"Direct-acting antivirals for chronic hepatitis C"

Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, Poropat G, Djurisic S, Weiss KH, Bjelakovic M, Bjelakovic G, Klingenberg SL, Liu JP, Nikolova D, Koretz RL, Gluud C.

Artwork by Dr David Goodsell who does scientifically precise watercolour paintings of the cells and microbes.

This is a systematic review of the Cochrane paper of the above title. The recommendations are authored by John R. Litaker.

Introduction

Hepatitis C is an infection of the liver that can manifest in both acute and chronic forms.  It is caused by the Hepatitis C Virus (HCV), a Flaviviridae virus, that is estimated to infect about 150 – 185 million people worldwide [1,2]. The HCV burden of care can manifest as hepatocarcinoma, viral hepatitis, liver failure, and even death[3] and HCV-related mortality is now greater than HIV-related mortality in some countries [4].

In Australia, the prevalence of HCV infection is approximately 0.9% of the total population,[3] which is consistent with HCV prevalence estimates in the United States (1.33 - 1.6%) [5,6] and the United Kingdom (0.67%) [7]. However, many of these studies do not account for HCV infection among incarcerated persons, thus underestimating overall HCV prevalence [8]. The distribution of HCV infection in a given population is based on a variety of factors including age, co-infection with other diseases (e.g., HIV and Hepatitis B), practices that put a person at high risk (e.g., men who have sex with men) and immigration patterns of people from countries with high rates of HCV infection [9]. New incidence of HCV infection is now largely due to needle sharing among injection drug users [2].

In the last two decades, there has been considerable progress in the ability to identify and treat HCV infection. Once designated the non-A and non-B hepatitis virus, HCV is now recognized as a scientifically distinct virus.  As such, there are laboratory assays available to determine if a person is infected with HCV and there are direct-acting antivirals (DAA) available to reduce viral load, show sustained virologic response, and to prevent transmission from an infected person to a non-infected person.

In 2017, a Cochrane review assessed DAA chemotherapy for patients suffering from chronic HCV infection [10]. This review was timely as there is a strong mandate by health authorities worldwide to diagnose and treat individuals with chronic HCV infection [2,9,11,12]. This mandate has implications for both physicians and patients alike. For physicians, this means there is a need to determine if clinical trial efficacy will translate into clinical practice effectiveness. For patients, there is a need to assess the willingness and ability to undergo the cascade of care required to successfully complete treatment. This summary document addresses the findings of the Cochrane review, discusses the approach that physicians and patients may wish to consider in preparation to undertake HCV treatment, and provides recommendations to physicians who are considering providing HCV-related DAA chemotherapy to patients.

Assessment of the Cochrane Review

The objective of the Cochrane review was to assess results of clinical trials for HCV DAA chemotherapy for a set of primary and secondary outcomes to determine if DAA chemotherapy is beneficial or harmful to patients [10]. Primary outcomes included HCV-related morbidity, serious adverse events associated with medications, and the status of health-related quality of life. Secondary outcomes included, but were not limited to, all-cause mortality and sustained virologic response [10].

The results of the Cochrane review were largely indeterminate, despite an assessment of 118 clinical trials that included a total of 25,232 participants [10]. The authors could not make a determination on the impact of current and future DAAs on HCV morbidity or all-cause mortality as such data was limited or not available. The impact of serious adverse events was also indeterminate because of what the authors deemed to be low quality clinical trial data. Health-related quality of life was addressed in only one trial; therefore, the ability to extrapolate findings more broadly were limited [10].

However, the Cochrane review noted that current and future DAAs show evidence of reducing sustained virologic response from 54.1% to 23.8% in treated versus untreated patients (RR: 0.44; 95% CI 0.37 – 0.52) [10]. Although the authors identified sustained virologic response as a secondary outcome, it is a clinically important indicator of drug efficacy since the purpose of DAAs is to show a sustained virologic response and to make HCV undetectable in blood [13]. This result appears promising as the relative risk reduction is 56% and there is a narrow 95% confidence interval, thus providing strong evidence of a beneficial impact for this key measure.

In terms of the overall findings, the Cochrane review authors noted that “The evidence for our main outcomes of interest come from short-term trials, and [that] we are unable to determine the effect of long-term treatment with DAAs” [10]. While this is a true statement, it does not accurately reflect how clinical trials involving drug chemotherapy interventions take place. That is, a clinical trial for a drug intervention is by nature of limited duration and is designed to assess clinical endpoints related to the drug under investigation. Therefore, it would not be reasonable to expect a clinical trial for a drug intervention to address long-term effects like HCV-related morbidity or all-cause mortality. Rather, the key outcome of interest for a short-term trial should be whether, in this instance, DAA chemotherapy is successful in mounting a sustained virologic response. This outcome was assessed and deemed statistically significant by the Cochrane review.

