The Big Picture

Patient Reported Outcomes Critical in the Fight Against HCV

Zobair M. Younossi

When you look at the consequences of any chronic liver disease such as hepatitis C, three different types of impact emerge.

The first impact is the clinical consequences of HCV infection. The clinical impacts of HCV can further be divided into hepatic manifestations like cirrhosis and liver cancer and extrahepatic manifestations of HCV infection such as cryoglobulinemia, chronic fatigue and diabetes. Both the hepatic and extrahepatic complications of HCV infection can lead to excess mortality and ultimately impact patient’s survival. In this context, clinical outcomes of HCV can be surrogates for survival.

The second type of impact of HCV infection is captured by patient reported outcomes, or PROs. PROs are reported directly by the patient without any changes or modifications by the physician or caregiver. PRO is an umbrella term that includes everything from health-related quality of life (HRQoL), functional status and even stigma associated with HCV infection. PROs are surrogates for the patients’ experience with their disease and its treatment. If you improve PRO scores, you are improving the patient experience with their disease.

The third type of impact of HCV infection is related to its economic consequences, which can include direct, indirect or intangible costs of the disease and its treatment. In this context, the economic impact represents a surrogate for resource utilization.

When you consider these three impacts of HCV infection together, you get a complete and comprehensive picture of HCV infection and its impact on the individual patient and the society.

Measuring PROs

Although the clinical outcomes of HCV have been relatively well studied, there has been less emphasis regarding the PRO aspects of HCV infection.

PROs are not something that can be measured directly by a clinician without patient input. To estimate PROs accurately, it is necessary to use PRO questionnaires, surveys or instruments to understand the patient’s perspective. These tools must be well developed and fully validated. As an example, HRQoL surveys can be divided into three kinds. First, there are generic surveys that can be used for any disease such as Short Form-36. The second type is disease-specific questionnaires. This includes the Chronic Liver Disease Questionnaire – HCV (CLDQ-HCV), which we use in our HCV research. The third type is health status assessment performed using utility-based measures. In this context, investigators use different methodologies to estimate patients’ preference for a state of health. An example of this is to use direct methods such as time-trade-off or indirect measures such as health utility index (HUI) or SF-6D.

By applying these instruments in studies of patients with HCV infection, it has been well documented that these patients’ HRQoL is quite impaired and that this impairment worsens with more advanced liver disease. In fact, fatigue related to HCV infection can negatively impact HRQoL as well as work productivity of these patients. Historically, treatment with interferon-based regimens further impaired PROs. In contrast, achieving sustained virologic response led to the improvement of HRQoL and other PROs.

PROs in the DAA Era

Data are also emerging about direct-acting antiviral therapies and PROs.

As noted previously, we have shown if you use peginterferon and ribavirin in the treatment regimens, the side effects will lead to a rapid decline in patient PRO scores. Degree of on-treatment PRO impairment was greatly improved with the new generation of drugs that are free of interferon but include ribavirin. This is true for subjects who are monoinfected with HCV or coinfected with HIV and HCV as well as those with early liver disease and advanced liver disease. It is important to note that by removing both interferon and ribavirin, subjects experienced on-treatment improvement of their PROs. Furthermore, PRO scores significantly improved after achieving SVR.

In one study, we surveyed 335 patients with HIV and HCV who were treated with sofosbuvir and ledipasvir (SOF/LDV; Harvoni, Gilead Sciences) and 223 patients treated with sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin. In this study, on-treatment assessment of PROs showed that patients in the SOF/LDV group improved regarding the activity/energy component of the CLDQ-HCV. These patients also showed improvement, while on treatment, in the fatigue component of FACIT-F, and in the physical component of SF-36. An average improvement in PROs of 5.1% was reported among patients who reached SVR12 with SOF/LDV.

We also performed a post-hoc analysis of the ASTRAL-1, -2, -3 and -4 phase 3 trials, which included patients with different HCV genotypes treated with sofosbuvir and velpatasvir (SOF/VEL; Epclusa, Gilead Sciences) with or without ribavirin for 12 or 24 weeks. Treatment with these regimens (especially ribavirin-free regimens) was associated with improvement by as much as 17% by 24 weeks after treatment, regardless of cirrhosis status. In a multivariable analysis, patients with compensated cirrhosis experienced an increase from baseline in PROs as much as 5% after treatment with the regimen. With decompensated cirrhosis, patients reported an increase as high as 9% from baseline in the multivariable model.

