On the other hand, extending duration to 16 or 24 weeks did not add additional PRO burden on these patients. Again fatigue, depression/anxiety, anaemia and RBV were predictors of PRO impairment.^[19,20]

Another important question assessed by PRO data from these four studies was related to the impact of SVR-12 on PROs. Results suggested that patients who were treated with 24 weeks of IFN + RBV in FISSION trial and achieved SVR-12 did not show improvement of their PROs.^[3,20] How do we reconcile this discrepancy with historical data suggesting that CH-C patients who achieved SVR-24 with IFN + RBV showed improvement of their PRO?^[124] We believe that the impact of IFN on the brain may take longer to clear and that at least 6 months may be necessary to observe PRO gains in patients cured with 24 weeks of IFN + RBV. On the hand, patients who were treated with SOF + IFN + RBV for only 12 weeks and achieved SVR-12, did show improvement of some aspects of their PROs. Again, shorter exposure time to IFN may explain this difference from the longer 24 week course of treatment with IFN + RBV. Nevertheless, patients who achieved SVR 12 weeks after discontinuation of SOF + RBV regimen showed substantial improvement of their PROs supporting that the side effect of RBV is washed off by 12 weeks of follow-up.^[19,20,23]

Worker productivity was also assessed in these trials. Similar to the decrease in HRQL, the patients who received interferon (Neutrino trial) had greater impairment in their work productivity (absenteeism and presenteeism) and took almost twice as long to reach their baseline after treatment completion when compared to patients who did not receive interferon [12 weeks (Neutrino) vs. 4–8 weeks (Fusion study)].^[20] Nevertheless, we believe that achieving SVR-12 can provide some improvement in work productivity. However, given the relative short follow-up (12 weeks) and the complexity of other factors involved in work productivity, longer follow-ups may be needed to provide additional benefit of SVR on work productivity.

PRO Data From Wave 2 New Treatment Regimens Containing the Second Generation of Direct Acting Anti-virals Without Interferon and Ribivarin–Ledipasvir and Sofosbuvir Regimens

In the past few years, there have been significant gains in developing treatment regimens with high efficacy, low side effect profiles and less complex administration (fewer pills, less frequent dosing, shorter duration and lack of response guided therapy).^[129]

In 2013, the first interferon-free regimens became available with high efficacy rates. Additionally, removal of interferon from the treatment regimen led to a better safety profile, fewer side effects and significant improvement in PROs.^[18,19] Furthermore, replacing the first generation relatively toxic DAAs with second-generation DAAs with minimal toxicity did not add to the PRO burden during treatment. Nevertheless, regimens that contained RBV still had side effects which can lead to PRO impairment. With the advent of interferon-free and ribavirin free regimens, side effect profiles and PROs have further improved.^{[2,15,18,21,22]} The impact of these regimens on PROs is discussed in the next few paragraphs. Given that there are very little published PRO data for 3D regimen by AbbVie and Simprevir by Janssen, we will primarily focus the discussion on SOF containing regimens; however, the results from any available information by AbbVie or Simeprevir will be briefly presented (Figure 3 and Table 4).

Although SOF + RBV provided substantial PRO advantage by removing IFN, presence of RBV contributed to the minimal but significant PRO impairment during treatment. The second wave of interferon-free and RBV-free regimens for CH-C genotype 1 patients were tested in ION 1, ION 2 and ION 3 clinical trials using the LDV + SOF which was recently approved by the FDA in the United States.^[123–125] These regimens were compared between 8, 12 or 24 weeks of treatment. LDV + SOF regimens were compared to LDV + SOF + RBV. Again, RBV containing LDV + SOF + RBV regimen showed a mild decrement in PROs during treatment. On the other hand, patients who were treated with IFN-free and RBV-free regimen with LDV + SOF, in fact, experienced improvement of their PROs during treatment. The improvements of PROs were noted as early as 2 weeks after treatment was initiated. This is first report of PRO improvement during treatment of CH-C patients. Although, the RBV containing arm of LDV + SOF + RBV also showed some initial improvement of PROs, this improvement was neutralised by RBV-related side effects. On the other hand, in the RBV-free LDV + SOF arm of the study, the improvement in PROs continued. This PRO gain within 2 weeks of treatment initiation also coincided with early viral suppression. It is believed that PRO impairment in HCV is at least partly related to HCV viremia. As soon as the virus was suppressed, the PRO improvement became obvious. Although the same could happen in LDV + SOF + RBV arm, RBV side effects seemed to mask this potential PRO benefit from viral suppression. Although a number of PRO gains occurred with LDV + SOF, the most prominent were in vitality, fatigue, presenteeism aspect of work productivity. Again, patients with cirrhosis or early fibrosis experienced the same PRO benefits. Finally, after 12 weeks of follow-up, all patients who achieved SVR-12, regardless of the regimen, showed substantial PRO benefits. All of these gains were higher than MCID in most of the subscales of the PRO instruments used.^[19–23]