Implications for Clinical Practice

Based on the primary outcomes identified in the Cochrane review, practising physicians would not likely initiate nor recommend DAA chemotherapy to their HCV infected patients. However, despite indeterminate findings of the Cochrane review, international and national health officials support a sustained strategy to prevent HCV infection, to diagnose HCV infection, and to treat infected individuals [2,9,11,12]. These health officials believe there is a scientific basis for prescribing DAAs and that DAAs are safe and effective in obtaining a sustained virologic response. The Cochrane review supports this view of a positive DAA impact on a sustained virologic response as compared to non-DAA groups.

In the recent past, treatment for HCV was referred to specialty clinics focusing on hepatic diseases or treatment was provided by specially trained general practitioners (GP).  With the availability of well-tolerated oral chemotherapeutic agents to treat HCV and the availability of these medications on the Pharmaceutical Benefits Scheme (PBS), GPs are now able to provide HCV DAA chemotherapy to uncomplicated patients in consultation with specialty physicians [14,15]. However, for GPs to be successful in providing this treatment regimen, they must be knowledgeable of the multifaceted cascade of care required to diagnose, treat, and confirm sustained virologic response 12 weeks post-chemotherapy,14  the details of which are beyond the scope of this paper.

GPs must also be aware of the impact that DAA chemotherapy will have on the patient. For example, pre-treatment assessment includes determining the viral genotype, whether the patient is treatment naïve, the clinical status of hepatic disease, and other clinical assessment items [15]. In addition, the genotype dictates the approved DAA chemotherapy to be provided and there is a need to assess treatment response 12 weeks post-chemotherapy. For clinical practice, this means that physicians, office managers, nurses, and front-line staff must have a thorough understanding of the treatment protocol and implement operational processes to support diagnosis, treatment, and follow-up [14].

Implications for Patient-Centered Care

Patient preferences are a cornerstone of today’s medical practice paradigm. It underpins the concept of patient-centred care in which patients and physicians make collaborative decisions about the patient’s care.  It involves understanding the needs, wants, beliefs, and culture of the patient and it supports a patient’s ability to discuss this information with their physician. For HCV treatment, these discussions are critically important as treatment requires acknowledgement by the patient that they intend to complete chemotherapy once initiated, an understanding that DAA treatment has cost implications on the health budget (with opportunity costs associated with funding for DAA versus other clinically relevant medications), and a shared understanding between physician and patient about barriers to care, some of which are described below.

For example, a recent analysis in the United States indicated that there are distinct demographic and clinical characteristics associated with choosing to obtain HCV treatment and deferral of such treatment. Characteristics that favour treatment include being white (versus non-white; p=0.008)), having cirrhosis of the liver (p=0.005), and having had previous HCV treatment (p=0.06).16  Further analysis indicated that the severity of treatment did not influence the decision to treat or defer.

There are also operational barriers to care. Allison, et al. in the American Board of Preventative Medicine consensus statement in support of HCV treatment noted that barriers to care may include contraindications for treatment, treatment duration, loss to follow-up, and access issues [2].  Options to mitigate barriers include the case management approach successfully used in HIV clinics, directly observed chemotherapy used in tuberculosis clinics, and the use of telemedicine to improve access [2].

Within the Australian context, general practitioners should consider how Aboriginal and Torres Strait Islander persons can benefit from treatment.  It is known that HCV treatment uptake among persons of Aboriginal and Torres Strait Islander descent is lower than among the Australian population at large [14,17]. Barriers to uptake include a reliance on GP services to provide routine care and a lack of access to specialty services [17]. With the availability of oral HCV DAA chemotherapy as part of the PBS and with a clinical approach that supports GP managed treatment, Aboriginal and Torres Strait Islander persons may now have more access to HCV DAA chemotherapy than before [14]. However, as noted above, it is necessary for physicians and patients to have a dialogue about HCV chemotherapy and to have a shared understanding of the approach that best meets the needs of the patient.

Recommendations

HCV infection is a national and international concern. It is one of the most common blood-borne infections in the world, carries a high burden of disease, and has higher patient mortality than HIV-related disease in some countries. Currently, oral DAA chemotherapy is available and is covered under the Australian PBS.  Treatment is safe, effective, and well-tolerated.  As such, general practitioners are encouraged to take a holistic approach to overall HCV care. This includes providing prevention messages to high-risk patients, screening for infection of high-risk patients, and providing treatment to those patients infected with HCV. For those physicians who opt to provide treatment, clinical guidelines are in place to support physician clinical decision making and physicians should diligently use and adhere to these clinical guidelines in order to affect a positive treatment outcome. Physicians should also enter into shared decision making with the patient and embrace a patient-centred approach to provide care that meets the needs, expectations, and beliefs of their HCV infected patients.

Acknowledgement

Thank you to John R. Litaker for writing this post and letting me share this on his behalf.

The Artwork was made by Dr David Goodsell who does scientifically precise watercolour paintings of the cells and microbes.

Published 15th December 2018. Last reviewed 30th December 2021.

Reference

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