Use of Protease Inhibitors in HIV/HCV Genotype 1 Coinfection
To develop its recommendations, the Scientific Committee relied on the few available studies of HIV/HCV-coinfected patients and, in the absence of sufficient specific information on HIV/HCV coinfection, an analysis of recommendations for patients with isolated HCV infection; each AFEF recommendation was examined to determine whether or not it needed to be adapted for HIV/HCV-coinfected patients.
Results of Peg-IFN + ribavirin + HCV protease inhibitor tritherapy in treatment-naïve patients. Initial results on the safety and efficacy of first-generation protease inhibitors in HIV/HCV-coinfected patients come from two phase III studies involving HCV-treatment-naïve patients with HCV genotype 1 coinfection.
The first trial evaluated tritherapy comprising telaprevir, Peg-IFN alfa-2a 180 μg weekly and ribavirin (fixed dose of 800 mg daily or adjusted to body weight)
The study population was divided into two groups:
71% of patients were infected by HCV genotype 1a, and 5% had stage F4 fibrosis.
The telaprevir dose was 750 mg three times a day (two 375-mg tablets at each intake) when combined with atazanavir, and 1125 mg three times a day when combined with efavirenz, to compensate for the effect of drug interaction.
Patients received telaprevir tritherapy for 12 weeks, followed by Peg-IFN and ribavirin bitherapy for a further 36 weeks. Telaprevir was discontinued if HCV RNA exceeded 1000 IU/ml at the 4th or 8th week. All treatment was discontinued if HCV RNA exceeded 1000 IU/ml or had fallen by less than 2 log10 after 12 weeks, or if HCV viral load was detectable at week 24 or 36.
Overall, 71% of patients receiving telaprevir-based combination therapy had a sustained virological response (SVR24), compared with 41% of patients treated with Peg-IFN and ribavirin bitherapy.
In the population not taking HIV antiretrovirals, the SVR24 rate was 71% with telaprevir tritherapy and 33% with bitherapy. In the group receiving HAART, the SVR24 rate among patients receiving telaprevir was 69% in the efavirenz arm and 73% in the boosted atazanavir arm, compared with, respectively, 38% and 50% in the corresponding patients receiving Peg-IFN/ribavirin bitherapy.
SVR24 rates were similar to SVR12 rates, confirming the value of SVR12 as a marker of cure. Note that two patients were lost to follow-up before the SVR24 visit (one patient in the T/PR atazanavir arm and one patient in the PR efavirenz arm), meaning that only the SVR12 data were available.
The most common adverse effects (at least 15% more frequent with telaprevir than with placebo) during 12 weeks of tritherapy were pruritus (34% vs 5%), headache (34% vs 23%), nausea (32% vs 18%), rash (29% vs 18%) and dizziness (21% vs 9%). Few patients receiving telaprevir developed severe anaemia (3% vs 5%), but they were more likely to be prescribed blood transfusions (11% vs 5%) or EPO (8% vs 5%).
None of the patients interrupted their antiretroviral treatment and no HIV escape was observed. Serum concentrations of telaprevir were similar in patients receiving and not receiving HIV antiretroviral treatment.
The second randomized phase IIb study compared tritherapy with boceprevir (800 mg 3 times/day), Peg-IFN alfa-2b (1.5 μg/kg/week) and ribavirin (600–1400 mg/day depending on bodyweight). This was a multicenter double-blind randomized trial (2:1), with a boceprevir arm (n = 64) and a placebo arm (n = 34).
All 98 patients included in this study received optimized antiretroviral therapy and had CD4 cell counts above 200/mm and HIV RNA loads below 50 copies/ml. Assuming that there would be no significant interaction, ritonavir-boosted HIV protease inhibitors were authorized but efavirenz and other non-nucleoside reverse transcriptase inhibitors were excluded (AZT, ddI, d4T, etravirine, nevirapine).
All the patients received initial bitherapy with Peg-IFN and ribavirin for 4 weeks, followed by tritherapy with Peg-IFN, ribavirin and boceprevir/placebo for 44 weeks. Treatment was discontinued if the decline in HCV RNA was less than 2 log10 at W12 or if HCV RNA was still detectable at W24. At baseline, 65% of patients had genotype 1a infection and 5% had stage F4 fibrosis.
The SVR24 rate, defined as the percentage of patients with undetectable HCV RNA 24 weeks after treatment cessation, was 63% (40/64) in the boceprevir arm and 29% in the placebo arm (10/34). Overall, the 34% difference in the SVR rate between the experimental and control arms is similar to that observed elsewhere in HCV-monoinfected patients.
The following adverse effects were more frequent in patients receiving boceprevir than in those receiving placebo: fever (36% vs 21%), decreased appetite (34% vs 18%), vomiting (28% vs 15%), dysgeusia (28% vs 15%), neutropaenia (19% vs 6%) and anaemia (41% vs 26%). However, the rate of severe anaemia (grade 3–4) was similar in the two groups (5% vs 3%). In total, 20% of patients in the experimental arm and 9% of those in the control arm left the study because of adverse events.