Summary of PRO Data From Wave 1 and Wave 2 Sof Regimens

The PRO data obtained from the SOF clinical trials were substantial both in terms of their breath and depth. These programmes used four validated PRO instruments assessing different aspects of the patients' experience while undergoing treatment and 6 months post-treatment. The instruments were administered using a rigorous protocol including the administration of the instruments during the time period the patients were unaware of their HCV RNA status (Table 3 and Table 4).

Wave 1 studies included RBV so a mild but significant RBV-induced decrement in PROs was observed. However, by treatment end and during follow-up, PRO scores had returned to baseline and in some cases increased.^{[19–23,112]} It is believed that some of these gains were related to viral suppression due to the high SVR rates associated with these treatment regimens (reported elsewhere).^{[3,44,119–126]} In the hard to treat groups such as patients who were co-infected with HIV and/or had developed cirrhosis, prior to treatment PRO assessment documented some PRO impairment; however, these patients tolerated the treatment regimens well with similar positive changes in their PRO scores by the end treatment and during follow-up.^[18,112] Patients with early stage liver disease also suffered from PRO impairment prior to treatment but enjoyed substantial PRO gains with treatment and after achieving SVR. Based on these patient experience findings, rationing treatment based on stage of fibrosis is not warranted.^[2]

These analyses also showed that patients who were cured of HCV enjoyed improvement in their work productivity.^{[44,113–116,63,75,117–120]} This is important not only from the patients' perspective but also from a societal perspective as gains in work productivity after SVR amounts to substantial economic gain for the employers and the society as a whole.^[2] Finally, these analysis provided a number of predictors of PRO impairment, some previously known while others being novel.

The second wave of PRO studies (Wave 2) clearly demonstrated the superiority of IFN-free regimen over IFN+RBV regimen from patient experience perspective.^{[2,20–23,112]} Regimens that were IFN-free and RBV-free (SOF + LDV) resulted in improvement of PRO scores that occurred during treatment some as early as 2 weeks after treatment started.^[89,90,112] These are very key results as they indicate better tolerability of these regimens which could potentially lead to better compliance to treatment with a very low 3% drop rate due to side effects.^[122–126]

Patient Reported Outcomes Data From 3D Regimen Containing ABT-450/Ritonavir + Dasabuvir and Ombitasvir

Another regimen which was recently approved is the so called 3D regimen. This regimen consists of the protease inhibitor ABT-450 boosted by ritonavir and co-formulated with the polymerase inhibitor dasabuvir, alongside NS5A inhibitor ombitasvir (AbbVie Pharmaceutical).^[129–132] This regimen has been developed for genotype 1 treatment naïve and experienced CH-C patients, dosed twice daily and administered with or without ribavirin.^[117] The reported SVR rates from clinical trials ranged from 90% to 99% with few side effects such as fatigue, nausea and headache.^[129–132] Patient reported outcomes from trials of 3D regimens have yet to be fully published. Nevertheless, the high SVR rates and low side effect profile reported may also be associated with improvement of PROs. Although not fully published, a recent presentation of the HRQOL data from the Aviator Study which showed favourable data in regards to PROs. In this study, the 3D IFN-free regimen showed minimal negative impact on HRQOL as measured by the SF-36, the EQ-5D and the HCV-PRO. In fact by 24 weeks post treatment, the SF-36 mental composite score exceeded the minimum important difference (MCID) of a change in score of 3 or more in the null responders and approached 3 in the naïve patients while the physical component score approached the MCID in the null responders only.^[131] These findings are also encouraging as supporting an appreciable positive impact on the mental health of CH-C.^[131] Nevertheless, fully published peer-reviewed data will better support the benefit of these regimens.

