HCV Rx

Challenges with Pharmacotherapy of HCV/HIV Coinfection

Hepatitis C virus infection is common among individuals already infected with HIV, affecting about one-third of patients. Experts anticipate this number may increase given the shared risk factors for acquisition of both infections. In fact, a proportional rise in the sexual transmission of HCV has been observed since antiretroviral therapy (ART) became widely available in the mid-1990s, possibly reflecting longer duration and improved quality of life, and perhaps a perception of fewer risks associated with unprotected sexual intercourse while receiving treatment for HIV. However, blood exposure remains the most efficient mode of infection, which explains the very high incidence, more than 90%, of HCV coinfection and injection drug use in the HIV-positive population.

Leah Molly PharmD

Leah Molloy

In addition to overlapping risk factors, HCV/HIV coinfected patients are at risk for more aggressive disease, likely owing to the chronic inflammation, enhanced viral translocation, impaired T-cell response and the baseline hepatic impairment often observed among patients infected with HIV infection. As a result, coinfected patients typically present with higher initial viral loads, lower rates of spontaneous viral clearance and faster progression to hepatic fibrosis and cirrhosis.

For these reasons, national guidelines recommend prioritizing all coinfected patients for prompt initiation of both HCV and HIV treatment.

Drug Targets

National recommendations for initial HIV treatment include four main classes of ART: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors (PIs); and integrase strand transfer inhibitors (INSTIs). Until recently, antiviral targets of HCV treatment options were not well understood. The historical mainstays of treatment, pegylated interferon-alfa-2a (PEG-IFN) and ribavirin (RBV) remain not fully elucidated, but involve immune system induction and direct antiviral activity including inhibition of HCV RNA polymerase.

Direct-acting antivirals for HCV have been developed much more recently. The first-generation DAAs, the NS3/4A PIs boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals) were introduced in 2011. These were followed in 2013 by another NS3/4A PI, simeprevir (Olysio, Janssen Therapeutics) and a novel NS5B RNA-dependent RNA polymerase inhibitor, sofosbuvir (Sovaldi, Gilead). Use of the first-generation of DAAs has been limited by an unfavorable pill burden, drug-drug interactions and safety profiles. However, the newer DAAs are much better tolerated and simpler to incorporate into the already complex treatment regimens of HCV/HIV coinfected patients.

Drug Toxicities and Interactions

As the toxicities of ART and HCV antivirals are numerous and varied, a thorough review is beyond the scope of this column, and focus will be placed on the potential for overlapping drug toxicities. For example, RBV can independently cause a number of adverse effects similar to, and often worsened by, several NRTIs.

Stavudine (Zerit, Bristol-Myers Squibb) and didanosine (Videx, Bristol-Myers Squibb), the agents most strongly implicated in hepatic failure, lactic acidosis, peripheral neuropathy and pancreatitis, are no longer widely used in practice. However, zidovudine (Retrovir, GlaxoSmithKline) is still commonly used and can cause some of these effects. Importantly, anemia is a serious side effect of both RBV and zidovudine, and for this reason co-administration is not recommended. As anemia has been linked to the first-generation HCV DAAs, zidovudine must not be given to any patient receiving one of these agents in combination with PEG-IFN plus RBV. Fortunately, the second-generation DAAs have significantly better tolerability and drug-drug interaction profiles.

Owing to their inhibition of the CYP3A4 enzyme, HIV PIs are classically implicated in drug-drug interactions when co-managing a variety of disease states. HCV treatment is no exception, as the three HCV NS3/4A PIs boceprevir, telaprevir and simeprevir are all CYP3A4 substrates and should not be co-administered with the CYP3A4 inhibitors ritonavir (Norvir, AbbVie) or cobicistat, nor with CYP3A4 inducers like efavirenz. Additionally, boceprevir and telaprevir are much stronger CYP3A4 inhibitors than simeprevir, which increases their propensity to interact with other drugs. Sofosbuvir has a generally more favorable drug-drug interaction profile than other HCV DAAs because it does not inhibit nor induce, and is not metabolized by any of the CYP450 enzymes. However, as sofosbuvir is metabolized by p-glycoprotein (P-gp), it must not be co-administered with inducers of this protein. Fortunately, very few antiretroviral drugs commonly used in today’s clinical practice are P-gp inducers. Namely, the HIV PIs tipranavir (Aptivus, Boehringer Ingelheim) and nelfinavir (Viracept, Agouron) should not be co-administered with sofosbuvir.

