Successful treatment of resistant HCV in a patient with Child-Pugh B cirrhosis using sofosbuvir and glecaprevir/pibrentasvir

Abstract

Treatments for hepatitis C are now well tolerated with very high rates of sustained virological response and almost all patients have a suitable and effective treatment option. However, treatment options remain limited for a minority of patients and are limited for patients with Child-Pugh B or C cirrhosis due to the risk of decompensation with protease inhibitors. We present a case of successful treatment with glecaprevir/pibrentasvir (Maviret) and sofosbuvir in a patient with Child-Pugh B cirrhosis and resistant virus who had failed three previous attempts of treatment including two courses of direct acting antiviral agents and in whom liver transplantation was deemed unsuitable. We propose that the balance of risks favours a trial of treatment with protease inhibitors in some circumstances in patients with Child-Pugh B cirrhosis where no other suitable alternatives including treatment post liver transplantation are available/appropriate.

Background

The treatment and ongoing management of hepatitis C is becoming an increasing focus for public health departments globally as countries strive to meet the WHO elimination targets. Treatments are now well tolerated with very high rates of sustained virological response and almost all patients have a suitable and effective treatment option.

However, treatment options remain limited for a minority of patients and are limited for patients with Child-Pugh B or C cirrhosis due to the risk of decompensation with protease inhibitors. We present a case of successful treatment with glecaprevir/pibrentasvir (Maviret) and sofosbuvir in a patient with Child-Pugh B cirrhosis and resistant virus who had failed three previous attempts of treatment including two treatments with direct acting antiviral agents and in whom liver transplantation was deemed unsuitable.

Case presentation

A 59-year-old retired chef was diagnosed with chronic hepatitis C, genotype 3a in 2012. He was treated with pegylated interferon and ribavirin. Treatment was terminated after 3 months before he developed a viral response due to intolerance of ribavirin.

He was first seen in our clinic in 2013. He had symptoms of fatigue, joint ache, poor appetite, low mood and occasional abdominal discomfort. He had been attacked in 1970, aged 17, and thinks he could have acquired the hepatitis from a blood transfusion given at that time. He was taking dihydrocodeine PRN and reported an anaphylactic allergy to penicillin (anaphylactic). He was living with his wife, smoked 1–2 cigarettes per day and did not drink alcohol. He had a history of COPD. On examination, he had multiple spider naevi and palmar erythema. Abdominal examination showed mild hepatosplenomegaly. FibroScan Score was 10.1 kPa. Blood tests from that clinic were consistent with Child-Pugh A cirrhosis, score of 6—albumin 29 g/L (2), bilirubin 17 µmol/L (1), international normalised ratio (INR) normal (1), no evidence of ascites (1) and no encephalopathy (1). His platelet count was 38×10⁹/L.

In 2014, he was treated on the Wales compassionate access programme with a combination of sofosbuvir and daclatasvir for 12 weeks. Addition of ribavirin was discussed but not given at that time because of the history of previous intolerance and because the patient did not want to take it. Baseline viral load was 26 740 323 IU/mL. His hepatitis C viral load was 54 IU/mL at the end of 4 weeks of treatment, 16 IU/mL after 8 weeks and undetectable at the end of treatment. Relapse was detected 8 weeks after treatment was stopped.

In 2015, he was started on a 24-week course of sofosbuvir and daclatasvir and ribavirin. He was unable to tolerate the ribavirin. He experienced severe nausea and constant retching, which was not controlled by metoclopramide and ribavirin was stopped. His baseline viral load was in excess of 1 195 000 IU/mL. Viral load was 55 IU/mL at the end of week 4, <12 IU/mL at the end of week 13, undetectable at the end of treatment and 4, 8 and 12 weeks post treatment. Relapse was detected 24 weeks post treatment. There were no risk factors for reinfection.

Genotyping demonstrated genotype 3a. Resistance testing revealed the presence of Y93H mutation, an NS5A resistance substitution associated with resistance to daclatasvir and velpatasvir.

Screening endoscopy in November 2016 demonstrated the presence of a small varix. Beta blocker therapy was not prescribed at that stage because of asthma.

In June 2017, he was admitted following a variceal bleed. At this stage, his Child-Pugh B Score was 9 (albumin 32 g/L (2), bilirubin 24 µmol/L (1), INR 1.5 (1), ascites moderate (3) and encephalopathy mild (2)) and his Model for End Stage Liver Disease (MELD) Score 12 (creatinine 63 µmol/L, sodium 139 µmol/L, bilirubin 24 µmol/L, INR 1.5, no dialysis). He was treated medically initially with blood replacement, terlipressin and antibiotics. The first oesophago-gastroduodenoscopy did not reveal evidence of recent bleeding. He was stable for the first week but on stopping intravenous treatment he had a further bleed prompting a second oesophago-gastroduodenoscopy and variceal banding. He was started on carvedilol. In view of ascites, he was also started on spironolactone. He was referred for liver transplant assessment but was declined. However, this option was not recommended by the surgical team due to his ongoing infection with hepatitis C, which at this point was deemed to be resistant to treatment.

