Newer direct-acting antivirals for hepatitis C virus infection: Perspectives for India

Introduction

Advances in hepatitis C virus (HCV) drug development in the last few years have taken a new turn and the evolution of antiviral therapy for HCV has rapidly progressed from plain interferon (IFN), to pegylated IFN (PEG-IFN) plus ribavirin (RBV), to PEG-IFN-based combinations with direct-acting antivirals (DAAs) and finally to IFN-free combinations of DAAs1. HCV infection can now be cured in almost all patients with these effective, safe and tolerable combinations of oral DAAs. Now even those patients who due to advanced liver disease, psychiatric conditions, anaemia or autoimmune disease were not eligible for treatment by PEG-IFN-based regimens, or those who had treatment failure with previous therapies, now have excellent choice of treatment options2.

In March 2015, sofosbuvir (SOF), the first DAA was launched in India at a compassionate price. This review article provides information on different DAAs and their possible roles in different genotypes and stages of liver disease. Since in India one can currently adopt only those DAAs containing management regimens which include SOF, considering the international23 and Indian recommendations4, an attempt has been made to devise strategies for the treatment of the most prevalent genotypes in our country (genotypes 3 and 1) using SOF.

Burden of the problem

Approximately three per cent of the world's population (170-200 million people) is chronically infected with HCV5, and almost 500,000 people die each year, mostly in lower middle-income countries, from complications secondary to HCV infection6. There are limited data on HCV prevalence from India with only a few population-based studies and blood bank data. It has been estimated that the prevalence of HCV in India is between 0.5 and 1.5 per cent7, but it can be presumed that this is just the tip of iceberg and many more HCV-infected patients remain undiagnosed.

Data from the US also suggest that only about 50 per cent of HCV patients are actually identified and 40 per cent of them receive specialist evaluation and ultimately only about 5-6 per cent are treated successfully8. Data from a tertiary care centre in north India on 777 HCV patients showed that 56 per cent of patients already had cirrhosis and seven per cent had HCC at the time of presentation. Only about 45 per cent were eligible for IFN-based antiviral treatment, and of these, only 24 per cent could receive antivirals and 14 per cent achieved a sustained viral response (SVR), which is considered as equivalent to cure. Hence, a large majority of HCV patients were left deprived of a cure to HCV infection9. Since HCV infection remains asymptomatic till the development of decompensated cirrhosis, an early diagnosis at this asymptomatic stage is required for timely intervention and to prevent progression to advanced liver disease and death.

Evolution of hepatitis c virus (HCV) treatment

In the last 20-25 yr, the treatment of HCV has emerged from IFN-based therapies with or without RBV, to PEG-IFN plus RBV combination, which was better tolerated by patients10. IFNs instead of targeting the HCV virus activate the immune mechanisms, which clears the virus. This activation of immune system by IFNs also leads to multiple unfavourable side effects leading to poor patient compliance to therapy. Thus, the goal of HCV researchers was to find shorter duration and IFN-free, orally administered drug combinations with minimum toxicity.

HCV is a small, enveloped, single-stranded, positive-sense RNA virus. The size of HCV genome is 9.6 kb with only one long open reading frame (ORF). This ORF encodes a polyprotein of 3000 amino acids or more, which undergoes a complex series of co- and post-translational cleavages, mediated by both host and viral proteinases to yield the individual HCV proteins which are required for replication11. The N-terminal portion of the genome codes for the core and structural proteins (C, p7, E1 and E2) while the nonstructural proteins (NS2-NS5) are coded by the remaining genomes. The newer DAAs act on these HCV-encoded proteins that are required for viral replication. Protease inhibitors such as boceprevir and telaprevir were the first-generation DAAs, which targeted the NS3/4A serine protease responsible for cleaving the HCV polyprotein at four sites10. Both these drugs were not tested in Indian population.

Within a couple of years, many newer DAAs were introduced and licensed in the West and many other countries and are believed to be the ‘game changers’ in HCV management. With the introduction of DAAs, there has been a remarkable improvement in SVR rates in spite of shorter duration of treatment, and with better tolerability in comparison to PEG-IFN- and RBV-based therapies used till now10.

