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Groups with Special Considerations for Therapy
The following recommendations for each subgroup of patients have taken into account the natural history of disease, the likelihood of achieving an SVR, and the adverse effects and need for dose discontinuations with treatment. Current management of patients with genotype 2, 3 or 4 infection, end-stage renal disease and other populations are available online in Supplementary Materials. Refer to the Appendix for summary recommendations in these groups.
PegIFN-RBV therapy without a PI for HCV genotype 1-infected patients.
There are some HCV genotype 1-infected patients who may be treated without an HCV PI in whom SVR rates to PegIFN-RBV alone are predicted to be very good (71) . Patients who experience an RVR to the 4-week lead-in with PegIFN-RBV, those who have a low baseline HCV RNA (<400,000 IU/ml), or those who have the IL-28B CC genotype have predicted sustained response rates to PegIFN-RBV of 60-90% (36, 42, 71) . Treatment options for patients who were previously intolerant to therapy include PegIFN alone, or PegIFN with reduced doses of RBV (72, 73) . Treatment should be discontinued if there is <2 log 10 decline in HCV RNA at week 12 and/or if HCV RNA remains dectectable at week 24.
Recommendations for PegIFN alfa with or without RBV treatment in genotype 1 patients:
- PegIFN alfa monotherapy may be used to treat patients with contraindications to RBV (Class I, Level A).
- For patients who achieve RVR and have a low baseline viral load (HCV RNA <400,000 IU/ ml), 24-weeks of treatment with PegIFN-RBV may be sufficient (Class I, Level B).
Patients with minimal histological evidence of liver disease
Patients with grade 1 inflammation and minimal fibrosis are at lower risk for developing advanced liver disease in the near future, and observation without treatment may be an option. Liver biopsy may be repeated after 5 years if results would change management. Despite minimal fibrosis, HCV treatment should be provided if patients desire treatment or have extrahepatic manifestations (leukocytoclastic vasculitis, membranoproliferative glomerulonephritis, symptomatic cryoglobulinemia) (74) .
Recommendations in patients with mild disease:
- Treatment can be deferred in patients with minimal inflammation and/or minimal portal fibrosis on liver biopsy (Class I, Level B).
Patients with compensated cirrhosis
Patients with compensated HCV-related cirrhosis (Child-Pugh Class A) can be treated successfully with HCV antiviral agents, but experience higher rates of adverse events and lower SVR compared with patients with early-stage disease (11, 12, 43, 44, 75, 76) . The decision to treat should be individualized in these patients.
Among treatment-naive genotype 1-infected patients with bridging fibrosis or cirrhosis treated in SPRINT-2 with BOC/PegIFN/RBV, higher SVR was achieved with 48 weeks of treatment as compared with 28 weeks of treatment (SVR 52 and 41%, respectively) or to control (SVR 38%) (11) . Among treatment-naive genotype 1-infected cirrhotics in ADVANCE treated with TVR (12 weeks)-PegIFN-RBV, SVR was achieved in 62% compared with 33% in the control arm (12) . In treatment-experienced patients with advanced fibrosis (METAVIR stage 3 or 4), who were re-treated with a BOC-containing regimen in RESPOND-2, SVR occurred in 68%, although 64% of patients in the trial were prior relapsers, 36% were prior partial responders, and null responders were not included. In treatment-experienced patients with METAVIR stage 3 or 4 fibrosis, who were re-treated with a TVR-containing regimen in REALIZE, SVR rates were 84-85% in prior relapsers, 34-56% in partial responders, and 14-39% in null responders. Child-Pugh Class B or C patients (score ≥ 7) were excluded from the PI trials. (refer to Supplementary Materials for additional information on PegIFN and RBV treatment in this population).
Improvements in liver histology and clinical outcomes occur among patients with cirrhosis who achieve SVR (9, 10, 77, 78, 79) . Despite achieving SVR, patients with cirrhosis remain at risk for developing HCC, and routine screening for HCC should continue. Recommendations in patients with cirrhosis:
Recommendations in patients with mild disease:
- HCV genotype 1-infected patients with compensated cirrhosis (Child-Pugh Class <7), adequate neutrophils (>1.5 k/ mm 3), and adequate platelet counts (>75 k/ mm 3) should be considered for treatment with BOC (for 44 weeks) or TVR (for 12 weeks) combined with PegIFN-RBV at standard doses for 48 weeks (Class I, Level B).
- Patients with cirrhosis remain at risk for HCC and should undergo routine screening regardless of viral clearance status, in accordance with current guidelines (Class I, Level B).
African Americans have the highest prevalence of HCV infection among the US veterans, but have lower rates of spontaneous viral clearance and lower SVR rates with all forms of IFN-RBV-based therapies than Caucasians. There is a lower prevalence of the IL28B CC in genotype 1-infected African Americans, which partly explains the lower SVR rates (19-28%) compared with Caucasians (39-52%) treated with PegIFN-RBV regimens (36, 45, 80, 81, 82) . SVR rates in African Americans receiving BOC-based regimens, who were treatment-naive (42-53%) and -experienced (53-61%) were higher than in those who received PegIFN-RBV alone (23 and 8%, respectively) (11, 14) . Similarly, African Americans receiving TVR-based regimens experienced higher SVR rates if they were treatment-naive (62%) or -experienced (55%), compared with patients receiving PegIFN-RBV alone in Phase 3 trials (25 and 9%, respectively) (12, 13) .
Recommendations in African Americans:
- BOC or TVR combined with PegIFN-RBV is the standard of care for genotype 1-infected African American patients (Class I, Level A).
The combination of PegIFN plus RBV remains the current standard of care for the treatment of HCV infection in HIV/HCV-coinfected patients. BOC or TVR plus PegIFN-RBV treatment in this population is under investigation. Treatment of HCV with a PI-containing regimen should be undertaken only with caution under the close supervision of a multidisciplinary team, with special attention to side effects and DDIs (83, 84) (refer to Supplementary Materials for additional information on PegIFN and RBV treatment in this population).
Patients with a history of liver transplantation
Use of a PI with PegIFN and RBV after liver transplant has not been studied sufficiently. The only published pharmacokinetic study evaluated DDIs between TVR and either cyclosporine or tacrolimus. Cyclosporine levels were increased by 4.6-fold and tacrolimus levels by 70-fold after a single-dose administration of TVR (11, 85) . Given the significant DDIs, use of PIs with PegIFN and RBV after liver transplant should be carefully considered and only undertaken cautiously under the careful supervision of a transplant center (refer to Supplementary Materials for additional information on PegIFN and RBV treatment in this population).