Liver International ISSN 1478-3223
REVIEW ARTICLE
Treating HCV in HIV 2013: on the cusp of change rie Martel-Laferrie re1 and Douglas T. Dieterich2 Vale 1 D epartement de Microbiologie et Infectiologie, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada 2 Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Keywords co-infection – direct acting antiviral agents – hepatitis C – HIV Abbreviations ARV, antiretrovirals; DAAs, direct acting antiviral agents; HCV, hepatitis C virus; PEGIFN, pegylated-interferon; RBV, ribavirin; RVR, rapid virological response; SVR12, sustained viral response at post-treatment week 12; SVR, sustained virological response.
Abstract Treating hepatitis C virus (HCV) in HIV/HCV co-infected patients is a challenge. Even if the benefits of achieving a sustained virological response are clear, the rates achieved with the combination of pegylated-interferon and ribavirin are disappointing. The addition of direct acting antiviral agents (DAAs) to the treatment of hepatitis C is revolutionizing the treatment of HCV in mono-infected patients. Even if there have not been any agents approved for the treatment of co-infected patients, many studies specifically designed for this population are ongoing. This article reviews available data on the use of DAAs in co-infected patients and the challenges associated with these new drugs.
Correspondence Douglas T. Dieterich, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA Tel: +212 241 7270 Fax: +212 241 4465 e-mail: [email protected] DOI:10.1111/liv.12396
Hepatitis C virus (HCV) co-infection is common in patients with HIV. Between 25 and 30% of HIV-infected patients are co-infected with HCV. Rates are even higher in populations where injection drug use is the principal mode of transmission of HIV. Co-infected patients tend to have lower on-treatment sustained virological response (SVR) rates. SVR rates in the first trials of co-infected patients using pegylatedinterferon (PEG-IFN) and fixed dose ribavirin (RBV), were 14–29% in genotype 1 and 44–73% in genotypes non-1 patients (1–3). The use of weight-based RBV improved the rates to 36–38% in genotype 1 and 53–72% in genotype non-1 patients, which are still lower than the rates in mono-infected patients (40–60% in genotype 1 and 70–80% in genotypes 2 and 3 patients) (1, 4). Nevertheless, co-infected patients can achieve a durable on-treatment SVR (5). Like in mono-infected patients, the benefits of the reduction in fibrosis, liver decompensation and all causes of mortality are clear (6, 7). The introduction of direct-acting antiviral agents (DAAs) has significantly improved the treatment outcomes in mono-infected patients (8). No agents have been approved for co-infected patients. The scope of this article is to review the management of HCV in coinfected patients in the era of DAAs. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pretreatment considerations HIV treatment optimization
There are no absolute rules on the optimization of HIV before initiating HCV treatment. Although most co-infected patients who are treated for HCV are on antiretroviral therapy (ARV), this is not essential. In patients with an indication for HIV treatment, ARV should be initiated first with a regimen that does not have any drug–drug interactions with HCV antivirals. Some co-infected patients may present elevated transaminases when ARV are begun and may need to receive HCV treatment first. Drug interactions
In the era of DAAs, drug–drug interactions are the biggest challenge that healthcare providers face in co-infected patients. For example, in our real-life study with telaprevir, 51.5% of co-infected patients had to change their HIV regimen before initiating HCV treatment to avoid drug–drug interactions (9). This is often complex for the healthcare provider, especially in multiexperienced patients. A switch in HIV regimen can be emotionally difficult for the patient, who may fear los-
53
Martel-Laferriere and Dieterich
Treating HCV in HIV 2013