The most prevalent HCV genotype in India is genotype 3, and the standard therapy for this genotype till now had been a combination of PEG-IFN and RBV for 24 wk, with an SVR rate of 70 per cent or more7. The SVR rate for those infected with genotype 1 (the second most common HCV genotype in India) was 40-60 per cent, with a treatment duration of 48 wk121314. Traditionally, HCV-genotypes 2 and 3 were considered to be easy to treat and 1 and 4 were considered to be difficult to treat with conventional PEG-IFN–RBV therapy12. With the advent of DAAs, genotype 1 has switched its position with genotype 3 to become the new easy-to-treat genotype. Most of these newer DAAs have shown excellent results with genotypes 1 and 4, in the initial trials with or without PEG-IFN. Combinations of various DAAs without PEG-IFN may also enhance opportunities for intervention even in the settings of advanced cirrhosis.

Newer guidelines have been published by various liver societies such as European Association for the Study of Liver (EASL)2 and American Association for the Study of Liver Diseases3 in 2014-2015 for HCV management and have included DAAs as the main therapeutic option for HCV. The guidelines have approved the combination of DAAs and IFN-free regimens. American and European regulatory authorities (FDA and EMA) have approved the following second-generation DAAs to be used in clinical practice: (i) Simeprevir - approved for genotypes 1 and 4; (ii) Combination pill containing SOF and ledipasvir - approved for genotypes 1, 4, 5 and 6; (iii) Combination pill containing ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets - approved for genotype 1; (iv) Daclatasvir - approved for all genotypes; and (v) SOF - approved for all genotypes.

Since in India only SOF is available, the Indian guidelines published recently4 have incorporated only SOF-containing regimens.

Results of DAA-based regimens

The results of the DAA-based regimens are shown in (Figure).

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Figure

Sustained viral response (SVR) rates with various regimens in genotypes 1 and 3. PEG, Peg-interferon; RBV, Ribavirin; SIM, Simeprevir; SOF, Sofosbuvir; OMB, Ombitasvir; PARIT, Paritaprevir; RITONA, Ritonavir; DASA, Dasabuvir; DACLAT, Daclatasvir; LEDI, Ledipasvir.

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Compensated and decompensated cirrhosis

In patients with cirrhosis or advanced fibrosis, PEG-IFN showed increased incidence of side effects and much lower SVR rates as compared to patients without advanced fibrosis or cirrhosis12. The ION-1 (treatment naïve) and ION 2 (treatment experienced) trials were phase III studies which assessed the efficacy of SOF and ledipasvir for 12 or 24 wk with and without RBV in HCV genotype 1 patients22. Among the total study population, 16 per cent of patients in the ION-1 study and 20 per cent in the ION-2 study had cirrhosis. The ION-1 study results demonstrated that SVR12 rates among treatment-naïve patients with liver cirrhosis in any of the different treatment arms (94-100%) were comparable to patients without cirrhosis (97-99%), and there was no significant difference. Even in ION-2 study, cirrhotic patients when treated for 12 wk with ledipasvir plus SOF with and without RBV achieved an SVR12 of 82 and 86 per cent, respectively. If the duration of treatment was extended for 24 wk, the SVR12 rates achieved were 99 per cent in both the RBV-containing and RBV-free groups.

The Cosmos study32 assessed the effectiveness of SOF and simepravir with and without RBV. In this study in the subgroup of treatment-naïve or treatment-experienced patients with F3-F4 fibrosis, the SVR rates achieved were 85 per cent in the 12 wk arm and 100 per cent in the 24 wk arms, without any significant difference achieved by adding additional RBV. Turquoise-II study33 included only cirrhotic patients (Child class A) and treated them with three new antiviral agents and RBV. This resulted in high rates of SVR in both treatment-naïve and treatment-experienced patients. SVR12 rate achieved after 12 wk of therapy was 92 per cent comparable to 96 per cent after 24 wk of therapy. Thus, these studies have indicated that oral, IFN-free regimens are effective in patients with HCV genotype 1 cirrhosis, and thus one can achieve high SVR rates in these difficult HCV patients and can ultimately cause disease regression34.