HIV virological breakthrough was observed in 3 of 64 patients on boceprevir and 4 of 34 patients on placebo.
In sum, tritherapy with Peg-IFN, ribavirin and telaprevir or boceprevir in HIV-1-infected patients with previously untreated HCV genotype 1 infection yields SVR rates of 71% with telaprevir (SVR24) and 60.7% with boceprevir (W12 SVR).
These two trials confirm:
Who to Treat? According to the latest guidelines, standard bitherapy (Peg-IFN + ribavirin) for hepatitis C is indicated in case of significant fibrosis (F ≥ 2) and/or extrahepatic manifestations, and/or factors predictive of a virological response (genotype 2 or 3, or genotype 1 with viral load <800 000 IU/ml).
The risks and benefits of anti-HCV tritherapy are different in patients with minimal fibrosis, due i) to better therapeutic efficacy and ii) to the possibility of new adverse effects, the risk of emergence of resistant viral variants in case of non-response, and the extra cost of protease inhibitors. The use of anti-HCV tritherapy in patients with minimal fibrosis must take into account both risk factors for fibrosis progression and predictors of a good response to pegylated biotherapy.
Like bitherapy, anti-HCV tritherapy is currently contraindicated in patients with decompensated cirrhosis. It has been shown that HCV eradication alleviates symptoms in patients with cryoglobulinaemia. It is therefore logical to use tritherapy in these subgroups, despite the lack of specific studies.
Predictors of the Response to Tritherapy. Pretreatment factors predictive of SVR have been analysed in phase III studies in HCV-monoinfected patients but not in HIV/HCV-coinfected patients.
In the ADVANCE trial of telaprevir, univariate analysis showed that age <40 years, female gender, absence of severe fibrosis, body mass index <25 kg/m and genotype 1b infection vs genotype 1a infection were all associated with a higher chance of SVR. The SVR rate was lower in patients with F3–F4 fibrosis than in those with F0–F2 fibrosis (62% vs 78% in the telaprevir arm (TRV12-PR). The IL28B polymorphism could be determined in 44% of these patients, and the SVR rate was 90% in CC patients, 71% in CT patients and 73% in TT patients. The gain provided by tritherapy compared with Peg-IFN + ribavirin bitherapy was larger in CT and TT patients than in CC patients (SVR: 50% vs 26%). The results of multivariate analysis are not yet available.
In the trial of boceprevir (SPRINT-2), predictors of SVR in multivariate analysis were ethnicity, HCV viral load, absence of cirrhosis and use of statins. SVR was more frequent in the absence of stage F3-F4 fibrosis (67% vs 52% in the boceprevir arm (BOC-PR48)). When included in a multivariate model, IL28B also emerged as an independent response predictor the SVR rate was 80% for genotype CC, 71% for CT and 59% for TT. Tritherapy was more effective than Peg-IFN + ribavirin bitherapy in CT carriers (SVR +41%) and TT carriers (+32%) but not in CC carriers (SVR: 78% vs 80%).
These analyses show that similar factors influence the response to Peg IFN-ribavirin bitherapy and to tritherapy, but that they have a smaller impact on tritherapy. Even in patients with predictors of poor response (IL28B non-CC genotypes, stage F3–F4 fibrosis), the chances of cure on tritherapy remain high (above 50%), and they are significantly higher than with bitherapy. In patients with factors of good response (IL28B genotype CC and fibrosis stage <F3), the chances of cure exceed 80%, although the gain provided by tritherapy seems smaller (telaprevir) or non-existent (boceprevir).
These factors now need to be studied in patients coinfected with HIV and HCV.
Can the Duration of Anti-HCV Tritherapy be Shortened in Some Patients? The effect of shortening tritherapy in HIV/HCV-coinfected patients has not been studied. In addition, HCV viral load is known to decay more slowly in coinfected patients. In the trial of boceprevir in coinfected HCV-treatment-naïve patients the proportion of patients with undetectable HCV viral load after 4 weeks of tritherapy seemed to be lower than that observed in HCV-monoinfected patients (42.2% vs 61–64% in the SPRINT 1 and SPRINT 2 trials) the two curves meeting after 8 weeks of tritherapy.
Trials are underway to determine whether shorter treatment can be offered to HIV/HCV-coinfected patients who experience RVR after one month of telaprevir tritherapy.
Can Some Anti-HCV-naïve Patients be Treated With the Peg-IFN + Ribavirin Combination? In HCV-monoinfected patients, AFEF considers that IL28B genotyping (currently not reimbursed in France) is useful for treatment decisions, including for naïve patients with genotype 1 infection and no severe fibrosis (F0–F2).
In naïve HCV genotype 1-monoinfected patients with predictors of a good response to treatment (IL28B CC genotype and fibrosis <F3), the chances of cure are of the order of 80% with bitherapy, while tritherapy adds little or nothing to the results. Bitherapy is thus considered a possible first-line treatment, and should be continued if an RVR is achieved.
