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Challenges with pharmacotherapy of HIV/HCV coinfection
Hepatitis C virus infection is common among individuals already infected with HIV, affecting about one-third of patients. Experts anticipate this number may only 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 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, explaining the very high incidence, more than 90%, of HCV coinfection and injection drug use in the HIV-positive population.
Besides overlapping risk factors, HIV/HCV 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. 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 HIV and HCV treatment.
Antiviral drug targets, toxicities and interactions
National recommendations for initial HIV treatment include four main classes of ART: 1) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs); 2) non-nucleoside reverse transcriptase inhibitors (NNRTIs); 3) 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) and ribavirin (RBV) remain not fully elucidated but involve immune system induction and direct antiviral activity including inhibition of HCV RNA polymerase.
Leah Molloy
Direct-acting antivirals (DAAs) for HCV have been developed much more recently, and the first-generation DAAs, the HCV NS3/4A PIs boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex), were introduced with 2011. These were followed in 2013 by another HCV NS3/4A PI, simeprevir (Olysio, Johnson & Johnson/Janssen), and a novel NS5B RNA-dependent RNA polymerase inhibitor, sofosbuvir (Sovaldi, Gilead). Use of the first generation of DAAs has been limited by their 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 HIV/HCV-coinfected patients.
As the toxicities of ART and HCV antivirals are numerous and varied, a thorough discussion of these is beyond the scope of this article. Ins tead, 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 used relatively commonly and can cause some of these effects. Importantly, anemia is a serious side effect of both RBV and zidovudine, and for this reason coadministration is not recommended. As anemia is also caused by the first-generation DAAs, HCV NS3/4A PIs boceprevir and telaprevir, zidovudine must not be given to any patient receiving one of these agents in combination with PEG 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 coadministered with the CYP3A4 inhibitors ritonavir (Norvir, AbbVie) or cobicistat, nor with CYP3A4 inducers such as efavirenz. Additionally, boceprevir and telaprevir are much stronger CYP3A4 inhibitors than simeprevir, increasing 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, nor is not metabolized by any of the CYP450 enzymes. However, as sofosbuvir is metabolized by p-glycoprotein (P-gp), it must not be coadministered 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 coadministered 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 coadministered 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 depended 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 for 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) demonstrate 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 considered.
A variety of initial treatment options exist for treatment-naive HIV patients, including the NNRTI-based regimen of efavirenz/tenofovir/emtricitabine (Atripla, Gilead) or PI-based regimens of tenofovir/emtricitabine (Truvada, Gilead) 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
Before the availability of DAAs, PEG plus RBV was the standard of care for HCV treatment, despite their 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 plus RBV compared with a higher, though 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 plus RBV alone. For example, 90% of monoinfected HCV patients, primarily genotype 1, treated with 12 weeks of PEG, RBV and sofosbuvir achieved SVR12. When the same regimen was given, with duration varying between 12 and 24 weeks, to HIV/HCV coinfected patients with genotypes 1, 2 and 3, SVR was achieved by 76%, 92% and 94%, respectively.
The advent of new DAAs, particularly sofosbuvir, has dramatically changed the approach taken for HCV treatment and presented an opportunity for PEG-sparing therapies. However, PEG may still be needed to treat patients urgently needing treatment who are unable to wait for soon-to-be approved new agents still in the drug development pipeline. Although PEG 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 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-eligible and PEG-ineligible HIV/HCV-coinfected patients. Expert recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America in collaboration with the International Antiviral Society-USA are continuously updated and available for public viewing at www.hcvguidelines.org.
For HIV-positive patients coinfected with HCV genotypes 2 or 3, a PEG-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 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, the most common and most difficult-to-treat genotype, should receive 24 weeks of PEG, 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 HIV/HCV-coinfected patients, and some extrapolation from monoinfected patient data. Coinfected HCV genotype 1 patients ineligible for PEG 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.
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