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Keywords:

  • boceprevir;
  • co-infection;
  • hepatitis C virus;
  • HIV ;
  • telaprevir

Abstract

  1. Top of page
  2. Abstract
  3. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HCV monoinfected patients
  4. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HIV/HCV co-infected patients (Table 1)
  5. Conclusions
  6. Disclosure
  7. References

Hepatitis C virus (HCV) co-infection is common among HIV-infected patients. Over the past 15 years, effective HIV treatment has led to dramatic reductions in the incidence of AIDS-related death; over the same time period, HCV-related liver disease has emerged as a major cause of morbidity and mortality. Treatment with peginterferon (PEG-IFN) and ribavirin (RBV) has been recommended for the treatment of HCV infection in HIV-infected patients at the greatest risk of developing liver disease. However, the effectiveness of this HCV treatment has been low because of limited efficacy in patients infected with HCV genotype 1. More recently, HCV NS3/4A protease inhibitors, telaprevir and boceprevir, in combination with PEG-IFN/RBV have led to significantly higher sustained viral response rates in HIV-uninfected patients with HCV genotype 1 infection. The potential use of these agents in patients with HIV/HCV co-infection is complicated by the potential for drug interactions between antiretroviral drugs and the HCV protease inhibitors and uncertainty regarding the safety and effectiveness of the combination therapy in this population.

Abbreviations
AUC

Area under the curve

DAAs

direct-acting antiviral agents

NNRTI

non-nucleoside reverse transcriptase inhibitors

PEG-IFN

peginterferon

PI

Protease Inhibitor

RVR

rapid virological response

RBV

ribavirin

SVR

sustained virological response

Since the development and widespread application of effective medications for the treatment of HIV disease, co-infection with hepatitis C virus (HCV) has become an important cause of morbidity and mortality in HIV-infected patients. Compared with those without HIV infection, people with HIV co-infection are more likely to acquire HCV infection and patients with chronic HCV infection are more likely to progress to cirrhosis and suffer the complications of end-stage liver disease, hepatocellular carcinoma and death [1-3]. For more than a decade, HCV treatment in HIV-infected patients has been peginterferon (PEG-IFN) plus ribavirin (RBV) [4]. Although this treatment regimen has been recommended for use in HIV/HCV co-infected patients, the impact of HCV treatment in this population has been small. The reasons for the limited efficacy of HCV treatment include low rates of sustained virological response (SVR) in HIV-infected patients with HCV genotype 1 co-infection (14–29%) and a high prevalence of contraindications to the use of interferon alfa (e.g. depression). In patients with HCV genotype 1 infection alone, the use of direct-acting antiviral agents (DAAs) – telaprevir or boceprevir – in combination with PEG-IFN/RBV has led to significantly higher rates of SVR. However, these medications have also introduced additional toxicities and drug interactions to the HCV treatment regimen through inhibition of CYP3A, which potentially complicates the use of these agents in persons with HIV co-infection. Nonetheless, data from completed phase 2a clinical trials of HCV treatment with telaprevir or boceprevir plus PEG-IFN/RBV in HIV-infected patients support the cautious use of these DAAs in carefully selected co-infected patients on appropriate antiretroviral regimens. Although higher rates of HCV eradication should be obtained with these regimens, novel, interferon-sparing regimens with multiple DAAs are urgently needed to overcome the substantial barriers to the use of IFN alfa in this population.

PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HCV monoinfected patients

  1. Top of page
  2. Abstract
  3. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HCV monoinfected patients
  4. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HIV/HCV co-infected patients (Table 1)
  5. Conclusions
  6. Disclosure
  7. References

