At the Conference on Retroviruses and Opportunistic Infections (CROI) 2013 meeting in Atlanta, first results were presented from two Agence Nationale de Recherche sur la SIDA (ANRS) studies which looked at the efficacy and safety of triple HCV therapy (either with telaprevir or boceprevir) in previous non-responders to dual pegIFN/RBV therapy [
12,
13]. Patients with previous null-response and cirrhosis were excluded because of the overall low probability of treatment response. Both studies were presented as pre-planned interim analyses at Week 16 of therapy. In the telaprevir ANRS HC26 study at the interim analyses, 69 patients who received at least one dosage were included [
12]. Background HIV therapy contained atazanavir (ATV), ritonavir-boosted atazanavir (ATV/r), efavirenz (EFV), raltegravir (RAL), tenofovir (TDF), emtricitabine (FTC) or lamivudine (3TC). Patients started with a four-week lead-in of pegIFN/RBV. This approach, which is outside the labeling of telaprevir, was chosen so the investigators could compare the results to the boceprevir study, which had a lead-in period of four weeks and because data from telaprevir studies in HCV mono-infection in treatment experienced patients had potentially promised some benefit for this approach. After Week 4, telaprevir was added for12 weeks. Patients who achieved a complete rapid virological response at Week 8 (RVR8) defined as HCV-RNA <15 IU/mL received 32 weeks of pegIFN/RBV after stopping telaprevir at Week 16 following12 weeks of triple therapy (full treatment: 48 weeks). Whereas patients who only obtained a partial RVR8 (15 IU/mL < HCV-RNA <1,000 IU/mL) received an additional 56 weeks of pegIFN/RBV (full treatment: 72 weeks). Telaprevir was administered as 750 mg q8h (1,125 mg q8h with EFV) and pegIFN α-2a as 180 μg sc/week. Ribavirin was dosed as 1,000 mg/day (≤75 kg) and 1,200 mg/day (>75 kg). Futility rules for telaprevir were HCV-RNA >1,000 IU/mL at Week 8 or Week 12 or virological breakthrough at any time. For study inclusion patients needed to have CD4 ≥200 cells/mm
3 and ≥15%, as well as plasma HIV-RNA levels <50 copies/mL. At baseline, the median CD4-count was 630 cells/mm
3 (range 459 to 736) and HIV-RNA was below 50 c/ml in 99% of patients. Eleven (18%) patients had Metavir F3 fibrosis and 16 (23%) had F4 fibrosis at inclusion into the study. A total of 39% of patients were previous relapsers to dual therapy, 9% had previous viral breakthrough, 22% were partial responders and 30% null-responders. With 88% achieving an undetectable HCV-RNA at Week 16 in this patient population comprising of 30% previous null-responders and 40% with F3/F4 fibrosis, this study has achieved surprising high early efficacy results. Most interestingly, efficacy remained high independent of a previous response to dual HCV therapy (early virological response at Week 16 (EVR
16) was 86% in relapsers versus 86% in previous null-responders) or baseline fibrosis stage (EVR16 was 92% in F1 and 94% in F4 patients). Concomitant antiretroviral therapy (ART) also had no impact on early virological response. Adverse events were frequent (99% of patients developed an AE) but were mostly related to pegIFN side effects. A total of 4% (n = 3) of patients discontinued study drugs because of psychiatric adverse events and cutaneous adverse events, respectively. Noteworthy, in contrast to the pilot trial in HCV treatment-naïve patients where no telaprevir discontinuation because of rash was recorded, a few discontinuations because of rash did occur in this study. Grade 3 to 4 anemia, erythropoietin (EPO) use, transfusion or RBV dose reduction was recorded in 61% of patients.
The second ANRSstudy looked at the efficacy and safety of a boceprevir containing triple therapy in 64 previous IFN/RBV non-responders [
13]. Following a lead-in with dual therapy, boceprevir was added at Week 4. Boceprevir was discontinued in all patients with a HCV viral load above 1,000 IU/ml at Week 8 and/or at Week 12. All HCV drugs were discontinued if HCV viral load was >1,000 IU/ml at Week 16 or still detectable at Week 28 or in case of virological breakthrough. Patients who achieved a complete rapid virological response at Week 8 (RVR8) defined as HCV-RNA <15 IU/mL received another 40 weeks of triple therapy. Patients who at Week 8 had an HCV viral load >15 IU/mL but <1,000 IU/mL triple therapy continued for four more weeks. If their HCV viral load at Week 12 was again >15 IU/mL but <1,000 IU/mL, they received an additional 36 weeks of triple therapy followed by a further 12 weeks of pegIFN/RBV. Patients recruited for the trial had to be on stable ART for at least three months, with at least three molecules among ATV (ritonavir boosted or not), RAL, TDF, ABC, FTC or 3TC. Again, only previous non-responders to dual therapy with HCV genotype 1 infection were included. Overall, 17% of patients had Metavir F4 fibrosis at baseline and 33% were previous null-responders. Overall, 63% achieved undetectability at Week 16, which was slightly higher in the RAL-treated patients than in patients on other ART regimens. Response rates at Week 16 were best for previous relapsers (with 90% <15 IU/ml) versus patients with previous breakthrough (60% <15 IU/ml), partial responders (60% <15 IU/ml) and null-responders (38% <15 IU/ml), respectively. Response rates according to fibrosis at baseline in contrast were comparable between the different fibrosis stages (62% <15 IU/ml at Week 16 with F1, 67% for F2, 50% for F3 and 73% for F4). Anemia occurred in 42% of patients but only 5% developed grade 3 to 4 anemia. A total of 42% of the patients received concomitant EPO.
Both of these studies show very impressive early treatment response rates independent of baseline fibrosis stage (please note that patients with prior null-response and F4 fibrosis, however, were excluded from the trial). Whether the good early response rates can be maintained and translate into good SVR rates remains to be seen, as at this time these studies are still ongoing. It is noteworthy, however, that triple therapy studies in HCV treatment-experienced patients (see the ANRS CO20-CUPIC trial) also showed good early treatment response rates, which, however, did not translate to high SVR rates after the end of therapy [
21]. Moreover, similar to CUPIC, significant hematological toxicity was observed in these studies despite proactive management of anemia. However, significant drop-out rates as a result of SAEs were not seen by Week 16. Moreover, in the CUPIC trial, there was a considerable incidence of severe complications and death, especially in patients with low platelet counts and low albumin. This has not as yet been reported in the early results from the ANRS co-infection trials but needs to be borne in mind with respect to treating patients with advanced fibrosis/cirrhosis with currently available triple therapy. These patients should be managed withincenters with experience in looking after co-infected patients with advanced liver disease.