In patients coinfected with HIV and HCV, these recommendations would require lengthy treatment (48 weeks), while tritherapy lasts only 24 weeks in similar patients with isolated HCV infection. A study presented at the 2012 AASLD meeting suggests that, in HCV-monoinfected patients with baseline viral load <600 000 IU/ml and RVR after four weeks of bitherapy, 24 weeks of bitherapy is as effective as boceprevir tritherapy, regardless of the IL28B genotype. However, this has not been demonstrated in coinfected patients, in whom a total treatment duration of 48 weeks remains necessary for the moment. If these arguments support the possibility of bitherapy in highly selected coinfected patients taking initial HCV viral load into account, and if, in addition, bitherapy is the only option in countries that do not have access to tritherapy for economic reasons, clinical trial results tend to favour tritherapy over bitherapy for HIV/HCV-coinfected patients.
Results of Tritherapy (Peg-IFN + Ribavirin + HCV Protease Inhibitor) in Patients With Prior Treatment Failure. Patients with HCV genotype 1 monoinfection in whom bitherapy with Peg-IFN + ribavirin (PR) has failed, a new course of bitherapy results in SVR rates ranging from 5 to 40%, depending on the type of response to first-line treatment (relapse, partial response or no response), using regimens that differ in terms of the dose and type of interferon, the ribavirin dose and the treatment duration. Ribavirin doses of 1000–1200 mg/day (based on body weight) and a treatment period of 72 weeks yield higher SVR rates in HIV/HCV-coinfected patients than lower doses and shorter treatment, in both patients with HCV genotype 1 and genotype 2–3 infection. However, in routine practice, treatment optimization (including patient education, residual ribavirin assay allowing the ribavirin dose to be adapted, 'recommendations' on erythropoietin or GCSF prescription to mitigate adverse effects, as well as longer treatment) seems to provide only a moderate additional benefit. This was confirmed by the modest results of the Syren study of monoinfected patients and the ETOC study of coinfected patients. Therapeutic alternatives are urgently needed for these patients.
In patients coinfected with HIV and HCV, two pilot trials sponsored by ANRS, named Telaprevih and Boceprevih, evaluated the relative effectiveness of telaprevir and boceprevir in patients in whom previous treatment had failed. The study populations consisted of patients with CD4 cell counts >200/mm and undetectable HIV viral load for at least 6 months, and did not include patients who were both cirrhotic and non-responders. After an initial 4 weeks of bitherapy, the planned total duration of treatment is 48 weeks for patients with an early virological response (HCV RNA <15 IU/ml at W8) and 72 weeks for patients with no RVR8 but HCV <1000 IU/ml after 4 weeks of tritherapy. Preliminary safety and efficacy results at W16 were presented at CROI 2013.
In the TelapreVIH trial, 69 patients (70% with genotype 1 infection and 39% with stage F3/F4 fibrosis) received tritherapy with telaprevir, Peg-IFN alfa-2a and ribavirin after an induction phase of 4 weeks with Peg-IFN and ribavirin alone. Overall, at W16, 88% of patients had undetectable HCV RNA, regardless of the type of anti-HIV therapy, the degree of fibrosis and the initial virological response to prior treatment. The most common adverse effect was haematoxicity (grade 4 in 6% of cases, with two deaths outside the telaprevir phase, one because of cerebromeningeal bleeding secondary to immune thrombocytopenia induced by Peg-IFN, and the other to gastrointestinal bleeding related to portal hypertension). No HIV treatment escape was observed.
The Boceprevih trial included 64 patients, 78% of whom were infected by HCV genotype 1, 1.17% of whom had stage F4 fibrosis and 33% of whom had not responded to bitherapy. All began tritherapy with boceprevir, Peg-IFN alfa-2a and ribavirin after a 4-week lead-in period with Peg-IFN and ribavirin alone. At W16, 63% of patients had undetectable HCV RNA. The early response rate seemed to be influenced by the type of response to prior therapy (90% response rate in relapsers, 38% in non-responders); it was 70% with raltegravir and 56% with atazanavir, and did not differ according to the degree of fibrosis.
Grade 4 haematoxicity was observed in 5% of patients. No HIV treatment escape was noted.
These preliminary results suggest that tolerability is acceptable and that early virological efficacy is encouraging. Boceprevir may be less effective than telaprevir in non-responders to previous bitherapy.
The total treatment duration in patients in whom previous treatment has failed will be 48 weeks, and any attempt to reduce the total treatment duration should be evaluated with care, especially in patients with severe fibrosis (F3–F4) and/or comorbidities.
The risk/benefit ratio should be evaluated very closely in cirrhotic patients, in whom thrombocytopaenia (<100 000/ml) and hypoalbuminaemia (<35 g/L) may be a contraindication, as shown by the CUPIC study in monoinfected cirrhotic patients with prior treatment failure (0.7 to 2.5% mortality).
Patients with extrahepatic manifestations qualify for retreatment with tritherapy comprising a first-generation HCV protease inhibitor, regardless of the stage of fibrosis.