ing control over HIV infection and developing new side effects. No relevant drug–drug interactions have been found for sofosbuvir (10). Telaprevir, boceprevir, faldaprevir and daclatasvir all act on the CYP3A (11–14). Faldaprevir also inhibits CYP2C9 and UGT1A1 (14). Simeprevir is an inhibitor of intestinal CYP3A and of CYP1A9 (15). Boceprevir and daclatasvir are p-glycoprotein inhibitors (12, 13). No clinically significant drug–drug interactions have been identified to date between tenofovir, emtricitabine and DAAs (11–15). Abacavir is generally considered to be an acceptable choice even if potential interactions involving the UDP-gucuronyltransferase cannot be ruled out for telaprevir. Zidovudine, stavudine and didanosine are contraindicated with PEG-IFN/RBV and are therefore not acceptable options with the PEG-IFN/ RBV-containing DAA regimens. Many interactions have been identified with non-nucleoside reverse transcriptase inhibitors. Efavirenz is contraindicated with boceprevir and simeprevir (12, 15). It can be used with telaprevir, faldaprevir and daclatasvir, but dosages of DAAs must be increased (telaprevir: 1125 mg p.o. t.i.d.; faldaprevir: 240 mg p.o. OD; daclatasvir: 90 mg p.o. OD (15–17). The integrase inhibitor raltegravir does not interact significantly with the telaprevir, boceprevir or simeprevir (15, 18, 19). The HIV protease inhibitors (PI) are more complicated. Atazanavir boosted with ritonavir (/r) is considered to be an acceptable combination with telaprevir, while significant interactions have been noted for lopinavir/r, darunavir/r and fosamprenavir/r (20). Even if they have been used in the phase II trials, PI should not be combined with boceprevir to avoid HIV escape (21). Boceprevir reduces lopinavir/r, atazanavir/r and darunavir/r concentrations (22). Although PI were tested in trials on daclatasvir and faldaprevir for co-infected patients, the dose of the DAA had to be reduced in both cases (daclatasvir: 30 mg p.o. OD; faldaprevir: 120 mg p.o. OD) (13, 14). Darunavir/r is not recommended with simeprevir (15). Evaluation of cirrhosis
Before initiating HCV treatment, it is important to identify if the patient has cirrhosis. Currently PEG-IFNbased regimens are contraindicated in patients with decompensated cirrhosis. Treatment can be attempted in patients with compensated cirrhosis but the patient’s medical condition should be optimized first. Cirrhosis should be managed with regular procedures such as screening for hepatocellular carcinoma and oesophageal varices. Historically, didanosine use, bilirubin above the normal limit and pre-existent cirrhosis have been associated with a higher risk of liver decompensation in the treatment of co-infected patients (23). The CUPIC study evaluated the outcome of mono-infected patients with cirrhosis treated with telaprevir or boceprevir in an
54
early access program. This study found that low albumin (
REVIEW ARTICLE
Treating HCV in HIV 2013: on the cusp of change rie Martel-Laferrie re1 and Douglas T. Dieterich2 Vale 1 D epartement de Microbiologie et Infectiologie, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada 2 Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Keywords co-infection – direct acting antiviral agents – hepatitis C – HIV Abbreviations ARV, antiretrovirals; DAAs, direct acting antiviral agents; HCV, hepatitis C virus; PEGIFN, pegylated-interferon; RBV, ribavirin; RVR, rapid virological response; SVR12, sustained viral response at post-treatment week 12; SVR, sustained virological response.
Abstract Treating hepatitis C virus (HCV) in HIV/HCV co-infected patients is a challenge. Even if the benefits of achieving a sustained virological response are clear, the rates achieved with the combination of pegylated-interferon and ribavirin are disappointing. The addition of direct acting antiviral agents (DAAs) to the treatment of hepatitis C is revolutionizing the treatment of HCV in mono-infected patients. Even if there have not been any agents approved for the treatment of co-infected patients, many studies specifically designed for this population are ongoing. This article reviews available data on the use of DAAs in co-infected patients and the challenges associated with these new drugs.