Additionally, interactions between medications and food must be considered, especially when conflicting recommendations exist for different agents. For example, the HIV NNRTI efavirenz should be taken on an empty stomach, but the HCV NS3/4A PIs must be co-administered with food, presenting even more pharmacologic challenges.

HIV Treatment Considerations

In the setting of HIV monoinfection, the decision of when to initiate treatment has historically been debated and dependent upon a variety of factors including CD4 count, AIDS-defining illnesses and other comorbid conditions. However, the most recent updates to national guidelines recommend treating all HIV patients regardless of CD4 count as a measure to limit disease progression, and patients coinfected with HCV remain a priority for ART, and the expected benefits of controlling HIV as a means of slowing progression to cirrhosis are generally considered to outweigh the risks of hepatotoxicity due to antiretroviral agents.

In the setting of a coinfected patient naive to treatment for both infections, treatment decisions could be influenced by patient characteristics and risk for disease progression. For example, the national HIV treatment guidelines state that coinfected patients with high CD4 counts (ie, >500 cells/mm3) may delay ART until HCV treatment is completed as a means to avoid excessive pill burden and drug-drug interactions. The guidelines also suggest that it may be preferable to delay the initiation of HCV treatment until patients presenting with low CD4 counts (ie, < 200 cells/mm3), which demonstrates some improvement in cd4 count with art. however, the overall recommendation is that art should be initiated promptly for all hcv coinfected patients, regardless of cd4 count, and the potentially dangerous consequences of delaying treatment of either disease state must be carefully>

A variety of initial treatment options exist for treatment-naive patients with HIV, including the NNRTI-based regimen of efavirenz/tenofovir/emtricitabine, or PI-based regimens of tenofovir/emtricitabine with ritonavir-boosted atazanavir or darunavir. Additionally, a variety of INSTI-based regimens exist, generally combining tenofovir/emtricitabine with one of raltegravir, dolutegravir, or cobicistat-boosted elvitegravir. When initiating ART for a patient with HCV/HIV coinfection, consideration must be given to planned or concurrent HCV treatment. As described above, all HCV DAAs interact to some extent with at least some of the PIs, as well as cobicistat and efavirenz. Therefore, an unboosted INSTI-based regimen will likely present the most easily manageable ART course for patients being concomitantly treated for HCV.

HCV Treatment Considerations

Prior to the availability of DAAs, PEG-IFN plus RBV was the standard of care for HCV treatment, despite a suboptimal safety and efficacy profile, especially in the setting of HIV coinfection. HCV treatment has historically been less effective for patients coinfected with HIV compared with patients with HCV monoinfection, particularly for patients with HCV genotype 1. Success rates as low as 14% have been reported for HIV-coinfected patients treated with PEG-IFN plus RBV, compared with a higher, although still suboptimal, 46% cure rate among monoinfected HCV genotype 1 patients given the same regimen.

In contrast, HCV cure rates among patients treated with the new DAAs are similar between patients with HIV coinfection and those without, and much better than PEG-IFN plus RBV alone. For example, 90% of monoinfected HCV patients, primarily genotype 1, treated with 12 weeks of PEG-IFN, RBV and sofosbuvir achieved sustained virologic response at 12 weeks. When the same regimen was given to HCV/HIV coinfected patients with genotypes 1, 2 and 3, with duration varying between 12 and 24 weeks, SVR was achieved by 76%, 92% and 94%, respectively.

The advent of new DAAs, particularly sofosbuvir, has dramatically changed the approach taken HCV treatment and presented an opportunity for PEG-IFN–paring therapies. However, PEG-IFN may still be needed to treat patients who urgently need treatment and are unable to wait for soon-to-be approved new agents still in the drug development pipeline. While PEG-IFN has a number of warnings and contraindications important for all patients, these barriers may be even more significant for HIV coinfected patients. For example, reported relapse of drug addiction among patients receiving PEG-IFN and a contraindication for use among patients with decompensated cirrhosis are concerning because injection drug use is common among coinfected patients, as is more rapid progression to end-stage liver disease. Thus, it is important to establish guidelines for both PEG-IFN–eligible and PEG-IFN–ineligible HIV/HCV coinfected patients. Expert recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (IDSA) in collaboration with the International Antiviral Society-USA are continuously updated and available for public viewing at hcvguidelines.org.