In 2011, the US Food and Drug Administration approved two HCV NS3/4A protease inhibitors (HCV PI) – telaprevir and boceprevir – for the treatment of chronic HCV genotype 1 infection [5-8] (Table 1). In combination with PEG-IFN/RBV, these DAAs administered orally every 8 h led to SVR in 68–75% of HCV genotype 1 infected treatment-naïve patients compared with only ∼40% of those treated with PEG-IFN/RBV plus placebo. These combination regimens also led to higher rates of SVR in persons who had failed prior treatment with PEG-IFN/RBV. However, the likelihood of response to the DAA regimen was influenced by the extent of the prior response to therapy. While triple therapy with an HCV PI plus PEG-IFN/RBV increased the SVR rate in nearly all patients, the effectiveness of IFN alfa in the specific patient or patient population has influenced the effectiveness of the combination regimen. Patients with unfavourable characteristics for a response to interferon such as IL28B genotype CT or TT, cirrhosis or African origin, were less likely to achieve SVR than those with more favourable characteristics. The extent of the response to interferon after 4 weeks of PEG-IFN/RBV before adding HCV PIs was also highly predictive of the likelihood of achieving SVR. Historically, patients with HIV co-infection have a poor response to PEG-IFN/RBV. In a recent large, multicentre, North American study of PEG-IFN/RBV, PARIDIGM, only ∼25% of Caucasian patients and ∼15% of African-American patients with HIV/HCV genotype 1 co-infection achieved SVR [9]. This relatively low SVR rate suggested that the extent of the increase in SVR with the addition of HCV PIs to PEG-IFN/RBV could be blunted in this patient population. While further clinical trials are needed, the relatively high SVR rates observed in phase 2a studies of telaprevir and boceprevir have addressed some of the questions on the impact of HCV PIs on SVR in HIV/HCV co-infected patients. Additional considerations for the use of these agents include the management of drug interactions between antiretroviral agents that induce or are metabolized by CYP3A and the HCV PIs as well as the toxicities of these agents including anaemia, rash and gastrointestinal symptoms.

Table 1. Phase 2a clinical trials of telaprevir or boceprevir plus peginterferon alfa and ribavirin for the treatment of HCV genotype 1 infection in persons co-infected with HIV
TelaprevirBoceprevir
Patient population
60 patients (Telaprevir, 38; placebo, 22)98 patients (Boceprevir, 64; placebo, 34)
HCV treatment naïveHCV treatment naïve
HCV genotype 1HCV genotype 1

Part A enrolled patients not receiving antiretroviral therapy (n = 13)

 Part B enrolled patients receiving antiretroviral therapy

All patient received antiretroviral therapy

CD4 ≥ 500 cells/mm3 if not on antiretroviral therapy

 CD4 ≥ 300 cells/mm3 if taking antiretroviral therapy

CD4 ≥ 200 cells/mm3
HIV RNA ≤100 000*; ≤50** copies/mlHIV RNA <50 copies/ml
Antiretroviral therapy
Efavirenz or ritonavir-boosted atazanavir plus tenofovir/emtricitabineRitonavir-boosted lopinavir or atazanavir or darunavir; raltegravir plus nucleos(t) reverse transcriptase inhibitors
Other drugs excludedEfavirenz excluded
HCV therapy

Telaprevir 750 mg every 8 h + PegIFN alfa-2a 180 mcg/week + RBV 800 mg/day*

Patients taking efavirenz received telaprevir 1125 mg every 8 h

 *5 patients received weight-based ribavirin dosing (1000 or 1200 mg/day)

Boceprevir 800 mg every 8 h + PegIFN alfa-2b (1.5 mcg/kg/day) + weight-based RBV (600–1400 mg/day)
No lead-in phase of PegIFN/RBVLead-in phase of PegIFN/RBV
Telaprevir duration, 12 weeksBoceprevir duration, 44 weeks
PegIFN/RBV duration, 48 weeksPegIFN/RBV duration, 48 weeks
Sustained virological response (12 weeks after stopping therapy)

74% Telaprevir

 45% Placebo

60.7% Boceprevir

26.5% Placebo

Three patients undetectable at FW4 have not yet reached post-treatment week 12 and were not included in SVR12 analysis

PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HIV/HCV co-infected patients (Table 1)

  1. Top of page
  2. Abstract
  3. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HCV monoinfected patients
  4. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HIV/HCV co-infected patients (Table 1)
  5. Conclusions
  6. Disclosure
  7. References

Efficacy

On March 5, 2012, the results of two phase 2a studies of HCV PI plus PEG-IFN/RBV for the treatment of HCV genotype 1 infection in HIV-infected patients were presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) [10].

In a study of telaprevir, 60 HIV-HCV co-infected patients were randomized to treatment with 12 weeks of combination therapy with telaprevir (n = 38) or placebo (n = 22) plus PEG-IFN/RBV, followed by 36 weeks of PEG-IFN/RBV alone. Response-guided therapy was not evaluated. All patients who met the protocol response criteria were treated for 48 weeks. Twelve weeks after stopping therapy, the SVR12 rate, defined as no detectable HCV RNA, was 74% (28/38) in patients treated with telaprevir plus PEG-IFN/RBV and 45% (10 of 22) in patients treated with PEG-IFN/RBV alone. Although the study was not powered to confirm the statistical significance of the increased SVR rate, the increase in SVR with telaprevir compared with the control group (+ 29%) was similar to that observed in other populations including patients with HCV infection alone. Based on these results, larger, phase 3 studies of telaprevir plus PEG-IFN/RBV are ongoing to evaluate the effectiveness of this regimen in HIV/HCV co-infected patients who are treatment naïve for HCV and in those who have failed prior treatment with PEG-IFN/RBV. These studies will test response-guided therapy with 24 weeks of treatment in patients who achieve a rapid virological response (RVR) as well as the use of telaprevir 1125 mg every 12 h (ClinicalTrials.gov Identifier: NCT01335529 and NCT01482767). These studies should be completed in 2014.