With HCV genotype 3 cirrhosis, results are not as encouraging and lag much behind that of genotype 1. Extended therapies for 24 wk with SOF/RBV29 or adding PEG-IFN to SOF/RBV regimen30 can improve outcomes to a certain extent. Many HCV patients present to healthcare system only after decompensation. The real challenge of DAAs now would be to treat these decompensated cirrhotic patients. The first available data showed a SVR4 rate of 89 per cent in 20 patients with HCV genotype 1 decompensated cirrhosis with Child B status who received ledipasvir plus SOF for 12 wk35. All patients in this study achieved a 100 per cent end-of-treatment-response.

A multicentre randomized controlled study36 in decompensated cirrhotic HCV genotypes 1 and 4 patients (The Solar-2 study) included 104 patients with Child-Turcotte-Pugh (CTP) class B cirrhosis or CTP class C who were treatment naive or treatment experienced. They were randomly assigned to receive daily combination of ledipasvir (90 mg) and SOF (400 mg) and RBV (initial dose of 600 mg, increased as tolerated) for 12 or 24 weeks. The SVR12 in the 12 wk treatment course was achieved in 87 per cent of patients and in the 24 wk treatment course was achieved in 89 per cent of patients36. The study also revealed improvement in baseline CTP and Model for End-Stage Liver Disease (MELD) scores in >50 per cent of the treated patients. This study suggested that a 12 wk course of ledipasvir plus SOF and RBV was an appropriate regimen for HCV genotype 1 or 4 patients who had decompensated cirrhosis.

These are preliminary findings and these results need validation including more patients with different genotypes, as patients with cirrhosis are less able to clear or cure infected cells. There is scarcity of data on the efficacy of IFN-free regimens in patients with decompensated cirrhosis, and the key question of improvement at this advanced stage of the disease even after achieving SVR has not been fully addressed.

HCV in end-stage renal disease (ESRD) and renal transplant recipients

HCV infection has a high prevalence rate in patients on haemodialysis and causes an increased risk for liver-related and all-cause mortality. If the patient is a candidate for renal transplantation, then antiviral therapy is indicated for all patients on haemodialysis as HCV-associated liver damage may be accelerated by immunosuppression being given after transplant. RBV usage is problematic in this setting and an individualized RBV dosing of 200 mg/day or 200 mg/every other day or 200 mg thrice weekly after haemodialysis is recommended, and substantial hematopoietic support is mandatory. According to the EASL guidelines2, patients who are on haemodialysis should receive an IFN-free regimen and preferably a RBV-free regimen, for duration of 12 wk in patients without cirrhosis and for 24 wk in patients with cirrhosis. DAAs such as simeprevir, daclatasvir and the combination of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir are cleared by hepatic metabolism and can be safely used in patients with severe renal disease. It is recommended to not use SOF in patients with an eGFR <30 ml/min/1.73 m² or with end-stage renal disease as there is paucity of safety data at this stage of renal disease. Since DAAs that are safe in patients with severe renal disease (simeprevir, daclatasvir, the combinations of paritaprevir, ritonavir, ombitasvir and dasabuvir or grazoprevir and elbasvir) are not available in India, currently, the only treatment option available for these patients is Peg-IFNα as monotherapy or with very low dose of RBV4. IFNα-based therapy cannot be given after renal transplantation as it may lead to graft rejection.

Patients with ESRD and chronic hepatitis C (CH-C) without cirrhosis are counselled to proceed to renal transplantation while still viraemic, with or without prior treatment of HCV infection for 12 wk, in the expectation that therapy with SOF /RBV or other SOF-based regimens can be started after renal functions improve following successful renal transplantation4. However, results with this approach have not yet been reported in any large case series.

HCV-HIV co-infection

HIV co-infection results in early occurrence of advanced liver fibrosis and cirrhosis in patients with HCV. Individuals co-infected with HIV-HCV are at three times greater risk of progression to cirrhosis or decompensated liver disease in comparison to patients who are only infected with HCV alone4. The indications for HCV treatment in co-infected patients are similar to those in patients with HCV monoinfection. With DAA therapy, strong immune system is less important and treatment is less likely to be affected by the CD4 count. However, for IFN-based regimens, in patients with CD4 cell count <350 cells/μl, antiretroviral therapy (ART) should be initiated first, beginning anti-HCV treatment only after improving CD4 cell count to >500/μl4.

