Hepatitis C genotype 1 infection in HIV–Infected patients in the era of direct-acting antiviral therapy

Authors


  • Financial support for this study came from the National Institute on Drug Abuse (grants K24DA034621 and R01DA16065) and from the National Center for Research Resources (grant UL1RR025005), which is a component of the National Institutes of Health and the National Institutes of Health Roadmap for Medical Research.

  • Potential conflict of interest: Mark S. Sulkowski received consulting fees and research grants (via Johns Hopkins University) from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals, Gilead, Janssen, Merck, Roche/Genentech, and Vertex.

Abstract

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With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality.1 In addition to the high prevalence of chronic HCV (particularly among HIV-infected injection drug users), the rate of incident infections with HCV is increasing among HIV-infected men who have sex with men.2 Although the sexual transmission of HCV is an important focus for prevention, the long-term complications of chronic HCV infection, including end-stage liver disease and hepatocellular carcinoma, are leading causes of death in this population. Liver transplantation is an accepted but limited option at select medical centers.3 Accordingly, effective HCV treatment is needed to reduce the HCV disease burden in this population.

Over the last decade, treatment with peginterferon (PEG-IFN) and ribavirin (RBV) has been recommended for coinfected patients who are at the greatest risk for liver disease; however, the effectiveness of HCV treatment in this population has been disappointing. The reasons for its limited effectiveness include the low rates of treatment initiation, the high prevalence of relative and absolute contraindications to the drugs, and the low rates of sustained virological response (SVR) among those treated (especially individuals coinfected with HCV genotype 1 and African Americans). For example, in one study conducted primarily in the United States, SVR was achieved by 21% of coinfected patients with an HCV genotype 1 infection who received PEG-IFN/RBV therapy for 48 weeks; the SVR rates observed for black and Hispanic patients were lower than the rate observed for Caucasian patients.4 In this context, direct-acting antivirals for HCV hold promise because by targeting the virus, these drugs may overcome host factors (e.g., immunodeficiency) that may impair the efficacy of PEG-IFN. However, there are significant challenges to the use of direct-acting antivirals in patients with HIV/HCV confections, including the potential for interactions between different drugs, the addition of drug toxicities, and the ongoing need for therapy with PEG-IFN. Despite these challenges, preliminary data indicate that the HCV protease inhibitors (PIs), telaprevir (TVR) and boceprevir (BOC) in combination with PEG-IFN/RBV increase the HCV eradication rate [the rate of sustained virological response 12 weeks after the end of treatment (SVR-12)] with manageable toxicity and drug-drug interactions in HIV-infected patients.

Abbreviations

ART, antiretroviral therapy; BOC, boceprevir; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PEG-IFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response; SVR-12, sustained virological response 12 weeks after the end of treatment; TVR, telaprevir.

Boceprevir Plus PEG-IFN/RBV

BOC is approved for the treatment of HCV genotype 1 infections in patients without HIV infections. After 4 weeks of PEG-IFN/RBV therapy, BOC is added to the regimen for 24, 32, or 44 additional weeks of HCV therapy.5, 6 At the time of the initial approval of this HCV treatment regimen in the United States (May 2011), data on the safety, tolerability, efficacy, and drug interactions with antiretroviral agents were not available to guide its use in coinfected patients.

Subsequently, the results of a phase 2 study of HIV/HCV-coinfected patients and drug interaction studies in healthy volunteers have been presented, and they have provided critical information for the use of BOC with PEG-IFN/RBV (Table 1). In the clinical trial, patients with HCV genotype 1 who were taking antiretroviral therapy (ART) were randomized to receive BOC (n = 64) or a placebo (n = 34) plus PEG-IFN/RBV for 44 weeks after the completion of a 4 week lead-in phase with PEG-IFN/RBV alone (BOC treatment duration, 44 weeks; total treatment duration, 48 weeks). Notably, the treatment duration was 48 weeks for all patients in whom HCV RNA became undetectable; these patients included those with a rapid virological response (RVR). The use of response-guided therapy to shorten the treatment duration in patients with RVR was not assessed. In March 2012, preliminary SVR-12 results were presented at the Conference on Retroviruses and Other Opportunistic Infections.7 SVR-12 was achieved by 61% of the patients treated with BOC and PEG-IFN/RBV and by 26% of the patients treated with PEG-IFN/RBV. The difference in the SVR-12 rates of the BOC and placebo groups was approximately 34%. The types and severity of BOC-related adverse effects observed in this population were similar to the profile observed for patients with HCV mono-infections and included anemia, neutropenia, and gastrointestinal symptoms. Overall, these preliminary data on the safety and efficacy of BOC and PEG-IFN/RBV for the treatment of HCV in HIV-infected patients were promising.