Predictors of the Response to Tritherapy. Predictors of the treatment response remain to be clarified in HIV/HCV-coinfected patients, but there is little reason to suppose they are not different from those observed in patients with isolated HCV infection in the phase III trials REALIZE and RESPOND-2.
The prior response profile is, statistically, the most powerful predictor. In the REALIZE trial of telaprevir the SVR rates in the tritherapy arm (with and without initial bitherapy, respectively) were 83% and 88% in relapsers, 54% and 59% in partial responders and 33% and 29% in non-responders. In the RESPOND-2 trial of boceprevir the SVR rates in the BOC-PR48 and BOC-PR-RGT arms were, respectively, 75% and 69% in relapsers, and 52% and 40% in partial responders. Non-responders excluded from this study were described in the PROVIDE study which suggested an SVR rate of 38%.
The stage of fibrosis was the second most important factor independently associated with SVR. In the REALIZE study, the overall results in the tritherapy arm in terms of SVR were 74% in patients at stage F0–F2, 66% at stage F3 and 47% in patients with cirrhosis. In relapsed patients, the fibrosis stage had no impact on SVR (F0–F2 86%, F3: 85%, F4: 84%). However, fibrosis had a major influence on SVR in partial responders (F0–F2 72%, F3: 56%, F4: 34%) and non-responders (F0–F2: 41%, F3: 39%, F4: 14%). It should be noted that the patients who are most difficult to treat with tritherapy are non-responders with cirrhosis, who had SVR rates below 15% (no significant difference with the control group, although numbers were small). In the RESPOND-2 study, fibrosis also had a major impact on the SVR rate, which ranged in the tritherapy arm from 66–68% in patients with stage F0–F2 fibrosis to 44–68% in patients with stage F3–F4 fibrosis.
Other, less important predictors of the virological response were also identified. Multivariate analysis of the REALIZE dataset identified, in addition to the prior response profile and fibrosis, the following predictors of a favourable response: a high level of LDL cholesterol, genotype 1b (vs 1a) and low baseline viral load and transaminase levels. In contrast, the IL28B polymorphism had no significant impact on SVR in either study, although this remains to be confirmed.
In sum, the response to prior treatment is the main predictor of the response to tritherapy. All these predictors are also likely to be valid in coinfected patients in whom treatment with Peg-IFN + ribavirin has failed.
Factors Influencing the Decision to use Tritherapy (Peg-IFN + Ribavirin + Protease Inhibitor) in Patients With Prior HCV Treatment Failure. In patients coinfected with HIV and HCV, the effectiveness of tritherapy must be carefully weighed up against the medium-term prognosis of liver disease (although the chance of SVR correlates negatively with the severity of fibrosis), the adverse effects of tritherapy, the complexity of drug-drug interactions, uncertainties surrounding the safety profile of newer antiretrovirals in patients with advanced-stage fibrosis or simple HCV coinfection, economic costs and the mid-term possibility of that new combinations of directly acting HCV antiviral agents will give better results as well as shorter and better-tolerated treatments. These patients are the first to enrol in clinical trials.
An additional consideration is the interactions of oral HCV antivirals with HIV antiretrovirals in patients for whom the priority is the treatment of HIV infection. These interactions are similar to those suggested in naïve patients. When possible, one should avoid antiretrovirals, and especially HIV protease inhibitors (atazanavir for boceprevir, telaprevir for fosamprenavir; lopinavir and darunavir for both boceprevir and telaprevir), which affect the metabolism of HCV protease inhibitors. Antiretroviral therapy should be adapted if necessary to the results of pharmacological monitoring (efavirenz combined with telaprevir).
In the case of telaprevir, the excellent results of the OPTIMIZE trial and the pharmacokinetic behaviour observed in coinfected patients support a simpler dose regimen of 1125 mg every 12 h with meals, which is more in line with current once- or twice-daily antiretroviral regimens.
How to Manage Patients' Expectations and to Prepare Them for Future Therapeutic Trials? One important issue is the need to better identify patients and the results of their previous treatments in hospital databases (Nadis®, Diamm G®), to offer them the best tritherapy or to advise them to wait for new treatments (second-generation protease inhibitors, nucleotide/nucleoside or other NS5B polymerase inhibitors, NS5A inhibitors of the replication complex), and to better define their therapeutic course and follow-up (treatment, concomitant antiretroviral combination, outcome of fibrosis and methods for its evaluation, doses, treatment periods, adherence to treatment, interactions, past and present comorbidities, dose adjustments and follow-up (especially psychiatric).
Who to Treat?
To develop its recommendations, the Scientific Committee relied on the few available studies of HIV/HCV-coinfected patients and, in the absence of sufficient specific information on HIV/HCV coinfection, an analysis of recommendations for patients with isolated HCV infection; each AFEF recommendation was examined to determine whether or not it needed to be adapted for HIV/HCV-coinfected patients.