For HIV-positive patients coinfected with HCV genotypes 2 or 3, a PEG-IFN–free regimen of sofosbuvir plus RBV may be used. For genotype 2, a 12-week duration of therapy is sufficient; however, 24 weeks of treatment should be given to patients infected with HCV genotype 3. PEG-IFN is still recommended, in combination with sofosbuvir and RBV, for eligible patients infected with HCV genotypes 1, 4, 5 and 6. Patients with genotype 1 should receive 24 weeks of PEG-IFN, RBV and sofosbuvir, while the duration of therapy may be shortened to 12 weeks for genotypes 4, 5 and 6. These recommendations are based on the PHOTON-1 study conducted in HCV/HIV co-infected patients, and some extrapolation from monoinfected patient data. Coinfected HCV genotype 1 patients ineligible for PEG-IFN should receive a 12-week course of off-label treatment with sofosbuvir with simeprevir, with the optional addition of RBV.

HIV/HCV coinfection presents a variety of unique challenges and treatment considerations, but is becoming increasingly safer and easier in the era of newer therapies for both infections.

References:

AASLD/IDSA/IAS-USA. Recommendations for testing, managing and treating hepatitis C. hcvguidelines.org. Accessed Aug. 11, 2014.

Chung RT. N Engl J Med. 2004;351:451-459.

Copegus [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2013.

Fried MW. N Engl J Med. 2002;347:975-982.

Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Inc.; 2013.

Lawitz E. N Engl J Med. 2013;368:1878-1887.

Naggie S. Gastroenterology. 2012;142:1324-1334.

Olysio [package insert]. Titusville, NJ: Janssen Products, LP; 2013.

Pegasys [package insert]. Nutley, NJ: Roche Pharmaceuticals; 2002.

Sovaldi [package insert]. Foster City, CA: Gilead Sciences Inc; 2013.

Sulkowski MS. JAMA. 2014;312:353-361.

Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.

Taylor LE. Clin Infect Dis. 2012;55:S33-S42.

US Department of Health and Human Services. AIDSinfo. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. http://aidsinfo.nih.gov. Accessed Aug. 11, 2014.

Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; 2013.

Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.

Disclosure: Molloy reports no relevant financial disclosures.

Hepatitis C virus infection is common among individuals already infected with HIV, affecting about one-third of patients. Experts anticipate this number may increase given the shared risk factors for acquisition of both infections. In fact, a proportional rise in the sexual transmission of HCV has been observed since antiretroviral therapy (ART) became widely available in the mid-1990s, possibly reflecting longer duration and improved quality of life, and perhaps a perception of fewer risks associated with unprotected sexual intercourse while receiving treatment for HIV. However, blood exposure remains the most efficient mode of infection, which explains the very high incidence, more than 90%, of HCV coinfection and injection drug use in the HIV-positive population.

Leah Molly PharmD

Leah Molloy

In addition to overlapping risk factors, HCV/HIV coinfected patients are at risk for more aggressive disease, likely owing to the chronic inflammation, enhanced viral translocation, impaired T-cell response and the baseline hepatic impairment often observed among patients infected with HIV infection. As a result, coinfected patients typically present with higher initial viral loads, lower rates of spontaneous viral clearance and faster progression to hepatic fibrosis and cirrhosis.

For these reasons, national guidelines recommend prioritizing all coinfected patients for prompt initiation of both HCV and HIV treatment.

Drug Targets

National recommendations for initial HIV treatment include four main classes of ART: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors (PIs); and integrase strand transfer inhibitors (INSTIs). Until recently, antiviral targets of HCV treatment options were not well understood. The historical mainstays of treatment, pegylated interferon-alfa-2a (PEG-IFN) and ribavirin (RBV) remain not fully elucidated, but involve immune system induction and direct antiviral activity including inhibition of HCV RNA polymerase.

Direct-acting antivirals for HCV have been developed much more recently. The first-generation DAAs, the NS3/4A PIs boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals) were introduced in 2011. These were followed in 2013 by another NS3/4A PI, simeprevir (Olysio, Janssen Therapeutics) and a novel NS5B RNA-dependent RNA polymerase inhibitor, sofosbuvir (Sovaldi, Gilead). Use of the first-generation of DAAs has been limited by an unfavorable pill burden, drug-drug interactions and safety profiles. However, the newer DAAs are much better tolerated and simpler to incorporate into the already complex treatment regimens of HCV/HIV coinfected patients.