Table 1. Phase 2 Clinical Trials of TVR and BOC With PEG-IFNα and RBV
 TVR*BOC
  • *

    The population consisted of HCV treatment–naive patients with genotype 1; 38 patients received TVR, and 22 patients received a placebo.

  • The population consisted of HCV treatment–naive patients with genotype 1; 64 patients received BOC, and 34 patients received a placebo.

HIV disease requirementsIf not on ART, CD4 < 500 and HIV RNA < 100,000 If on ART, CD4 > 300 and HIV RNA < 50CD4 ≥ 200 cells/mm3 HIV RNA < 50 copies/mL
  
Antiretroviral TherapyEfavirenz and tenofovir/emtricitabineNo non-nucleos(t)ide analogue reverse-transcriptase inhibitors
Atazanavir and tenofovir/emtricitabineAll other HIV drugs permitted
No ARTYesNo
HCV regimenTVR (750 mg every 8 hours or 1125 mg every 8 hours if efavirenz is coadministered), PEG-IFNα2a (180 μg/week), and fixed-dose RBV (800 mg/day)BOC (800 mg every 8 hours), PEG-IFNα2b (1.5 μg/kg/day), and weight-based RBV (600-1400 mg/day)
Duration of TVR or BOC12 weeks44 weeks (after a 4-week PEG-IFN/RBV lead-in period)
Duration of PEG-IFN/RBV48 weeks48 weeks
Response-guided therapyNoNo
SVR-12 rateTVR/PEG-IFN/RBV: 74%BOC/PEG-IFN/RBV: 61%
PEG-IFN/RBV: 45%PEG-IFN/RBV: 26%

However, in February 2012, studies of BOC interactions with antiretrovirals in healthy volunteers identified potentially important bidirectional interactions with several commonly used antiretrovirals, including some of the drugs used in the phase 2 clinical trial of BOC and PEG-IFN/RBV; these findings were reported in a letter to health care providers.8 BOC is primarily metabolized by aldo-keto reductase, but the drug is also a substrate and inhibitor of cytochrome P450 3A4/5 and P-glycoprotein enzymes and appears to interact with HIV antiretrovirals metabolized by these pathways. According to drug interaction studies in healthy volunteers, BOC can be coadministered with raltegravir; however, the coadministration of BOC with efavirenz and several ritonavir-boosted HIV1 PIs (including atazanavir, darunavir, and lopinavir) cannot be recommended because of the lowering of the antiretroviral and/or BOC concentrations to levels that may be associated with decreased effectiveness. Interestingly, because the pharmacokinetic interactions of HIV PIs with BOC were not identified before the approval of BOC and before the completion of the HIV/HCV coinfection trial; some coinfected patients have received HIV PIs and BOC during HCV treatment. Although in the clinical trial no significant clinical impact of these drug interactions was observed in the treated coinfected patients taking ritonavir-boosted HIV PIs, because of the small number of exposed patients, the potential for clinical consequences of these combinations (e.g., HIV breakthrough) cannot be excluded. As such, the prescribing information for BOC has been updated to reflect the need to avoid the coadministration of BOC and ritonavir-boosted HIV PI regimens. Although additional trials are underway to determine the clinical importance of these interactions, current guidance suggests that BOC treatment with PEG-IFN/RBV should be limited to HIV-infected patients taking raltegravir plus two nucleos(t)ide analogue reverse transcriptase inhibitors or to HIV-infected patients with high CD4 cell counts who do not require ART.

Telaprevir Plus PEG-IFN/RBV

TVR is approved for the treatment of HCV genotype 1 infections in patients without HIV infections. TVR is administered in combination with PEG-IFN/RBV for the initial 12 weeks of HCV therapy, and this is followed by 12 or 36 weeks of additional treatment with PEG-IFN/RBV.9 At the time of the initial approval of this regimen in the United States (May 2011), data on the safety, tolerability, efficacy, and drug interactions with antiretroviral agents were not available to guide its use in coinfected patients.