A decision was made to offer treatment with sofosbuvir and glecaprevir/pibrentasvir for 16 weeks on the basis that he was not deemed suitable for a liver transplant and the risks of not treating probably outweighed the risk of treating. The risks and benefits of treatment including the risk of decompensation through use of a protease inhibitor were discussed with the patient and after due consideration, treatment was started in November 2017. Baseline viral load was 202 196 IU/mL. Viral load was 50 IU/mL after 1 week, 17 IU /mL after 2 weeks, <12 IU/mL after 4 weeks and 6 weeks and undetectable from 8 weeks onwards. He has now achieved sustained viral response (SVR) 24 and has maintained a virological response to date.

He reported no significant side effects from this treatment. At the end of treatment, he reported that he had 16 doses of sofosbuvir remaining. The reason for this is unclear but likely represents missed doses.

MELD Score was 8 after 6 months of treatment (creatinine 62 µmol/L, albumin 34 g/L, sodium 139 µmol/L, INR 1.1, no dialysis), Child-Pugh B Score 8 (albumin 34 g/L (2), bilirubin 21 µmol/L (1), INR 1.1 (1), ascites mild or moderately controlled (2), encephalopathy mild (2)) B. Platelet count was 32×10⁹/L.

Treatment

2014—Sofosbuvir and daclatasvir for 12 weeks—relapse.

2015—Sofosbuvir and daclatasvir for 24 weeks (intolerant of ribavirin)—relapse.

2017—Sofosbuvir and glecaprevir/pibrentasvir for 16 weeks—SVR.

Outcome and follow-up

Completion of treatment with minimal side effects. Sustained virological response at 6 months with improvement in status as measured by a subjective improvement in cognition and improved MELD Score from 12 pre treatment to 8 at 6 months post treatment.

Discussion

Eradication of virus in patients with Child-Pugh B decompensated cirrhosis is associated with a significant rate of recompensation, an improvement in liver function/liver parameters and improvement in MELD Score as compared with untreated individuals.^{1 2}

Glecaprevir/pibrentasvir (Maviret) is a highly active, pangenotypic, once daily, directly acting antiviral therapy that achieves a sustained virological response in the vast majority of patients who are treated. It is a fixed-dose combination of an NS3/4A protease inhibitor, glecaprevir, and an NS5A inhibitor, pibrentasvir (NS5A inhibitor). NS3/4A protease is necessary for the proteolytic cleavage of the hepatitis C virus (HCV) encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A and NS5B proteins) and is essential for viral replication. NS5A is essential for viral RNA replication and virion assembly.

It has high activity in patients with G3 virus achieving SVR 12 of 95% in treatment-naïve patients without cirrhosis treated for 8 weeks, 97% in treatment-naïve patients with compensated cirrhosis treated for 12 weeks, 96% in previously treated patients without cirrhosis treated for 16 weeks and 98% of treatment experienced patients with compensated cirrhosis treated for 16 weeks.³

Pibrentasvir is a new NS5a inhibitor with improved ‘pan-genotypic anti-HCV activity compared with all other NS5A inhibitors’.⁴ It is active against some resistant-associated substitutions that confer resistance to other antiviral agents. In particular, it maintains high activity against genotype 3 HCV with Y93H. Pibrentasvir demonstrates little loss in activity against most of the double or triple amino acid substitutions^{5 6} and is said to be ‘active against common resistance-conferring substitutions in HCV genotypes 1–6 that confer resistance and decreased therapeutic response to other NS5A inhibitors, including positions 24, 28, 30, 31, 58, 92 or 93 in NS5A’.⁷

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication.⁸ It is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.⁸ It is combined with other agents for treatment of hepatitis C.

No dose adjustment is required when sofosbuvir is combined with glecaprevir/pibrentasvir but the levels of sofosbuvir are increased. The C_max is increased by 1.66 (1.23, 2.22) and the area under the curve (AUC) by 2.25 (1.86, 2.72).⁸ The levels of the metabolite GS-331007 are also increased, C_min increased by 1.85 (1.67, 2.04).⁸

Sofosbuvir has been combined with glecaprevir/pibrentasvir in a limited number of patients with difficult to treat infection.^{9 10} High rates of SVR 12 have been achieved with this combination in these studies (virological response of 100% in 14 fully evaluable patients⁷ and in all 14 patients with G3 virus.¹⁰