Treatment-Naïve Patients
Results of Peg-IFN + ribavirin + HCV protease inhibitor tritherapy in treatment-naïve patients. Initial results on the safety and efficacy of first-generation protease inhibitors in HIV/HCV-coinfected patients come from two phase III studies involving HCV-treatment-naïve patients with HCV genotype 1 coinfection.
The first trial evaluated tritherapy comprising telaprevir, Peg-IFN alfa-2a 180 μg weekly and ribavirin (fixed dose of 800 mg daily or adjusted to body weight)
The study population was divided into two groups:
A first group of 13 patients with CD4 cell counts ≥500/μl who were naïve of antiretroviral treatment,
A second group of 47 patients receiving effective antiretroviral therapy (HIV RNA <50 copies/ml). Based on drug interaction studies, two combinations were selected (efavirenz plus tenofovir/emtricitabine; or atazanavir boosted with ritonavir, plus tenofovir/emtricitabine or lamivudine).
71% of patients were infected by HCV genotype 1a, and 5% had stage F4 fibrosis.
The telaprevir dose was 750 mg three times a day (two 375-mg tablets at each intake) when combined with atazanavir, and 1125 mg three times a day when combined with efavirenz, to compensate for the effect of drug interaction.
Patients received telaprevir tritherapy for 12 weeks, followed by Peg-IFN and ribavirin bitherapy for a further 36 weeks. Telaprevir was discontinued if HCV RNA exceeded 1000 IU/ml at the 4th or 8th week. All treatment was discontinued if HCV RNA exceeded 1000 IU/ml or had fallen by less than 2 log10 after 12 weeks, or if HCV viral load was detectable at week 24 or 36.
Overall, 71% of patients receiving telaprevir-based combination therapy had a sustained virological response (SVR24), compared with 41% of patients treated with Peg-IFN and ribavirin bitherapy.
In the population not taking HIV antiretrovirals, the SVR24 rate was 71% with telaprevir tritherapy and 33% with bitherapy. In the group receiving HAART, the SVR24 rate among patients receiving telaprevir was 69% in the efavirenz arm and 73% in the boosted atazanavir arm, compared with, respectively, 38% and 50% in the corresponding patients receiving Peg-IFN/ribavirin bitherapy.
SVR24 rates were similar to SVR12 rates, confirming the value of SVR12 as a marker of cure. Note that two patients were lost to follow-up before the SVR24 visit (one patient in the T/PR atazanavir arm and one patient in the PR efavirenz arm), meaning that only the SVR12 data were available.
The most common adverse effects (at least 15% more frequent with telaprevir than with placebo) during 12 weeks of tritherapy were pruritus (34% vs 5%), headache (34% vs 23%), nausea (32% vs 18%), rash (29% vs 18%) and dizziness (21% vs 9%). Few patients receiving telaprevir developed severe anaemia (3% vs 5%), but they were more likely to be prescribed blood transfusions (11% vs 5%) or EPO (8% vs 5%).
None of the patients interrupted their antiretroviral treatment and no HIV escape was observed. Serum concentrations of telaprevir were similar in patients receiving and not receiving HIV antiretroviral treatment.
The second randomized phase IIb study compared tritherapy with boceprevir (800 mg 3 times/day), Peg-IFN alfa-2b (1.5 μg/kg/week) and ribavirin (600–1400 mg/day depending on bodyweight). This was a multicenter double-blind randomized trial (2:1), with a boceprevir arm (n = 64) and a placebo arm (n = 34).
All 98 patients included in this study received optimized antiretroviral therapy and had CD4 cell counts above 200/mm and HIV RNA loads below 50 copies/ml. Assuming that there would be no significant interaction, ritonavir-boosted HIV protease inhibitors were authorized but efavirenz and other non-nucleoside reverse transcriptase inhibitors were excluded (AZT, ddI, d4T, etravirine, nevirapine).
All the patients received initial bitherapy with Peg-IFN and ribavirin for 4 weeks, followed by tritherapy with Peg-IFN, ribavirin and boceprevir/placebo for 44 weeks. Treatment was discontinued if the decline in HCV RNA was less than 2 log10 at W12 or if HCV RNA was still detectable at W24. At baseline, 65% of patients had genotype 1a infection and 5% had stage F4 fibrosis.
The SVR24 rate, defined as the percentage of patients with undetectable HCV RNA 24 weeks after treatment cessation, was 63% (40/64) in the boceprevir arm and 29% in the placebo arm (10/34). Overall, the 34% difference in the SVR rate between the experimental and control arms is similar to that observed elsewhere in HCV-monoinfected patients.
The following adverse effects were more frequent in patients receiving boceprevir than in those receiving placebo: fever (36% vs 21%), decreased appetite (34% vs 18%), vomiting (28% vs 15%), dysgeusia (28% vs 15%), neutropaenia (19% vs 6%) and anaemia (41% vs 26%). However, the rate of severe anaemia (grade 3–4) was similar in the two groups (5% vs 3%). In total, 20% of patients in the experimental arm and 9% of those in the control arm left the study because of adverse events.
HIV virological breakthrough was observed in 3 of 64 patients on boceprevir and 4 of 34 patients on placebo.