Patient Reported Outcomes Data From Simeprevir Regimen

Simeprevir (Janssen Therapeutics), a once-daily, oral HCV NS3/4A protease inhibitor given in conjunction with Peg INF a-2a and RBV won FDA approval in November of 2013.^[131] The reported SVR rates were 79%–80% for prior nonresponders and treatment naïve patients, respectively. In the QUEST trials, the impact of simeprevir on patient reported outcomes of fatigue and health related state were investigated.^[133–136] Findings indicated that fatigue, as measured by the fatigue severity scale (FSS), increased during treatment, improved approximately 12 weeks after treatment ended (PILLAR Study), was no worse than the placebo/PEG/IFN group, and in fact, was better due to the shortened duration of the treatment.^[130] In the ASPIRE study, the prior treatment patients did not see an improvement in their fatigue scores until week 60, but according to the investigators this was due to having to receive treatment for 48 weeks. A striking finding was that the majority of the placebo group stopped treatment at week 20 as they had no virologic response to the PEGIFN/RBV treatment whereas the group receiving simeprevir the majority were able to complete treatment as noted by the rate of SVR. Their PRO scores as measured by the EQ-5D improved in both study groups who received simeprevir by week 48 and continued to improve through week 72.^[133–136]

The Role of Treatment Regimen Adherence and PRO's

Historically, for patients with CH-C, adherence was partly defined as the ability to take all prescribed medications and attend all office visits. Another commonly used definition for adherence was to achieve >80% rate of treatment completion and >80% receipt of the prescribed treatment regimens. Despite which definition used while treating patients with CH-C, adherence to the full regimen is important to optimise the efficacy of anti-viral therapy.^[7,8,49,50] Furthermore, adherence to the treatment regimen will become even more important when drugs are approved and are utilised in the "real world" setting. Studies have shown that the adherence rate from the well-controlled environment of clinical trials can be substantially reduced when patients are treated in the real world setting of clinical practice. One example of this difference between efficacy and effectiveness of anti-HCV treatment is the efficacy rates reported for the first generation of protease inhibitors (TVR and BOC). The efficacy rates from clinical trials (SVR = 65–75%) dropped to less than 50% when introduced into 'a real world' clinical practice (Figure 4).^[51–54]

Figure 4 Factors influencing adherence in chronic hepatitis C.

Although a number of factors can contribute to the difference between efficacy and effectiveness, non-adherence due to treatment-related side effects such as anaemia, fatigue and depression play an important role (Figure 4).^{[7–10,55,56]} In fact, study results have shown that fatigue and depression at the beginning of treatment are also predictors for failure to attain SVR, probably due to non-adherence to complete full regimen.^{[11,12,57–62]} In addition, treatment-related depression and fatigue secondary to interferon and RBV can further lead to non-adherence and treatment discontinuation.^[14,55,61]

In general, non-adherence can be classified as intentional or unintentional. The unintentional non-adherence can be exemplified when a patient forgets to take a dose of medication. This aspect of non-adherence can be negatively influenced by the complexity of the regimen, frequency of taking treatment medications and the duration of the regimen.^[16,63] Other issues classified as unintentional may be related to the lack of appropriate level of knowledge or experience in the providers. Physicians and other health care providers may not have adequate experience to appropriately manage side effects, dose adjust medication and provide other necessary support needed for these highly complex patients and treatment regimens.^{[15,16,55–61,64,65]}

Other drivers of non-adherence that are specific to patients include less than 12 years of education, history of incarceration, current alcohol and drug use, and failure to show for follow-up appointments.^{[13,49,50,66–68]} In addition, treatment-associated fatigue and impairment of HRQOL during treatment can predict non-adherence.^{[7,8,11,56,63,67,69]} These findings tie the differences seen in the efficacy rates of anti-viral treatment (SVR in clinical trials) to the effectiveness rates of these regimens (SVR in real world setting) to the impact of treatment regimens on patient-reported outcomes such as HRQOL.