In patients on antiretroviral drugs, drug interactions between DAA and HIV antiviral drugs need to be looked at critically when initiating therapy in HIV/HCV co-infected patients. SOF is an ideal drug as there are very few significant drug interactions. Simeprevir has significant drug interactions with efavirenz and darunaprevir/ritonavir. The concomitant administration of RBV and didanosine may result in mitochondrial toxicity leading to hepatomegaly, hepatic steatosis, pancreatitis and lactic acidosis4. Concomitant zidovudine use enhances the risk of RBV-associated anaemia and should be avoided. SOF is not recommended with tipranavir as this drug induces P-gp. For Indian patients, the choice of SOF and RBV with or without Peg-IFNα is based on the same principles as in HCV mono-infected patients, keeping the availability of DAAs and drug interactions in mind4.

Suggested regimens for India

In this section, the potential use of SOF in the management of HCV as a solo available DAA in India is discussed, with stress on the management of genotype 1 and genotype 3 which together account for >95 per cent of HCV-infected patients of India7. Other DAAs that are likely to be approved in near future, will also be discussed. The suggested SOF-based regimen for Indian patients is summarized in Table I.

Table I Suggested sofosbuvir (SOF)-based regimens for India

Cirrhosis

With the advent of DAAs, it is now reasonable that most of the patients with compensated cirrhosis should be treated if there are no contraindications and will prevent short- to mid-term complications of cirrhosis. However, HCV treatment of cirrhotics should be given by only experienced practitioners31.

Compensated cirrhotic patients with good liver function and without cytopaenia tolerate a 12-24 wk IFN-based DAA regimen well and these cirrhotic patients can be treated as recommended above across all genotypes. Daily SOF (400 mg) and weight-based RBV [1000 mg (<75 kg) to 1200 mg (>75 kg)] for up to 48 wk are recommended for patients with HCV genotype 3 who have decompensated cirrhosis (CTP class B or C)4. No regimen without ledipasvir can be given for decompensated HCV genotype 1 patients4. This group will have to wait for newer DAAs to be approved in India.

Adverse effects, interactions and precautions with the use of sofosbuvir

The most common adverse effects of SOF in combination with RBV were fatigue and headache (incidence ≥20%). When SOF is used in combination with PEG-IFN and RBV, the most common adverse events observed are fatigue, headache, nausea, insomnia and anaemia4. Cardiac patients who are taking amiodarone can develop severe bradycardia when SOF is taken in combination with another DAA. This effect increases in patients who are also receiving beta-blockers and have advanced liver disease. Thus, co-administration of amiodarone with SOF is not recommended3. If there are no alternative and viable treatment options, a strict cardiac monitoring is recommended.

Since many regimens contain RBV and PEG-IFN, care must be taken before their administration. RBV can lead to foetal death or birth defects, and animal studies have shown that IFNs have abortifacient effects. Thus, it is advisable to avoid pregnancy in female patients who are on these drugs. Pregnancy should be ruled out prior to initiating therapy, and couples should be counselled for using contraception and to have monthly pregnancy tests4.

RBV cannot be recommended for patients with severe renal impairment or end-stage renal disease4.

Recommendations of Indian National Association for Study of the Liver (INASL) guidelines

The Indian National Association for Study of the Liver (INASL) published their guidelines for antiviral therapy against HCV infection in 20154. According to the INASL, the current limitations for the treatment of HCV in India include the poor response of genotype 3, non-availability of many of the DAAs recommended by other guidelines and the high cost of therapy that cannot be afforded by the population of India. Since only one DAA, SOF, is available in India, only two SOF-based regimens are possible: either dual drug therapy in combination with RBV alone for six months or triple drug therapy in combination with RBV and PEG IFN for three months. The utility of these regimens in various situations has been discussed by the INASL4. The recommended regimens by INASL are summarized in Table II.

Table II Indian National Association for Study of the Liver recommendations for treatment of hepatitis C virus in India

Conclusions

With the availability of DAAs, highly effective, short duration and safe regimens have created better outcomes for patients with HCV infection, especially in those groups where SVR was low with prior therapies or in those where IFN-based treatment strategies were contraindicated. Having SOF and other DAAs will definitely benefit Indian HCV patients, but efforts should be made to make DAAs accessible to all patients.