European Association for the Study of the Liver guidance states that glecaprevir/pibrentasvir is contraindicated in patients with Child-Pugh B or C cirrhosis.³ Pharmacokinetic analysis shows that glecaprevir AUC was 100% higher in those with Child-Pugh B cirrhosis and increased to 11-fold in those with severe hepatic impairment (Child-Pugh C).⁷ The summary of product characteristics states that glecaprevir/pibrentasvir is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C).⁷ American Association for the Study of Liver Diseases guidance states that ‘the daily fixed dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) administered as three 100 mg/40 mg fixed-dose combination pills has not been studied in patients with decompensated cirrhosis, and pending additional safety data are not recommended’.¹¹

Some of the concerns relating to use of protease inhibitor therapy have developed as a consequence of use of earlier protease inhibitors in patients with cirrhosis. The early protease inhibitors boceprevir and telaprevir that were used in combination with interferon and ribavirin had high adverse event rates with 12% of patients in one real-world cohort experiencing serious adverse events, including five deaths and decompensation events in 3%. Among patients with a history of decompensation, 33% experienced significant adverse effects, 83% suffered from anaemia and 24% had a decompensation event. In these patients with a history of decompensation, the rate of premature treatment discontinuation was 59%, mostly due to adverse effects, compared with 47% of well-compensated cirrhotic patients.¹²

Recent data reported by the US Food and Drug Administration (FDA) have demonstrated that some patients with compensated cirrhosis treated with paritaprevir/ritonavir/ombitasvir±dasabuvir may develop rapid-onset direct hyperbilirubinemia without alanine aminotransferase (ALT) elevation within 1–4 weeks of starting treatment, which can lead to rapidly progressive liver failure and death.¹¹ Paritaprevir/ritonavir/ombitasvir±dasabuvir is, therefore, contraindicated in all patients with decompensated cirrhosis due to concerns about hepatotoxicity.¹¹ More recently, the FDA have warned patients and healthcare professionals about rare instances of serious liver injury or failure when using glecaprevir/pibrentasvir, elbasvir/grazoprevir or sofosbuvir/velpatasvir/voxilaprevir to treat chronic HCV in patients with moderate-to-severe liver impairment.¹³

Whether the high adverse event rates demonstrated with early protease inhibitor therapy represent a class effect and will be replicated with newer protease inhibitors remains to be fully determined. The relative risk of decompensation in a patient with advanced liver disease also needs to be borne in mind when assessing any events during treatment.

Glecaprevir/pibrentasvir is very well tolerated with fewer side effects compared with previous regimens. The safety assessment of glecaprevir/pibrentasvir in patients with compensated liver disease (with or without cirrhosis) was based on phase 2 and 3 studies, which evaluated approximately 2300 subjects.⁷ Less than 0.1% of subjects treated with glecaprevir/pibrentasvir had serious adverse reactions and the proportion of subjects treated with glecaprevir/pibrentasvir who permanently discontinued treatment due to adverse reactions was 0.1%.⁷ Elevations in total bilirubin of at least 2× upper limit normal were observed in 1.3% of subjects related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism.⁷

In this case report, glecaprevir/pibrentasvir and sofosbuvir have been used safely and effectively in combination to treat a patient with Child-Pugh B cirrhosis who had failed previous treatment and was harbouring the Y93H NS5A resistance associated substitution. The patient was not eligible for liver transplant and had very limited treatment options. Without treatment, his disease was likely to continue to progress.

The patient did not experience any side effects on medication and achieved a sustained virological response despite relapse following previous directly acting antiviral therapies. He has also experienced an improvement in his liver status since treatment.

Where all other treatments have failed and in patients where other options are not appropriate, the use of glecaprevir/pibrentasvir can be a suitable option for patients with Child-Pugh B cirrhosis. The risks associated with therapy must first be explained to the patient but in many cases the risk of not treating the patient is likely to outweigh the risk of treating.

Close follow-up of these patients is recommended. Given that the risks of decompensation we followed, the patient weekly initially and then fortnightly until the end of treatment.

Learning points.

• Use of glecaprevir/pibrentasvir (and other newer generation protease inhibitor medications) may be appropriate in patients with decompensated cirrhosis (Child-Pugh B) following a risk benefit analysis and when alternative options for therapy including treatment post liver transplantation are not appropriate.

• Experience with the use of glecaprevir and voxilaprevir (newer generation protease inhibitor medications) in patients with decompensated cirrhosis (Child-Pugh B) is limited and risks in these settings are largely based on concerns from the effects of earlier protease inhibitor therapies such as paritaprevir.

• Protease inhibitor therapy should not be used in patients with Child-Pugh C cirrhosis as drug exposure is significantly increased relative to patients with normal hepatic function and significant recovery in status post treatment in this group is unlikely.