In another study, we retrospectively looked at PRO data from phase 3 trials of sofosbuvir with and without interferon or ribavirin. There were 3,425 patients, with 546 receiving interferon plus ribavirin and sofosbuvir, 1,721 who received sofosbuvir plus ribavirin and 1,158 who received SOF/LDV without interferon or ribavirin. On-treatment assessment of PROs indicated a decline of 23.6% in the interferon group and of 7% in the sofosbuvir and ribavirin group compared with an increase of 11.6% in the interferon/ribavirin-free group. This trend held through multivariable analysis.

In another analysis from the ASTRAL-1 study, we looked at 624 patients who received active therapy with SOF/VEL. By treatment week 4, patients treated with active drug, as opposed to placebo, improved in terms of general health, emotional well-being and all domains of the CLDQ-HCV. At the end of treatment, and then at 12 and 24 weeks after treatment, the average improvement in PRO was 3.7, compared to –2.6 in the placebo arm. This placebo-controlled trial shows that patients treated with SOF/VEL experience significant improvement of their PROs during treatment and after achieving SVR. In fact, this is the first study that indicated that improvement of PROs is related to viral eradication and not related to “euphoria” of treatment. It is important to note that there have not been many studies, like this one, comparing novel DAA drugs with placebo. When we compare patients’ PROs before treatment to PROs after cure with an active agent, we see improved HRQoL. The DAAs not only eradicate the virus but also lack previously seen side effects. Those patients who receive placebo do not see the same improvement in HRQoL.

This is not just a perception issue, which is something we have now proven with PROs. It is also worth noting that patients who take medications that not only cure their disease but also make them feel better tend to be more adherent. Improving PROs can become self-perpetuating.

The implications of all of this is that we are not only reducing mortality from HCV by curing patients from this virus, we are improving the HRQoL of these patients. Additionally, HCV cure can reduce the future economic burden of HCV by reducing cost of complications of HCV infection and by improving worker productivity. In this context, HCV cure impacts every level of consequences of HCV that I discussed above — clinical, PROs and economic. When patients are cured, they live longer and feel better. They will have less complications of advanced liver disease and their work productivity improves, which could potentially reduce the economic impact of HCV infection. Overall, this helps reduce the cost of caring for these patients and tips the scale for cost–benefit analyses of medications like DAAs.

Disclosure: Younossi reports consulting for AbbVie, Bristol-Myers Squibb, Gilead and Intercept, and serving on advisory committees or review panels for GlaxoSmithKline and Bristol-Myers Squibb.

Zobair M. Younossi

When you look at the consequences of any chronic liver disease such as hepatitis C, three different types of impact emerge.

The first impact is the clinical consequences of HCV infection. The clinical impacts of HCV can further be divided into hepatic manifestations like cirrhosis and liver cancer and extrahepatic manifestations of HCV infection such as cryoglobulinemia, chronic fatigue and diabetes. Both the hepatic and extrahepatic complications of HCV infection can lead to excess mortality and ultimately impact patient’s survival. In this context, clinical outcomes of HCV can be surrogates for survival.

The second type of impact of HCV infection is captured by patient reported outcomes, or PROs. PROs are reported directly by the patient without any changes or modifications by the physician or caregiver. PRO is an umbrella term that includes everything from health-related quality of life (HRQoL), functional status and even stigma associated with HCV infection. PROs are surrogates for the patients’ experience with their disease and its treatment. If you improve PRO scores, you are improving the patient experience with their disease.

The third type of impact of HCV infection is related to its economic consequences, which can include direct, indirect or intangible costs of the disease and its treatment. In this context, the economic impact represents a surrogate for resource utilization.

When you consider these three impacts of HCV infection together, you get a complete and comprehensive picture of HCV infection and its impact on the individual patient and the society.

Measuring PROs

Although the clinical outcomes of HCV have been relatively well studied, there has been less emphasis regarding the PRO aspects of HCV infection.

PROs are not something that can be measured directly by a clinician without patient input. To estimate PROs accurately, it is necessary to use PRO questionnaires, surveys or instruments to understand the patient’s perspective. These tools must be well developed and fully validated. As an example, HRQoL surveys can be divided into three kinds. First, there are generic surveys that can be used for any disease such as Short Form-36. The second type is disease-specific questionnaires. This includes the Chronic Liver Disease Questionnaire – HCV (CLDQ-HCV), which we use in our HCV research. The third type is health status assessment performed using utility-based measures. In this context, investigators use different methodologies to estimate patients’ preference for a state of health. An example of this is to use direct methods such as time-trade-off or indirect measures such as health utility index (HUI) or SF-6D.