Correspondence Douglas T. Dieterich, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA Tel: +212 241 7270 Fax: +212 241 4465 e-mail: [email protected] DOI:10.1111/liv.12396
Hepatitis C virus (HCV) co-infection is common in patients with HIV. Between 25 and 30% of HIV-infected patients are co-infected with HCV. Rates are even higher in populations where injection drug use is the principal mode of transmission of HIV. Co-infected patients tend to have lower on-treatment sustained virological response (SVR) rates. SVR rates in the first trials of co-infected patients using pegylatedinterferon (PEG-IFN) and fixed dose ribavirin (RBV), were 14–29% in genotype 1 and 44–73% in genotypes non-1 patients (1–3). The use of weight-based RBV improved the rates to 36–38% in genotype 1 and 53–72% in genotype non-1 patients, which are still lower than the rates in mono-infected patients (40–60% in genotype 1 and 70–80% in genotypes 2 and 3 patients) (1, 4). Nevertheless, co-infected patients can achieve a durable on-treatment SVR (5). Like in mono-infected patients, the benefits of the reduction in fibrosis, liver decompensation and all causes of mortality are clear (6, 7). The introduction of direct-acting antiviral agents (DAAs) has significantly improved the treatment outcomes in mono-infected patients (8). No agents have been approved for co-infected patients. The scope of this article is to review the management of HCV in coinfected patients in the era of DAAs. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pretreatment considerations HIV treatment optimization
There are no absolute rules on the optimization of HIV before initiating HCV treatment. Although most co-infected patients who are treated for HCV are on antiretroviral therapy (ARV), this is not essential. In patients with an indication for HIV treatment, ARV should be initiated first with a regimen that does not have any drug–drug interactions with HCV antivirals. Some co-infected patients may present elevated transaminases when ARV are begun and may need to receive HCV treatment first. Drug interactions
In the era of DAAs, drug–drug interactions are the biggest challenge that healthcare providers face in co-infected patients. For example, in our real-life study with telaprevir, 51.5% of co-infected patients had to change their HIV regimen before initiating HCV treatment to avoid drug–drug interactions (9). This is often complex for the healthcare provider, especially in multiexperienced patients. A switch in HIV regimen can be emotionally difficult for the patient, who may fear los-
53
Martel-Laferriere and Dieterich
Treating HCV in HIV 2013
ing control over HIV infection and developing new side effects. No relevant drug–drug interactions have been found for sofosbuvir (10). Telaprevir, boceprevir, faldaprevir and daclatasvir all act on the CYP3A (11–14). Faldaprevir also inhibits CYP2C9 and UGT1A1 (14). Simeprevir is an inhibitor of intestinal CYP3A and of CYP1A9 (15). Boceprevir and daclatasvir are p-glycoprotein inhibitors (12, 13). No clinically significant drug–drug interactions have been identified to date between tenofovir, emtricitabine and DAAs (11–15). Abacavir is generally considered to be an acceptable choice even if potential interactions involving the UDP-gucuronyltransferase cannot be ruled out for telaprevir. Zidovudine, stavudine and didanosine are contraindicated with PEG-IFN/RBV and are therefore not acceptable options with the PEG-IFN/ RBV-containing DAA regimens. Many interactions have been identified with non-nucleoside reverse transcriptase inhibitors. Efavirenz is contraindicated with boceprevir and simeprevir (12, 15). It can be used with telaprevir, faldaprevir and daclatasvir, but dosages of DAAs must be increased (telaprevir: 1125 mg p.o. t.i.d.; faldaprevir: 240 mg p.o. OD; daclatasvir: 90 mg p.o. OD (15–17). The integrase inhibitor raltegravir does not interact significantly with the telaprevir, boceprevir or simeprevir (15, 18, 19). The HIV protease inhibitors (PI) are more complicated. Atazanavir boosted with ritonavir (/r) is considered to be an acceptable combination with telaprevir, while significant interactions have been noted for lopinavir/r, darunavir/r and fosamprenavir/r (20). Even if they have been used in the phase II trials, PI should not be combined with boceprevir to avoid HIV escape (21). Boceprevir reduces lopinavir/r, atazanavir/r and darunavir/r concentrations (22). Although PI were tested in trials on daclatasvir and faldaprevir for co-infected patients, the dose of the DAA had to be reduced in both cases (daclatasvir: 30 mg p.o. OD; faldaprevir: 120 mg p.o. OD) (13, 14). Darunavir/r is not recommended with simeprevir (15). Evaluation of cirrhosis
Before initiating HCV treatment, it is important to identify if the patient has cirrhosis. Currently PEG-IFNbased regimens are contraindicated in patients with decompensated cirrhosis. Treatment can be attempted in patients with compensated cirrhosis but the patient’s medical condition should be optimized first. Cirrhosis should be managed with regular procedures such as screening for hepatocellular carcinoma and oesophageal varices. Historically, didanosine use, bilirubin above the normal limit and pre-existent cirrhosis have been associated with a higher risk of liver decompensation in the treatment of co-infected patients (23). The CUPIC study evaluated the outcome of mono-infected patients with cirrhosis treated with telaprevir or boceprevir in an
54
early access program. This study found that low albumin (