In a study of boceprevir, 98 patients with HIV-HCV co-infection were randomized to treatment with 4 weeks of PEG-IFN/RBV (‘lead-in’ phase) followed by 44 weeks of combination therapy with boceprevir 800 mg every 8 h (n = 64) or placebo (n = 34) plus PEG-IFN/RBV. The SVR12 rate, defined as no detectable HCV RNA 12 weeks after discontinuing treatment, was 60.7% (37/61 patients)) in patients treated with boceprevir plus PEG-IFN/RBV compared with 26.5% (9/34) in patients treated with PEG-IFN/RBV alone. In addition, three patients treated with boceprevir plus PEG-IFN/RBV had undetectable HCV RNA 4 weeks after treatment (SVR4), but had not yet reached the 12-week post-treatment assessment. As in the telaprevir study, the size of the protocol was not large enough to determine the significance of the increase in SVR between the groups. However, the increase in SVR between boceprevir and the control group (+ 34%) was similar to that observed in other populations including HCV monoinfected patients. Larger, phase 3 studies of boceprevir plus PEG-IFN/RBV are ongoing to evaluate the effectiveness of this regimen in HIV/HCV co-infected patients who are HCV treatment naïve and in those who have failed prior treatment with PEG-IFN/RBV (ClinicalTrials.gov Identifier NCT01482767). Besides confirming the safety and efficacy of this regimen in co-infected patients, the study by the AIDS Clinical Trials Group (ACTG) will carefully assess the pharmacokinetics of boceprevir and antiretroviral drugs as well as response-guided therapy with 28 weeks of treatment in patients who achieve RVR. These studies should be completed by 2015.

Safety

The addition of telaprevir to PEG-IFN/RBV in patients with HCV monoinfection has been associated with rash in approximately 56% with severe rash leading to telaprevir discontinuation in 5–7% of treated patients. In addition, patients taking telaprevir were more likely to experience anaemia compared with the control group, which in some cases resulted in RBV dose reduction or discontinuation, blood transfusion or treatment cessation. Gastrointestinal side effects such as nausea and anorectal pain were also noted. In the study of telaprevir in HIV/HCV co-infected patients, the adverse effect profile was similar to that observed in HCV monoinfected patients with an increased incidence of nausea, rash (34% vs. 23%) and anaemia observed in patients taking telaprevir. However, no severe rash events were observed and the rate of anaemia in the telaprevir group was not markedly increased compared with placebo. The reason for the modest anaemia effect in this population compared with prior studies was not expected, but may be caused by the use of lower dose of RBV. Thirty three of 38 patients treated with telaprevir took 800 mg day dose of RBV as this is the approved dose in the United States for the treatment of HCV in HIV/HCV co-infected patients with PEG-IFN alfa-2a plus RBV. Whether higher doses of RBV will cause more anaemia with telaprevir in HIV/HCV co-infected patients is not known. Overall, three telaprevir-treated patients discontinued treatment because of adverse effects.

In patients with HCV monoinfection, the addition of boceprevir to PEG-IFN/RBV has been associated with anaemia with approximately 43% of patients requiring epoetin alfa. In a study of boceprevir in HIV-infected patients, boceprevir-treated patients were more likely to experience anaemia (41% vs. 26%), neutropaenia (19% vs. 6%) and gastrointestinal symptoms including diarrhoea and vomiting compare with those treated with placebo. However, the incidence of haemoglobin below 8 g/dl was similar in both groups (3%, placebo; 5% boceprevir) and the use of epoetin alfa and blood transfusion was also similar in both groups. Treatment discontinuation owing to an adverse event was more common in the boceprevir group (20%) than in the placebo group (9%).

The results of the phase 2a studies suggest that the adverse effect profile of telaprevir and boceprevir is similar in HIV/HCV co-infected patients and HCV monoinfected patients. However, this must be confirmed in larger phase 3 studies before the safety and tolerability of these agents can be fully described in this population.

Antiretroviral drug interactions

Telaprevir and boceprevir both interact with CYP3A as inhibitors and substrates, raising the potential for interactions. Boceprevir is metabolized primarily by aldo-ketoreductase and is also a strong inhibitor of and partially metabolized by CYP3A4. Telaprevir is also an inhibitor and substrate of CYP3A4 [11, 12].