By applying these instruments in studies of patients with HCV infection, it has been well documented that these patients’ HRQoL is quite impaired and that this impairment worsens with more advanced liver disease. In fact, fatigue related to HCV infection can negatively impact HRQoL as well as work productivity of these patients. Historically, treatment with interferon-based regimens further impaired PROs. In contrast, achieving sustained virologic response led to the improvement of HRQoL and other PROs.

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PROs in the DAA Era

Data are also emerging about direct-acting antiviral therapies and PROs.

As noted previously, we have shown if you use peginterferon and ribavirin in the treatment regimens, the side effects will lead to a rapid decline in patient PRO scores. Degree of on-treatment PRO impairment was greatly improved with the new generation of drugs that are free of interferon but include ribavirin. This is true for subjects who are monoinfected with HCV or coinfected with HIV and HCV as well as those with early liver disease and advanced liver disease. It is important to note that by removing both interferon and ribavirin, subjects experienced on-treatment improvement of their PROs. Furthermore, PRO scores significantly improved after achieving SVR.

In one study, we surveyed 335 patients with HIV and HCV who were treated with sofosbuvir and ledipasvir (SOF/LDV; Harvoni, Gilead Sciences) and 223 patients treated with sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin. In this study, on-treatment assessment of PROs showed that patients in the SOF/LDV group improved regarding the activity/energy component of the CLDQ-HCV. These patients also showed improvement, while on treatment, in the fatigue component of FACIT-F, and in the physical component of SF-36. An average improvement in PROs of 5.1% was reported among patients who reached SVR12 with SOF/LDV.

We also performed a post-hoc analysis of the ASTRAL-1, -2, -3 and -4 phase 3 trials, which included patients with different HCV genotypes treated with sofosbuvir and velpatasvir (SOF/VEL; Epclusa, Gilead Sciences) with or without ribavirin for 12 or 24 weeks. Treatment with these regimens (especially ribavirin-free regimens) was associated with improvement by as much as 17% by 24 weeks after treatment, regardless of cirrhosis status. In a multivariable analysis, patients with compensated cirrhosis experienced an increase from baseline in PROs as much as 5% after treatment with the regimen. With decompensated cirrhosis, patients reported an increase as high as 9% from baseline in the multivariable model.

In another study, we retrospectively looked at PRO data from phase 3 trials of sofosbuvir with and without interferon or ribavirin. There were 3,425 patients, with 546 receiving interferon plus ribavirin and sofosbuvir, 1,721 who received sofosbuvir plus ribavirin and 1,158 who received SOF/LDV without interferon or ribavirin. On-treatment assessment of PROs indicated a decline of 23.6% in the interferon group and of 7% in the sofosbuvir and ribavirin group compared with an increase of 11.6% in the interferon/ribavirin-free group. This trend held through multivariable analysis.

In another analysis from the ASTRAL-1 study, we looked at 624 patients who received active therapy with SOF/VEL. By treatment week 4, patients treated with active drug, as opposed to placebo, improved in terms of general health, emotional well-being and all domains of the CLDQ-HCV. At the end of treatment, and then at 12 and 24 weeks after treatment, the average improvement in PRO was 3.7, compared to –2.6 in the placebo arm. This placebo-controlled trial shows that patients treated with SOF/VEL experience significant improvement of their PROs during treatment and after achieving SVR. In fact, this is the first study that indicated that improvement of PROs is related to viral eradication and not related to “euphoria” of treatment. It is important to note that there have not been many studies, like this one, comparing novel DAA drugs with placebo. When we compare patients’ PROs before treatment to PROs after cure with an active agent, we see improved HRQoL. The DAAs not only eradicate the virus but also lack previously seen side effects. Those patients who receive placebo do not see the same improvement in HRQoL.

This is not just a perception issue, which is something we have now proven with PROs. It is also worth noting that patients who take medications that not only cure their disease but also make them feel better tend to be more adherent. Improving PROs can become self-perpetuating.

The implications of all of this is that we are not only reducing mortality from HCV by curing patients from this virus, we are improving the HRQoL of these patients. Additionally, HCV cure can reduce the future economic burden of HCV by reducing cost of complications of HCV infection and by improving worker productivity. In this context, HCV cure impacts every level of consequences of HCV that I discussed above — clinical, PROs and economic. When patients are cured, they live longer and feel better. They will have less complications of advanced liver disease and their work productivity improves, which could potentially reduce the economic impact of HCV infection. Overall, this helps reduce the cost of caring for these patients and tips the scale for cost–benefit analyses of medications like DAAs.

Disclosure: Younossi reports consulting for AbbVie, Bristol-Myers Squibb, Gilead and Intercept, and serving on advisory committees or review panels for GlaxoSmithKline and Bristol-Myers Squibb.