Subsequently, the results of a phase 2 study of HIV/HCV-coinfected patients and drug interaction studies in healthy volunteers have been presented, and they have provided critical information for the use of TVR with PEG-IFN/RBV (Table 1). In the clinical trial, patients with HCV genotype 1 who were or were not taking ART (ritonavir-boosted atazanavir or efavirenz plus tenofovir/emtricitabine) were randomized to receive TVR (n = 38) or a placebo (n = 22) plus PEG-IFN/RBV for 12 weeks, and this was followed by 36 additional weeks of PEG-IFN/RBV alone (TVR treatment duration, 12 weeks; total treatment duration, 48 weeks).10 Notably, the treatment duration was 48 weeks for all patients in whom HCV RNA became undetectable; these patients included those with RVR. The use of response-guided therapy to shorten the treatment duration in persons with RVR was not assessed. In March 2012, preliminary SVR-12 results were presented at the Conference on Retroviruses and Other Opportunistic Infections. SVR-12 was achieved by 74% of the 38 patients treated with TVR and PEG-IFN/RBV and by 45% of the 22 patients treated with PEG-IFN/RBV. The difference in the SVR-12 rates of the BOC and placebo groups was 29%. The types and severity of TVR-related adverse effects observed in this population were similar to the profile observed for patients with HCV mono-infections and included anemia, pruritus, rash, and gastrointestinal symptoms. Overall, these preliminary data on the safety and efficacy of TVR and PEG-IFN/RBV for the treatment of HCV in HIV-infected patients were promising.

Because TVR is a substrate and inhibitor of cytochrome P450 3A4 and P-glycoprotein enzymes, the drug may interact with antiretroviral drugs metabolized by these pathways. According to drug interaction studies in healthy volunteers and data from coinfected patients in the trial, TVR can be coadministered with ritonavir-boosted atazanavir (atazanavir 300 mg/ritonavir 100 mg) and raltegravir at the standard recommended dose (750 mg of TVR every 7-9 hours) and with efavirenz at an increased dose (1125 mg of TVR every 7-9 hours); however, the coadministration of TVR with other ritonavir-boosted HIV1 PIs, including darunavir and lopinavir, is not recommended because of bidirectional drug interactions.11 In addition, the use of higher dose TVR (1125 mg) with efavirenz may be associated with increased costs for the HCV treatment regimen. Interaction studies with TVR and other antiretroviral drugs are needed before combinations with other agents can be recommended. Although additional trials are underway, current guidance suggests that TVR treatment with PEG-IFN/RBV should be limited to HIV-infected patients taking raltegravir or efavirenz (higher TVR dose) or atazanavir/ritonavir plus two nucleos(t)ide analogue reverse-transcriptase inhibitors or to HIV-infected patients with high CD4 cell counts who do not require ART (Table 2).

Table 2. Preliminary Recommendations for the Use of the HCV PIs TVR and BOC in HIV-Infected Patients With HCV Genotype 1 Infections
HIV RegimenHCV Regimen
  1. This table was adapted with permission from AIDSinfo.12

Not on ARTUse either BOC or TVR.
Raltegravir and 2 nucleos(t)ide analogue reverse-transcriptase inhibitorsUse either BOC or TVR.
Atazanavir/ritonavir and 2 nucleos(t)ide analogue reverse-transcriptase inhibitorsUse TVR.
Efavirenz and 2 nucleos(t)ide analogue reverse-transcriptase inhibitorsUse TVR at an increased dose of 1125 mg every 7 to 9 hours.
Other antiretroviral drugsIn accordance with the HIV treatment history and the HIV drug resistance (genotype) testing results, consider switching to the listed ART regimens to permit the use of BOC or TVR if possible.
Defer HCV treatment if the patient has no or mild portal fibrosis and agrees to regular monitoring of his or her HCV disease.
Consider PEG-IFN/RBV alone if the patient has characteristics that predict a favorable treatment response (the interleukin-28B CC genotype or an HCV RNA level < 400,000 IU/mL).

Conclusion

The treatment of HCV genotype 1 infections with TVR or BOC plus PEG-IFN/RBV in the setting of HIV coinfections is feasible; however, it is complicated by a high pill burden, drug interactions, and overlapping drug toxicities. In this context, the decision to treat chronic HCV should also consider the medical need for such treatment and should be based on an assessment of the HCV disease stage; some clinicians may choose to defer HCV therapy in HIV/HCV-coinfected patients with no or minimal liver fibrosis. If treatment with the PEG-IFN/RBV combination and one of the HCV nonstructural protein 3/4A PIs (BOC or TVR) is initiated, the HIV ART regimen may need to be modified to reduce the potential for drug interactions and/or toxicities that may develop during the period of concurrent HIV and HCV treatment. The challenges related to the use of TVR and BOC with concurrent ART underscore the importance of conducting studies to assess the potential for drug interactions with HCV direct-acting antiviral agents before the approval of the anti-HCV agents. Furthermore, the promising SVR-12 rates observed with TVR and BOC plus PEG-IFN/RBV provide further justification for assessing novel HCV therapies in this population.

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