In sum, tritherapy with Peg-IFN, ribavirin and telaprevir or boceprevir in HIV-1-infected patients with previously untreated HCV genotype 1 infection yields SVR rates of 71% with telaprevir (SVR24) and 60.7% with boceprevir (W12 SVR).
These two trials confirm:
A 30–35% increase in SVR compared with standard bitherapy, as also observed in HCV-monoinfected patients,
No difference in SVR between the two antiretroviral drugs used in these trials.
The doses of Peg-IFN and ribavirin were those validated for bitherapy in patients with HCV genotype 1 infection.
The OPTIMIZE study compared, in previously untreated HCV-monoinfected patients, 2 vs 3 daily doses of telaprevir and showed that the two modalities were equivalent in terms of virological responses and tolerability. These excellent results justify the administration of 1125 mg of telaprevir every 12 h (with meals), which is simpler and more in line with current once- or twice-daily antiretroviral regimens.
Who to Treat? According to the latest guidelines, standard bitherapy (Peg-IFN + ribavirin) for hepatitis C is indicated in case of significant fibrosis (F ≥ 2) and/or extrahepatic manifestations, and/or factors predictive of a virological response (genotype 2 or 3, or genotype 1 with viral load <800 000 IU/ml).
The risks and benefits of anti-HCV tritherapy are different in patients with minimal fibrosis, due i) to better therapeutic efficacy and ii) to the possibility of new adverse effects, the risk of emergence of resistant viral variants in case of non-response, and the extra cost of protease inhibitors. The use of anti-HCV tritherapy in patients with minimal fibrosis must take into account both risk factors for fibrosis progression and predictors of a good response to pegylated biotherapy.
Like bitherapy, anti-HCV tritherapy is currently contraindicated in patients with decompensated cirrhosis. It has been shown that HCV eradication alleviates symptoms in patients with cryoglobulinaemia. It is therefore logical to use tritherapy in these subgroups, despite the lack of specific studies.
Predictors of the Response to Tritherapy. Pretreatment factors predictive of SVR have been analysed in phase III studies in HCV-monoinfected patients but not in HIV/HCV-coinfected patients.
In the ADVANCE trial of telaprevir, univariate analysis showed that age <40 years, female gender, absence of severe fibrosis, body mass index <25 kg/m and genotype 1b infection vs genotype 1a infection were all associated with a higher chance of SVR. The SVR rate was lower in patients with F3–F4 fibrosis than in those with F0–F2 fibrosis (62% vs 78% in the telaprevir arm (TRV12-PR). The IL28B polymorphism could be determined in 44% of these patients, and the SVR rate was 90% in CC patients, 71% in CT patients and 73% in TT patients. The gain provided by tritherapy compared with Peg-IFN + ribavirin bitherapy was larger in CT and TT patients than in CC patients (SVR: 50% vs 26%). The results of multivariate analysis are not yet available.
In the trial of boceprevir (SPRINT-2), predictors of SVR in multivariate analysis were ethnicity, HCV viral load, absence of cirrhosis and use of statins. SVR was more frequent in the absence of stage F3-F4 fibrosis (67% vs 52% in the boceprevir arm (BOC-PR48)). When included in a multivariate model, IL28B also emerged as an independent response predictor the SVR rate was 80% for genotype CC, 71% for CT and 59% for TT. Tritherapy was more effective than Peg-IFN + ribavirin bitherapy in CT carriers (SVR +41%) and TT carriers (+32%) but not in CC carriers (SVR: 78% vs 80%).
These analyses show that similar factors influence the response to Peg IFN-ribavirin bitherapy and to tritherapy, but that they have a smaller impact on tritherapy. Even in patients with predictors of poor response (IL28B non-CC genotypes, stage F3–F4 fibrosis), the chances of cure on tritherapy remain high (above 50%), and they are significantly higher than with bitherapy. In patients with factors of good response (IL28B genotype CC and fibrosis stage <F3), the chances of cure exceed 80%, although the gain provided by tritherapy seems smaller (telaprevir) or non-existent (boceprevir).
These factors now need to be studied in patients coinfected with HIV and HCV.
Can the Duration of Anti-HCV Tritherapy be Shortened in Some Patients? The effect of shortening tritherapy in HIV/HCV-coinfected patients has not been studied. In addition, HCV viral load is known to decay more slowly in coinfected patients. In the trial of boceprevir in coinfected HCV-treatment-naïve patients the proportion of patients with undetectable HCV viral load after 4 weeks of tritherapy seemed to be lower than that observed in HCV-monoinfected patients (42.2% vs 61–64% in the SPRINT 1 and SPRINT 2 trials) the two curves meeting after 8 weeks of tritherapy.
Trials are underway to determine whether shorter treatment can be offered to HIV/HCV-coinfected patients who experience RVR after one month of telaprevir tritherapy.
Can Some Anti-HCV-naïve Patients be Treated With the Peg-IFN + Ribavirin Combination? In HCV-monoinfected patients, AFEF considers that IL28B genotyping (currently not reimbursed in France) is useful for treatment decisions, including for naïve patients with genotype 1 infection and no severe fibrosis (F0–F2).