Drug Toxicities and Interactions

As the toxicities of ART and HCV antivirals are numerous and varied, a thorough review is beyond the scope of this column, and focus will be placed on the potential for overlapping drug toxicities. For example, RBV can independently cause a number of adverse effects similar to, and often worsened by, several NRTIs.

Stavudine (Zerit, Bristol-Myers Squibb) and didanosine (Videx, Bristol-Myers Squibb), the agents most strongly implicated in hepatic failure, lactic acidosis, peripheral neuropathy and pancreatitis, are no longer widely used in practice. However, zidovudine (Retrovir, GlaxoSmithKline) is still commonly used and can cause some of these effects. Importantly, anemia is a serious side effect of both RBV and zidovudine, and for this reason co-administration is not recommended. As anemia has been linked to the first-generation HCV DAAs, zidovudine must not be given to any patient receiving one of these agents in combination with PEG-IFN plus RBV. Fortunately, the second-generation DAAs have significantly better tolerability and drug-drug interaction profiles.

Owing to their inhibition of the CYP3A4 enzyme, HIV PIs are classically implicated in drug-drug interactions when co-managing a variety of disease states. HCV treatment is no exception, as the three HCV NS3/4A PIs boceprevir, telaprevir and simeprevir are all CYP3A4 substrates and should not be co-administered with the CYP3A4 inhibitors ritonavir (Norvir, AbbVie) or cobicistat, nor with CYP3A4 inducers like efavirenz. Additionally, boceprevir and telaprevir are much stronger CYP3A4 inhibitors than simeprevir, which increases their propensity to interact with other drugs. Sofosbuvir has a generally more favorable drug-drug interaction profile than other HCV DAAs because it does not inhibit nor induce, and is not metabolized by any of the CYP450 enzymes. However, as sofosbuvir is metabolized by p-glycoprotein (P-gp), it must not be co-administered with inducers of this protein. Fortunately, very few antiretroviral drugs commonly used in today’s clinical practice are P-gp inducers. Namely, the HIV PIs tipranavir (Aptivus, Boehringer Ingelheim) and nelfinavir (Viracept, Agouron) should not be co-administered with sofosbuvir.

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Additionally, interactions between medications and food must be considered, especially when conflicting recommendations exist for different agents. For example, the HIV NNRTI efavirenz should be taken on an empty stomach, but the HCV NS3/4A PIs must be co-administered with food, presenting even more pharmacologic challenges.

HIV Treatment Considerations

In the setting of HIV monoinfection, the decision of when to initiate treatment has historically been debated and dependent upon a variety of factors including CD4 count, AIDS-defining illnesses and other comorbid conditions. However, the most recent updates to national guidelines recommend treating all HIV patients regardless of CD4 count as a measure to limit disease progression, and patients coinfected with HCV remain a priority for ART, and the expected benefits of controlling HIV as a means of slowing progression to cirrhosis are generally considered to outweigh the risks of hepatotoxicity due to antiretroviral agents.

In the setting of a coinfected patient naive to treatment for both infections, treatment decisions could be influenced by patient characteristics and risk for disease progression. For example, the national HIV treatment guidelines state that coinfected patients with high CD4 counts (ie, >500 cells/mm3) may delay ART until HCV treatment is completed as a means to avoid excessive pill burden and drug-drug interactions. The guidelines also suggest that it may be preferable to delay the initiation of HCV treatment until patients presenting with low CD4 counts (ie, < 200 cells/mm3), which demonstrates some improvement in cd4 count with art. however, the overall recommendation is that art should be initiated promptly for all hcv coinfected patients, regardless of cd4 count, and the potentially dangerous consequences of delaying treatment of either disease state must be carefully>

A variety of initial treatment options exist for treatment-naive patients with HIV, including the NNRTI-based regimen of efavirenz/tenofovir/emtricitabine, or PI-based regimens of tenofovir/emtricitabine with ritonavir-boosted atazanavir or darunavir. Additionally, a variety of INSTI-based regimens exist, generally combining tenofovir/emtricitabine with one of raltegravir, dolutegravir, or cobicistat-boosted elvitegravir. When initiating ART for a patient with HCV/HIV coinfection, consideration must be given to planned or concurrent HCV treatment. As described above, all HCV DAAs interact to some extent with at least some of the PIs, as well as cobicistat and efavirenz. Therefore, an unboosted INSTI-based regimen will likely present the most easily manageable ART course for patients being concomitantly treated for HCV.

