(Last updated: April 8, 2015; last reviewed: April 8, 2015)
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
The management of hepatitis C virus (HCV)-infected patients is rapidly evolving. Data suggest that HIV/HCV-coinfected patients treated with all-oral HCV regimens have sustained virologic response rates comparable to those of HCV-monoinfected patients. The purpose of this section is to discuss hepatic safety and drug-drug interaction issues related to HIV/HCV coinfection and the concomitant use of antiretroviral (ARV) agents and HCV drugs. For specific guidance on HCV treatment, please refer to http://www.hcvguidelines.org/.
Among patients with chronic HCV infection, approximately one-third progress to cirrhosis, at a median time of less than 20 years.1,2 The rate of progression increases with older age, alcoholism, male sex, and HIV infection.3-6 A meta-analysis found that HIV/HCV-coinfected patients had a three fold greater risk of progression to cirrhosis or decompensated liver disease than HCV-monoinfected patients.5 The risk of progression is even greater in HIV/HCV-coinfected patients with low CD4 T lymphocyte (CD4) cell counts. Although antiretroviral therapy (ART) appears to slow the rate of HCV disease progression in HIV/HCV-coinfected patients, several studies have demonstrated that the rate continues to exceed that observed in those without HIV infection.7,8 Whether HCV infection accelerates HIV progression, as measured by AIDS-related opportunistic infections (OIs) or death,9 is unclear. Although some older ARV drugs that are no longer commonly used have been associated with higher rates of hepatotoxicity in patients with chronic HCV infection,10,11 newer ARV agents currently in use appear to be less hepatotoxic.
For more than a decade, the mainstay of treatment for HCV infection was a combination regimen of peginterferon and ribavirin (PegIFN/RBV), but this regimen was associated with a poor rate of sustained virologic response (SVR), especially in HIV/HCV-coinfected patients. Rapid advances in HCV drug development led to the discovery of new classes of direct acting antiviral (DAA) agents that target the HCV replication cycle. These new agents, when used with or without PegIFN and RBV, have been shown to achieve high SVR rates. The first DAA agents approved for the treatment of HCV infection in combination with PegIFN/RBV were the HCV protease inhibitors (PI), boceprevir and telaprevir. In HCV genotype 1 infected patients, the combined use of either boceprevir or telaprevir with PegIFN/RBV was associated with higher rates of SVR than use of PegIFN/RBV alone.12-15 However, combined use of these drugs was associated with a large pill burden, increased dosing frequency, and adverse effects. Subsequently approved DAA agents in the same class and in newer classes that are used with or without RBV have higher SVR rates, reduced pill burden, less frequent dosing, fewer side effects, and shorter durations of therapy.14,16-19 Therefore, the combination of boceprevir or telaprevir and PegIFN/RBV is no longer recommended, and has been replaced by newer combination regimens. Additional guidance on the treatment and management of HCV in HIV-infected and uninfected adults can be found at http://www.hcvguidelines.org/.20
Assessment of HIV/Hepatitis C Virus Coinfection
Antiretroviral Therapy in HIV/Hepatitis C Virus Coinfection
When to Start Antiretroviral Therapy
The rate of liver disease (liver fibrosis) progression is accelerated in HIV/HCV-coinfected patients, particularly in individuals with low CD4 counts (≤350 cells/mm3). Data largely from retrospective cohort studies are inconsistent regarding the effect of ART on the natural history of HCV disease;6,24,25 however, some studies suggest that ART may slow the progression of liver disease by preserving or restoring immune function and by reducing HIV-related immune activation and inflammation.26-28 Therefore, ART should be initiated in most HIV/HCV-coinfected patients, regardless of CD4 count (BII). However, in HIV treatment-naive patients with CD4 counts >500 cells/mm3, some clinicians may choose to defer ART until HCV treatment is completed to avoid drug-drug interactions (CIII). Compared to patients with CD4 counts>350 cells/mm3, those with CD4 counts <200 had lower HCV treatment response rates and higher rates of toxicity due to PegIFN/RBV.29 Data regarding HCV treatment response to combination therapy with DAA agents in those with advanced immunosuppression is lacking. For patients with lower CD4 counts (e.g., <200 cells/mm3), ART should be initiated promptly (AI) and HCV therapy may be delayed until the patient is stable on HIV treatment (CIII).23,30-32
