Hepatitis C Direct Acting Antivirals

Hepatitis C direct acting antivirals block specific viral proteins and cure more than 95% of chronic infections with 8 to 12 weeks of oral treatment. Cure is defined as undetectable HCV RNA 12 weeks after the end of treatment (sustained virological response). Pangenotypic combinations have removed the need for genotyping in most patients.

Targets.

• NS5B nucleotide polymerase inhibitor: sofosbuvir. Chain terminator, high barrier to resistance.
• NS5A inhibitors: velpatasvir, daclatasvir, ledipasvir, pibrentasvir, elbasvir. Highly potent, lower barrier to resistance.
• NS3/4A protease inhibitors: glecaprevir, voxilaprevir, grazoprevir.

• Sofosbuvir 400 mg with velpatasvir 100 mg, once daily: pangenotypic, 12 weeks; the most used combination.
• Sofosbuvir 400 mg with daclatasvir 60 mg, once daily, 12 weeks: low-cost generic option; daclatasvir dose changes with interacting drugs (30 mg with atazanavir and ritonavir, 90 mg with efavirenz).
• Glecaprevir 300 mg with pibrentasvir 120 mg, once daily with food: 8 weeks without cirrhosis, 12 weeks with compensated cirrhosis. Safe at any level of kidney function.
• Sofosbuvir, velpatasvir and voxilaprevir (400, 100, 100 mg) once daily with food for 12 weeks: retreatment after a direct acting antiviral failure.
• Ledipasvir 90 mg with sofosbuvir 400 mg: genotypes 1, 4, 5 and 6.
• Ribavirin: added for decompensated cirrhosis (weight-based, 1000 mg daily under 75 kg and 1200 mg daily from 75 kg, in two doses).

Who to treat. All adults and children with detectable HCV RNA, with priority to cirrhosis, HIV or hepatitis B coinfection, kidney disease and women planning pregnancy.

Selection.

• Compensated or no cirrhosis: sofosbuvir with velpatasvir for 12 weeks, or sofosbuvir with daclatasvir for 12 weeks, or glecaprevir with pibrentasvir for 8 to 12 weeks.
• Decompensated cirrhosis (Child-Pugh B or C): sofosbuvir with velpatasvir or daclatasvir plus ribavirin for 12 weeks, under specialist care. Protease inhibitor regimens are contraindicated.
• Treatment failure: sofosbuvir, velpatasvir and voxilaprevir, or glecaprevir and pibrentasvir with sofosbuvir and ribavirin for 12 to 16 weeks, in a specialist centre.

Interactions.

• Amiodarone with sofosbuvir: severe bradycardia; avoid.
• Strong inducers (rifampicin, carbamazepine, phenytoin, St John's wort): lower sofosbuvir and velpatasvir levels; avoid.
• Acid suppression: velpatasvir absorption falls; avoid proton pump inhibitors, or use omeprazole 20 mg or less with food 4 hours after the dose; antacids 4 hours apart.
• Statins: glecaprevir and voxilaprevir raise atorvastatin and simvastatin levels; hold the statin.
• Antiretrovirals: efavirenz lowers velpatasvir and is avoided; tenofovir needs renal monitoring with sofosbuvir and velpatasvir.

Region. In East Africa, low-cost generic sofosbuvir-based regimens are available in some countries, and pangenotypic regimens avoid dependence on genotyping. Screen all people with HIV, hepatitis B, injecting drug use, and previous unsafe injections or transfusion.

Baseline tests. HCV RNA, full blood count, liver enzymes, bilirubin, albumin, INR, creatinine, HBsAg and anti-HBc, HIV, pregnancy test, fibrosis staging (elastography or APRI and FIB-4).

Serious adverse effects. Generally mild (headache, fatigue, nausea). Hepatitis B reactivation in coinfected patients, sometimes fatal: give tenofovir or entecavir to HBsAg-positive patients, and monitor anti-HBc-positive patients. Hepatic decompensation with protease inhibitors in advanced liver disease. Ribavirin: haemolytic anaemia, teratogenicity.

Monitoring. Liver enzymes and HCV RNA at week 4 if clinically needed, and HCV RNA at 12 weeks after treatment. Continue ultrasound surveillance for liver cancer in cirrhosis even after cure.

Special groups.

• Pregnancy: not advised; data are limited, so treatment is deferred until after delivery. Avoid conception during ribavirin and for 6 months afterwards.
• Breastfeeding: limited data; usual practice is to defer.
• Children: sofosbuvir with velpatasvir and glecaprevir with pibrentasvir are used from 3 years by weight.
• Kidney impairment: glecaprevir with pibrentasvir at any level; sofosbuvir-based regimens are used down to dialysis under specialist direction.

Referral and escalation. Refer cirrhosis, decompensation, treatment failure, HIV coinfection with complex regimens, and kidney transplant candidates.