In the studies in healthy volunteers, telaprevir was combined with ritonavir-boosted HIV protease inhibitors including atazanavir, darunavir, fosamprenavir and lopinavir. Telaprevir led to significant reductions in the concentrations of darunavir (area under the curve (AUC) decreased by 40%) and fosamprenavir (AUC decreased by 47%), but there was less impact with lopinavir (AUC unchanged) and atazanavir (AUC decreased by 17%). Conversely, the HIV protease inhibitors led to significant reductions in telaprevir concentrations (AUC decreased by 20% to 54%) with the least impact observed with atazanavir. Based on these studies, atazanavir boosted with ritonavir was permitted in the phase 2 study of telaprevir in HIV-infected patients while other HIV protease inhibitors were not allowed. Co-administration with efavirenz led to a 20% reduction in the AUC of telaprevir. This effect was offset by the administration of a higher dose of telaprevir, 1125 mg every 8 h. More recently, similar healthy volunteer studies did not show any significant interactions between telaprevir and the HIV integrase inhibitor, raltegravir or the HIV non-nucleoside reverse transcriptase inhibitors (NNRTI), etravirine and rilpivirine. Thus, studies in healthy volunteers and patients suggest that telaprevir can be used in combination with two NNRTI plus other agents including atazanavir/ritonavir, efavirenz, etravirine or rilpivirine.

In healthy volunteer studies, co-administration of boceprevir increased efavirenz concentrations, but reduced boceprevir concentrations. Similar interactions were observed with the HIV protease inhibitor, ritonavir, an inhibitor of CYP3A4. In the phase 2a clinical trial, patients receiving efavirenz and other NNRTI were not enrolled. Based on the predictions of an absence of clinically significant drug interactions, the phase 2a trial of boceprevir enrolled co-infected patients receiving ritonavir-boosted HIV protease inhibitors. However, in February 2012, data from healthy volunteers suggested that potentially significant interactions between boceprevir and ritonavir-boosted atazanavir, lopinavir and darunavir might reduce the effectiveness of these drugs when they are used together. The co-administration of boceprevir resulted in reduced mean concentrations of ritonavir-boosted atazanavir, lopinavir and darunavir by 49, 43 and 59% respectively. The co-administration of lopinavir/ritonavir and ritonavir-boosted darunavir decreased the AUC of boceprevir by 45 and 32% respectively. Thus, based on current data, the use of boceprevir should be limited to HIV/HCV co-infected patients who are not receiving antiretroviral therapy and those receiving raltegravir in combination with two NRTI.

Conclusions

  1. Top of page
  2. Abstract
  3. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HCV monoinfected patients
  4. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HIV/HCV co-infected patients (Table 1)
  5. Conclusions
  6. Disclosure
  7. References

In this era of effective antiretroviral therapy, liver disease as a result of chronic HCV infection is an important cause of morbidity and mortality in HIV-infected patients. Treatment of HCV infection in this population has been limited by the relatively poor response to PEG-IFN/RBV therapy with only 15–29% of SVR in patients infected with HIV and HCV genotype 1 infection. DAAs are very promising for the treatment of HCV in this population. However, initial studies of telaprevir and boceprevir did not include co-infected patients. The risk of drug interactions between these agents and antiretroviral drugs increases the complexity of their use in co-infected patients. Nevertheless, data from two small, phase 2a studies are promising with higher SVR rates in patients treated with these HCV PIs than in placebo groups and adverse effects similar to those observed in people without HIV. While larger studies are needed to confirm the safety, tolerability and efficacy of these agents, their cautious use may be justified in carefully selected HIV/HCV co-infected patients.

Disclosure

  1. Top of page
  2. Abstract
  3. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HCV monoinfected patients
  4. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HIV/HCV co-infected patients (Table 1)
  5. Conclusions
  6. Disclosure
  7. References

Dr Sulkowski reported receiving consulting fees and research grants to Johns Hopkins University from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals, Gilead, Janssen, Merck, Roche/Genentech, and Vertex.

Financial support: Financial support for this study came from grants K24DA034621 and R01DA16065 from the National Institute on Drug Abuse (NIDA), and UL1RR025005 from the National Center for Research Resources (NCRR), components of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research.

References

  1. Top of page
  2. Abstract
  3. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HCV monoinfected patients
  4. PEG-IFN/RBV plus HCV NS3/4A protease inhibitors in HIV/HCV co-infected patients (Table 1)
  5. Conclusions
  6. Disclosure
  7. References