In naïve HCV genotype 1-monoinfected patients with predictors of a good response to treatment (IL28B CC genotype and fibrosis <F3), the chances of cure are of the order of 80% with bitherapy, while tritherapy adds little or nothing to the results. Bitherapy is thus considered a possible first-line treatment, and should be continued if an RVR is achieved.
In patients coinfected with HIV and HCV, these recommendations would require lengthy treatment (48 weeks), while tritherapy lasts only 24 weeks in similar patients with isolated HCV infection. A study presented at the 2012 AASLD meeting suggests that, in HCV-monoinfected patients with baseline viral load <600 000 IU/ml and RVR after four weeks of bitherapy, 24 weeks of bitherapy is as effective as boceprevir tritherapy, regardless of the IL28B genotype. However, this has not been demonstrated in coinfected patients, in whom a total treatment duration of 48 weeks remains necessary for the moment. If these arguments support the possibility of bitherapy in highly selected coinfected patients taking initial HCV viral load into account, and if, in addition, bitherapy is the only option in countries that do not have access to tritherapy for economic reasons, clinical trial results tend to favour tritherapy over bitherapy for HIV/HCV-coinfected patients.
Patients With Prior Treatment Failure
Results of Tritherapy (Peg-IFN + Ribavirin + HCV Protease Inhibitor) in Patients With Prior Treatment Failure. Patients with HCV genotype 1 monoinfection in whom bitherapy with Peg-IFN + ribavirin (PR) has failed, a new course of bitherapy results in SVR rates ranging from 5 to 40%, depending on the type of response to first-line treatment (relapse, partial response or no response), using regimens that differ in terms of the dose and type of interferon, the ribavirin dose and the treatment duration. Ribavirin doses of 1000–1200 mg/day (based on body weight) and a treatment period of 72 weeks yield higher SVR rates in HIV/HCV-coinfected patients than lower doses and shorter treatment, in both patients with HCV genotype 1 and genotype 2–3 infection. However, in routine practice, treatment optimization (including patient education, residual ribavirin assay allowing the ribavirin dose to be adapted, 'recommendations' on erythropoietin or GCSF prescription to mitigate adverse effects, as well as longer treatment) seems to provide only a moderate additional benefit. This was confirmed by the modest results of the Syren study of monoinfected patients and the ETOC study of coinfected patients. Therapeutic alternatives are urgently needed for these patients.
In patients coinfected with HIV and HCV, two pilot trials sponsored by ANRS, named Telaprevih and Boceprevih, evaluated the relative effectiveness of telaprevir and boceprevir in patients in whom previous treatment had failed. The study populations consisted of patients with CD4 cell counts >200/mm and undetectable HIV viral load for at least 6 months, and did not include patients who were both cirrhotic and non-responders. After an initial 4 weeks of bitherapy, the planned total duration of treatment is 48 weeks for patients with an early virological response (HCV RNA <15 IU/ml at W8) and 72 weeks for patients with no RVR8 but HCV <1000 IU/ml after 4 weeks of tritherapy. Preliminary safety and efficacy results at W16 were presented at CROI 2013.
In the TelapreVIH trial, 69 patients (70% with genotype 1 infection and 39% with stage F3/F4 fibrosis) received tritherapy with telaprevir, Peg-IFN alfa-2a and ribavirin after an induction phase of 4 weeks with Peg-IFN and ribavirin alone. Overall, at W16, 88% of patients had undetectable HCV RNA, regardless of the type of anti-HIV therapy, the degree of fibrosis and the initial virological response to prior treatment. The most common adverse effect was haematoxicity (grade 4 in 6% of cases, with two deaths outside the telaprevir phase, one because of cerebromeningeal bleeding secondary to immune thrombocytopenia induced by Peg-IFN, and the other to gastrointestinal bleeding related to portal hypertension). No HIV treatment escape was observed.
The Boceprevih trial included 64 patients, 78% of whom were infected by HCV genotype 1, 1.17% of whom had stage F4 fibrosis and 33% of whom had not responded to bitherapy. All began tritherapy with boceprevir, Peg-IFN alfa-2a and ribavirin after a 4-week lead-in period with Peg-IFN and ribavirin alone. At W16, 63% of patients had undetectable HCV RNA. The early response rate seemed to be influenced by the type of response to prior therapy (90% response rate in relapsers, 38% in non-responders); it was 70% with raltegravir and 56% with atazanavir, and did not differ according to the degree of fibrosis.
Grade 4 haematoxicity was observed in 5% of patients. No HIV treatment escape was noted.
These preliminary results suggest that tolerability is acceptable and that early virological efficacy is encouraging. Boceprevir may be less effective than telaprevir in non-responders to previous bitherapy.
The total treatment duration in patients in whom previous treatment has failed will be 48 weeks, and any attempt to reduce the total treatment duration should be evaluated with care, especially in patients with severe fibrosis (F3–F4) and/or comorbidities.