Another factor contributing to non-adherence is the stigma associated with the disease. Stigmatisation has been shown to be an important contributor to non-adherence in patients with hepatitis C. Financial insecurity, internalised shame, and social rejection can lead to the behaviours that are emotionally burdensome and negatively affect patients adherence to treatment (Figure 2).^[70,71]

In order to improve adherence, a number of initiatives have been uundertaken. In recent work completed within the Veteran's Administration hospital system, investigators have developed a population based clinical and comprehensive programme led by pharmacists which led to an increase in appropriate testing, treatment and an increase in adherence resulting in an increase in SVR achievement.^[64] In the hard to treat populations including patients with HIV, cirrhosis, psychiatric disorders, and use of intravenous drugs, studies have reported successful treatment when patients were monitored closely, received personalised treatment, and had their pre-existing conditions such as depression addressed prior to the initiation of treatment and vigorously treating treatment side effects.^{[12,50,55,58–60,66,72,73]}

Another technique that has been used in treatment of CH-C is providing positive motivation by sharing the results of virologic response. In fact, providing anti-HCV treatment with lots of side effects and long duration of treatment presented a challenge to keep patients adherent to the regimen. In this instance, investigators recognised that sharing information about early virologic response at week 4, 8 or 12 helped patients stay adherent to treatment regimen.^[72–76]

Another approach to deal with non-adherence included programmes led by a nurse practitioner. These programmes involved structured training and monthly follow-up phone calls. After 3 months of treatment, patients expressed satisfaction with this approach and reported that 99.8% of total medication (interferon and ribavirin) doses were taken. Other investigators have studied the effects of practitioner led support efforts and have also found improved adherence. Nevertheless, they have cautioned against allowing side effect management that may be beyond the boundaries of training for these providers (ex. guiding treatment of a patient's psychiatric side effects).^[64,65] Additionally, others have assessed the success of these initiatives in CH-C patients who inject drugs and, again, reported a great deal of success in terms of both improved adherence and increased SVR rates.^[72]

Finally, there is evidence to suggest that improving self-efficacy (confidence to take all medications as prescribed and attend doctor visits) as part of these multi-disciplinary initiatives may contribute to the improvement of adherence. Researchers using data from the Virahep-C study found that treatment adherence self-efficacy as measured by the HCV Treatment Self-Efficacy scale was higher in patients who were in a relationship, educated, privately insured and less depressed. In addition, better communication between the health care provider and patient at baseline and week 24 had better adherence between baseline and week 24 of treatment and between week 24 and 48.^[69] In a recent study, also conducted within the Veterans Administration, hepatitis C patients who were in a 6 week cognitive-behavioural programme to learn self-efficacy and self-management strategies, gained more knowledge about HCV and showed significant improvement on the SF-36 vitality and physical functioning domains, the quality of well-being scale and the epidemiological scales for depression. These trends held for up to 12 months after the initial group session along with improved health care utilisation measures indicating better self- management.^[10,73]

One issue that requires special attention in CH-C patients is appropriate management of depression. Since there is a high prevalence depression within the CH-C population and treatment associated depression, inadequately managed depression may potentially impact adherence to treatment. In this context, prophylactic treatment of depression and other treatment-induced neuropsychiatric problems may theoretically improve PROs and adherence. Several studies have investigated the prophylactic treatment of depression with serotonin reuptake inhibitors (SSRI's).^[77,78] Results of these studies have been inconclusive. The study that investigated the use of escitalopram found a reduction in the number of patients reporting depression.^[79] However, a study using citalopram in 76 patients did not find an increase in patient adherence to their medication regimen and did not reduce the number of patients reporting depression or depression symptoms.^[59] Nonetheless, another study which emphasised a multidisciplinary, multi-prong approach focusing on psychiatric and health related quality of life issues during HCV treatment showed an improvement in adherence to treatment.^[13,73,81]

All of these data suggest that practitioner-led self-management programmes and interventions geared towards self- efficacy could improve PROs and adherence to treatment. Additionally, newer treatment regimens with high efficacy, few side effects and simpler administration regimen could positively contribute to adherence. Furthermore, communication between health care provider and patients about the state of their disease (HCV negativity) can motivate patients and positively impact their behaviour to maximise adherence. In turn, high adherence to the treatment regimen may not only improve SVR and HCV cure rates but also lead to better patient experience and improved resource utilisation.

