Protease inhibitor therapy for hepatitis C virus-infection

ABSTRACT

Introduction: The hepatitis C virus (HCV) has affected an estimated of 80 million individuals worldwide and is a strain on public health. Around 25–30% of patients in Europe and the US who are infected with HIV are coinfected with HCV. Prior to 2013, treatment modalities containing an NS3/4A protease inhibitor in combination with pegylated interferon and ribavirin improved sustained virological response (SVR) rates. However, rates of severe side effects were high. Nowadays, oral direct-acting antiviral (DAA) combination therapy offers excellent treatment efficacy, safety and tolerability.

Areas covered: This review focuses on the current literature and clinical evidence and their impact regarding NS3/4A protease inhibitors. The pitfalls encountered in treating HIV- and HBV-coinfected patients are also discussed.

Expert opinion: In the era of DAA treatment, third-generation pan-genotypic NS3/4A protease inhibitors (mainly glecaprevir and voxilaprevir) show high antiviral activity and a genetic resistance barrier with cure rates of over 95% when combined with an NS5A inhibitor, irrespective of baseline resistance associated variants (RASs) being present. These new key components of DAA combination therapy are impressive options to eradicate HCV in the so-called difficult-to-treat population (e.g. compensated cirrhosis, end-stage renal disease and patients who failed previous DAA treatment).

KEYWORDS:

• Direct-acting antiviral
• hepatitis C
• HIV
• NS3/4A protease inhibitor

Article highlights

• The novel third generation NS3/4A protease inhibitors (namely GLE and VOX) in combination with other DAAs can be a substantial step in the eradication of HCV in individuals from the so-called difficult-to-treat population (e.g. compensated cirrhosis, end-stage renal disease and patients who failed previous DAA treatment).

• The new DAA combinations with a pan-genotypic third generation NS3/4A protease inhibitor represent an opportunity in low and middle-income countries to treat HCV infected patients without prior genotype testing.

• The use of protease inhibitors can be limited due to significant higher drug levels in patients with Child-Pugh B and Child-Pugh C decompensated cirrhosis.

• Recently presented data confirms that HIV-coinfected patients should be treated and retreated the same as patients without HIV infection. Nonetheless, there is one important exception: In the setting of acute HCV infection SVR rates were significantly lower in patients with HIV-coinfection.

• HBV reactivation can occur under/after DAA treatment; therefore, it is important to remember that HBV screening is mandatory for all HCV patients before initiating treatment with DAAs. Especially patients with anti-HBc should be monitored more closely during DAA treatment and post-treatment follow-up. The updated EASL guideline recommends nucleos(t)ide analogue prophylaxis for HBsAg-positive patients undergoing DAA therapy until week 12 post DAA treatment.

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Declaration of interest

P de Leuw has received consultancy, speaker’s bureau and travel support fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hexal AG, Merck Sharp and Dohme, and Janssen-Cilag. C Stephan is the recipient of grants and research support from Merck Sharp and Dohme. C Stephan also received consultancy fees from AbbVie, Merck Sharp and Dohme, ViiV Healthcare, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Astellas, and STADA Arzneimittel AG. C Stephan is also the recipient of travel grants within the last two years from Janssen Pharmaceuticals, Gilead Sciences and Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript was not funded.