The risk/benefit ratio should be evaluated very closely in cirrhotic patients, in whom thrombocytopaenia (<100 000/ml) and hypoalbuminaemia (<35 g/L) may be a contraindication, as shown by the CUPIC study in monoinfected cirrhotic patients with prior treatment failure (0.7 to 2.5% mortality).
Patients with extrahepatic manifestations qualify for retreatment with tritherapy comprising a first-generation HCV protease inhibitor, regardless of the stage of fibrosis.
Predictors of the Response to Tritherapy. Predictors of the treatment response remain to be clarified in HIV/HCV-coinfected patients, but there is little reason to suppose they are not different from those observed in patients with isolated HCV infection in the phase III trials REALIZE and RESPOND-2.
The prior response profile is, statistically, the most powerful predictor. In the REALIZE trial of telaprevir the SVR rates in the tritherapy arm (with and without initial bitherapy, respectively) were 83% and 88% in relapsers, 54% and 59% in partial responders and 33% and 29% in non-responders. In the RESPOND-2 trial of boceprevir the SVR rates in the BOC-PR48 and BOC-PR-RGT arms were, respectively, 75% and 69% in relapsers, and 52% and 40% in partial responders. Non-responders excluded from this study were described in the PROVIDE study which suggested an SVR rate of 38%.
The stage of fibrosis was the second most important factor independently associated with SVR. In the REALIZE study, the overall results in the tritherapy arm in terms of SVR were 74% in patients at stage F0–F2, 66% at stage F3 and 47% in patients with cirrhosis. In relapsed patients, the fibrosis stage had no impact on SVR (F0–F2 86%, F3: 85%, F4: 84%). However, fibrosis had a major influence on SVR in partial responders (F0–F2 72%, F3: 56%, F4: 34%) and non-responders (F0–F2: 41%, F3: 39%, F4: 14%). It should be noted that the patients who are most difficult to treat with tritherapy are non-responders with cirrhosis, who had SVR rates below 15% (no significant difference with the control group, although numbers were small). In the RESPOND-2 study, fibrosis also had a major impact on the SVR rate, which ranged in the tritherapy arm from 66–68% in patients with stage F0–F2 fibrosis to 44–68% in patients with stage F3–F4 fibrosis.
Other, less important predictors of the virological response were also identified. Multivariate analysis of the REALIZE dataset identified, in addition to the prior response profile and fibrosis, the following predictors of a favourable response: a high level of LDL cholesterol, genotype 1b (vs 1a) and low baseline viral load and transaminase levels. In contrast, the IL28B polymorphism had no significant impact on SVR in either study, although this remains to be confirmed.
In sum, the response to prior treatment is the main predictor of the response to tritherapy. All these predictors are also likely to be valid in coinfected patients in whom treatment with Peg-IFN + ribavirin has failed.
Factors Influencing the Decision to use Tritherapy (Peg-IFN + Ribavirin + Protease Inhibitor) in Patients With Prior HCV Treatment Failure. In patients coinfected with HIV and HCV, the effectiveness of tritherapy must be carefully weighed up against the medium-term prognosis of liver disease (although the chance of SVR correlates negatively with the severity of fibrosis), the adverse effects of tritherapy, the complexity of drug-drug interactions, uncertainties surrounding the safety profile of newer antiretrovirals in patients with advanced-stage fibrosis or simple HCV coinfection, economic costs and the mid-term possibility of that new combinations of directly acting HCV antiviral agents will give better results as well as shorter and better-tolerated treatments. These patients are the first to enrol in clinical trials.
An additional consideration is the interactions of oral HCV antivirals with HIV antiretrovirals in patients for whom the priority is the treatment of HIV infection. These interactions are similar to those suggested in naïve patients. When possible, one should avoid antiretrovirals, and especially HIV protease inhibitors (atazanavir for boceprevir, telaprevir for fosamprenavir; lopinavir and darunavir for both boceprevir and telaprevir), which affect the metabolism of HCV protease inhibitors. Antiretroviral therapy should be adapted if necessary to the results of pharmacological monitoring (efavirenz combined with telaprevir).
In the case of telaprevir, the excellent results of the OPTIMIZE trial and the pharmacokinetic behaviour observed in coinfected patients support a simpler dose regimen of 1125 mg every 12 h with meals, which is more in line with current once- or twice-daily antiretroviral regimens.
How to Manage Patients' Expectations and to Prepare Them for Future Therapeutic Trials? One important issue is the need to better identify patients and the results of their previous treatments in hospital databases (Nadis®, Diamm G®), to offer them the best tritherapy or to advise them to wait for new treatments (second-generation protease inhibitors, nucleotide/nucleoside or other NS5B polymerase inhibitors, NS5A inhibitors of the replication complex), and to better define their therapeutic course and follow-up (treatment, concomitant antiretroviral combination, outcome of fibrosis and methods for its evaluation, doses, treatment periods, adherence to treatment, interactions, past and present comorbidities, dose adjustments and follow-up (especially psychiatric).
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