Conclusions

In the past decade, inclusion of PROs in the clinical trials of CH-C patients has become increasingly important. The current data support the fact that CH-C patients suffer substantial PRO burden. This burden becomes significantly exaggerated during treatment with IFN + RBV with or without first generation DAAs. The impact of this impairment is not only on patients' experience but also on work productivity and adherence to treatment regimen, indirectly affecting SVR rates. Early PRO assessment of IFN based therapy informed the medical community of the harshness of this treatment from the patients' perspective partially explaining the low completion rate and consequently a very low 'cure' rate.

With the development of the direct acting anti-viral agents, not only was there a substantial improvement in SVR rates, but also the tolerance for the second generation of DAA's was substantially better. This improvement in patient experience was documented through substantially better PRO scores as compared to IFN regimens. Nevertheless, these regimens still contained RBV with its side effects and mild impairment of PROs. The newer IFN-free and RBV-free regimens are not only more advantageous in regard to the high efficacy and shorter duration of treatment, but also improvement of PROs during treatment and after achieving SVR. Although substantial data exist for LDV/SOF regimen, there are emerging data from 3D and simprevir regimens which support the same PRO concepts.

In summary, the measurement of PRO's established with the current clinical trials of the second generation of DAA's have created a very robust and important programme addition to the field of liver disease. Of special importance is that across all SOF based clinical trials four PRO instruments (SF-36, CLDQ-HCV, FACIT-F and WPAI) were used. In fact, the consistent use of the same tools allowed the comparisons of PRO results which showed consistent results across these instruments providing support for the validity of these data.

It is only with the inclusion of PROs that we can fully assess the impact of these new treatments on patients, their families and society. Nevertheless, further work is needed to document the benefit of PROs on treatment adherence. Direct and indirect economic benefit of PRO improvement must also be fully documented. Work must continue on providing practitioner led support and improvement in self-efficacy to patients to increase treatment adherence among HCV patients.

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Source

Ombitasvir/Paritaprevir/r and Dasabuvir Plus Ribavirin in HCV Genotype 1-Infected Patients on Methadone or Buprenorphine

Journal of Hepatology

Articles in Press

Jacob Lalezari, J. Greg Sullivan, Peter Varunok, Edward Galen, Kris V. Kowdley, Vinod Rustgi, Humberto Aguilar, Franco Felizarta, Barbara McGovern, Martin King, Akshanth R. Polepally, Daniel E. Cohen

DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.029
Open access funded by the Author(s)
Publication stage: In Press Accepted Manuscript

Publication History

Published Online: March 31, 2015
Accepted: March 25, 2015
Received in revised form: March 17, 2015
Received: September 19, 2014

Abstract

Background & Aims

HCV-infected patients with a history of injection drug use have low rates of initiation and completion of interferon-based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir +ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy.

Methods

This was a phase 2, multicenter, open-label, single arm study in treatment-naïve or peginterferon/ribavirin-treatment experienced HCV genotype 1-infected patients on methadone or buprenorphine +/-naloxone. Patients received 12 weeks of co-formulated ombitasvir/paritaprevir/ritonavir(25mg/150mg/100mg once daily) and dasabuvir(250mg twice daily) +weight-based ribavirin. The primary efficacy endpoint was sustained virologic response 12 weeks post-treatment.

Results

Thirty-eight non-cirrhotic patients on chronic methadone(n=19) or buprenorphine(n=19) were enrolled. A total of 37 patients(97.4%) had a sustained virologic response 12 weeks post-treatment. No patient had a viral breakthrough or relapse. One patient discontinued due to serious adverse events unrelated to study drug (cerebrovascular accident and sarcoma). The most frequent adverse events were nausea, fatigue, and headache. Eight patients had on-treatment hemoglobin concentrations <10g/dL. Pharmacokinetic analyses indicated no clinically meaningful impact of methadone or buprenorphine on ombitasvir, paritaprevir, ritonavir, dasabuvir, or dasabuvir M1 metabolite exposures. No dose adjustments of methadone or buprenorphine were required

Conclusions

The interferon-free regimen of ombitasvir/paritaprevir/r and dasabuvir +ribavirin for 12 weeks was well-tolerated and achieved sustained virologic response in 97.4% of patients on opioid substitution therapy in this study. This all-oral regimen may provide an effective alternative to interferon-based therapies for HCV-infected patients with a history of injection drug use.

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