Hepatitis C virus treatment: is it possible to cure all hepatitis C virus patients?
Muir A. and Naggie S.
Clinical Gastroenterology and Hepatology 2015;13:2166–2172

A number of DAA medications have been approved and are now available. In combination, they offer interferon-free, well-tolerated regimens with sustained virologic response (SVR) rates greater than 90% in clinical trials. As we hear the calls for global eradication, there remain many challenges in the pursuit of “cure for all.”

Although we can cure the majority of patients with genotypes 1, 2, and 4 in 12 weeks, many genotype 1 patients and all genotype 3 patients require 24 weeks of treatment.

No DAA agents have been approved for patients with end-stage renal disease, and the continued requirement of ribavirin for most regimens in various patient subgroups is especially challenging for patients with chronic kidney disease because of the risk of severe anemia. In fact, we have yet to establish the appropriate dose of ribavirin when used as a component of DAA combination therapies. A laundry list of patients who have been excluded from clinical trials to HIV patients on complex antiretroviral regimens, immunocompromised hosts, patients with hepatitis B virus coinfection, children, and the elderly, who represent an increasingly recognized and identified subgroup of patients living with HCV.

Viral resistance has a role to play in retreatment success. Is there a price to pay for DAA treatment failure, other than the cost of the failed regimen itself ? Early reports of baseline resistance associated variants (RAVs) suggest that the answer may be yes at a minimum in some of our more difficult-to-treat patient subgroups.

Baseline and treatment emergent variants (TEVs) have been observed with the NS3/4A protease inhibitors and the NS5A inhibitors. The degree of the impact of RAVs on treatment outcomes with these potent antiviral regimens remains unknown, but the development of resistance at the time of treatment failure is almost universal. NS5A RAVs maintain remarkable fitness and are likely to be more problematic in the setting of retreatment.

There are now several patient subgroups where baseline NS5A RAVs may lower SVR including genotype 3 patients with cirrhosis treated with daclatasvir (NS5A inhibitor) and sofosbuvir and treatment-experienced patients receiving ledipasvir and sofosbuvir.

Poor adherence and the presence of RAVs have been reported most often as reasons for treatment failure in the clinical trials.

Viral resistance testing is available commercially but is not currently recommended in routine clinical practice and yet may become important in the identification of the most effective regimens for patients with prior DAA treatment failure. Efforts are also underway to evaluate potent regimens with multiple agents for longer durations for this group of patients.

There are obstacles that will impact broad scale-up of treatment across the globe. Current regimens vary according to the genotypes and subtypes, and some regimens still require ribavirin, leading to anemia with requisite monitoring. Treatment durations currently range from 8 to 24 weeks depending on absence or presence of cirrhosis, treatment history, and baseline HCV RNA. This results in a complex treatment paradigm.

One strategy of current research programs is to develop well-tolerated pan-genotypic regimens of 4–8 weeks duration, ideally once-weekly, which cure all patient subgroups. Although shorter duration will be important to achieve broad treatment of HCV throughout the world, this cannot with a cost in efficacy.

A recent cost-effectiveness analysis demonstrated that treatment of all eligible HCV-infected Americans with sofosbuvir-based regimens was cost-effective compared with the previous standard of care. The costs of these medicines are prohibitive to the low- and middle-income countries. Voluntary licenses to generic companies will be needed for all DAAs including those in combination before we can offer universal access to HCV cure.

For the medications to achieve their potential, we need more effective programs to identify persons living with HCV infection. Because of the asymptomatic nature of chronic infection, screening programs are required to uncover the burden of this “silent infection.” Efforts will be needed to identify strategies for screening in other settings and particularly in the community to engage these high-risk populations.

Approaches include screening of patients presenting to the emergency department regardless of their presenting complaint, and outreach initiatives to persons who inject drugs, immigrant communities from high prevalence countries, and prison populations.

With no HCV vaccine expected in the near future, current efforts are evaluating whether antiviral treatment regimens can play a role in impacting the prevalence in a population.

In 2014, the World Health Organization released guidelines to provide the outline for national HCV programs for prevention, diagnosis, and treatment. Leadership and commitment at the highest levels of government will be required for these programs to succeed. Persons who inject drugs have high prevalence of HCV infection, and screening and treatment in this population would identify a large number of patients efficiently and provide an opportunity to lower prevalence and possibly transmission. In countries with established infrastructure to care for patients with HIV, the addition of HCV care will be more easily accomplished than in settings where the infrastructure must be created. To achieve widespread HCV care in all parts of the world, clinicians from a variety of backgrounds will need to be engaged and trained.

Dr Susanna Naggie's Perspective

«  The currently available direct acting antivirals (DAA) provide opportunity for patients with access to these life saving medications. Yet, the hope created by these medications is over-shadowed by the challenges that remain ahead for those who believe that access to HCV cure is a right for all of those infected. The majority of people with chronic HCV infection have not benefited from the new DAA. The reasons for these disparities are many and include the cost of the medications, lack of access to healthcare, and lack of knowledge that they harbor the infection. The potential human impact of DAA is enormous but the barriers to realizing the potential are equally vast. As the first fixed dose combination, pangenotypic regimen awaits regulatory approval we must begin to address the issues of access to care and cure for all  »