HCV Treatment Considerations

Prior to the availability of DAAs, PEG-IFN plus RBV was the standard of care for HCV treatment, despite a suboptimal safety and efficacy profile, especially in the setting of HIV coinfection. HCV treatment has historically been less effective for patients coinfected with HIV compared with patients with HCV monoinfection, particularly for patients with HCV genotype 1. Success rates as low as 14% have been reported for HIV-coinfected patients treated with PEG-IFN plus RBV, compared with a higher, although still suboptimal, 46% cure rate among monoinfected HCV genotype 1 patients given the same regimen.

In contrast, HCV cure rates among patients treated with the new DAAs are similar between patients with HIV coinfection and those without, and much better than PEG-IFN plus RBV alone. For example, 90% of monoinfected HCV patients, primarily genotype 1, treated with 12 weeks of PEG-IFN, RBV and sofosbuvir achieved sustained virologic response at 12 weeks. When the same regimen was given to HCV/HIV coinfected patients with genotypes 1, 2 and 3, with duration varying between 12 and 24 weeks, SVR was achieved by 76%, 92% and 94%, respectively.

The advent of new DAAs, particularly sofosbuvir, has dramatically changed the approach taken HCV treatment and presented an opportunity for PEG-IFN–paring therapies. However, PEG-IFN may still be needed to treat patients who urgently need treatment and are unable to wait for soon-to-be approved new agents still in the drug development pipeline. While PEG-IFN has a number of warnings and contraindications important for all patients, these barriers may be even more significant for HIV coinfected patients. For example, reported relapse of drug addiction among patients receiving PEG-IFN and a contraindication for use among patients with decompensated cirrhosis are concerning because injection drug use is common among coinfected patients, as is more rapid progression to end-stage liver disease. Thus, it is important to establish guidelines for both PEG-IFN–eligible and PEG-IFN–ineligible HIV/HCV coinfected patients. Expert recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (IDSA) in collaboration with the International Antiviral Society-USA are continuously updated and available for public viewing at hcvguidelines.org.

PAGE BREAK

For HIV-positive patients coinfected with HCV genotypes 2 or 3, a PEG-IFN–free regimen of sofosbuvir plus RBV may be used. For genotype 2, a 12-week duration of therapy is sufficient; however, 24 weeks of treatment should be given to patients infected with HCV genotype 3. PEG-IFN is still recommended, in combination with sofosbuvir and RBV, for eligible patients infected with HCV genotypes 1, 4, 5 and 6. Patients with genotype 1 should receive 24 weeks of PEG-IFN, RBV and sofosbuvir, while the duration of therapy may be shortened to 12 weeks for genotypes 4, 5 and 6. These recommendations are based on the PHOTON-1 study conducted in HCV/HIV co-infected patients, and some extrapolation from monoinfected patient data. Coinfected HCV genotype 1 patients ineligible for PEG-IFN should receive a 12-week course of off-label treatment with sofosbuvir with simeprevir, with the optional addition of RBV.

HIV/HCV coinfection presents a variety of unique challenges and treatment considerations, but is becoming increasingly safer and easier in the era of newer therapies for both infections.

References:

AASLD/IDSA/IAS-USA. Recommendations for testing, managing and treating hepatitis C. hcvguidelines.org. Accessed Aug. 11, 2014.

Chung RT. N Engl J Med. 2004;351:451-459.

Copegus [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2013.

Fried MW. N Engl J Med. 2002;347:975-982.

Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Inc.; 2013.

Lawitz E. N Engl J Med. 2013;368:1878-1887.

Naggie S. Gastroenterology. 2012;142:1324-1334.

Olysio [package insert]. Titusville, NJ: Janssen Products, LP; 2013.

Pegasys [package insert]. Nutley, NJ: Roche Pharmaceuticals; 2002.

Sovaldi [package insert]. Foster City, CA: Gilead Sciences Inc; 2013.

Sulkowski MS. JAMA. 2014;312:353-361.

Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.

Taylor LE. Clin Infect Dis. 2012;55:S33-S42.

US Department of Health and Human Services. AIDSinfo. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. http://aidsinfo.nih.gov. Accessed Aug. 11, 2014.

Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; 2013.

Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.

Disclosure: Molloy reports no relevant financial disclosures.