Antiretroviral Drugs to Start and Avoid
Initial ARV combination regimens recommended for most HIV treatment-naive patients with HCV are the same as those recommended for patients without HCV infection. Special considerations for ARV selection in HIV/HCV-coinfected patients include the folllowing:
Drug-induced liver injury (DILI) following the initiation of ART is more common in HIV/HCV-coinfected patients than in those with HIV monoinfection. The greatest risk of DILI may be observed in coinfected individuals with advanced liver disease (e.g., cirrhosis, end-stage liver disease).33 Eradication of HCV infection with treatment may decrease the likelihood of ARV-associated DILI.34
Concurrent Treatment of HIV and Hepatitis C Virus Infection
Concurrent treatment of HIV and HCV is feasible but may be complicated by pill burden, drug-drug interactions, and toxicities. In this context, the stage of HCV disease should be assessed to determine the medical need for HCV treatment and inform decision making on when to start HCV. Additional guidance on the treatment and management of HCV in HIV-infected and uninfected adults can be found at http://www.hcvguidelines.org/. If the decision is to treat HCV, the ART regimen may need to be modified before HCV treatment is initiated to reduce the potential for drug-drug interactions and/or toxicities that may develop during the period of concurrent HIV and HCV treatment. (See Table 12 for recommendations on the concomitant use of selected drugs for treatment of HCV and HIV infection.) In patients with suppressed plasma HIV RNA and modified ART, HIV RNA should be measured within 4 to 8 weeks after changing HIV therapy to confirm the effectiveness of the new regimen. After completion of HCV treatment, the modified ART regimen should be continued for at least 2 weeks before reinitiating the original regimen. Continued use of the modified regimen is necessary because of the prolonged half-life of some HCV drugs and the potential risk of drug-drug interactions if a prior HIV regimen is resumed soon after HCV treatment is completed.
Considerations for the concurrent use of ART and recommended HCV agents (per http://hcvguidelines.org) are discussed below. Table 12 provides recommendations on the concomitant use of selected drugs for treatment of HCV and HIV infection.
Sofosbuvir is an HCV NS5B nucleotide polymerase inhibitors that is not metabolized by the cytochrome P450 enzyme system and, therefore, can be used in combination with most ARV drugs. Sofosbuvir is a substrate of p-glycoprotein (P-gp). P-gp inducers, such as tipranavir (TPV), may decrease sofosbuvir plasma concentrations and should not be co-administered with sofosbuvir. No other clinicially significant pharmocokinetic intractions between sofosbuvir and ARVs have been identified. Drug-drug interaction studies in healthy volunteers did not find any significant interaction between sofosbuvir and darunavir/ritonavir (DRV/r), efavirenz (EFV), rilpivirine (RPV), raltegravir (RAL), tenofovir disoproxil fumarate (TDF), or emtricitabine (FTC).36 See Table 12 for recommendations on the concomitant use of selected drugs for treatment of HCV and HIV infection.
Ledipasvir is an HCV NS5A inhibitor and is part of a fixed-dose drug combination of sofosbuvir and ledipasvir.37 Similar to sofosbuvir, ledipasvir is not metabolized by the cytochrome P450 system (CYP) of enzymes and is a substrate for P-gp. Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. The use of P-gp inducers is not recommended with ledipasivir/sofosbuvir. The coadministration of ledipasvir/sofosbuvir and ARV regimens containing TDF is associated with increased exposure to TDF, especially when TDF is taken with an HIV PI boosted with either RTV or cobicistat (COBI) (see Table 12 for recommendations on the concomitant use of selected drugs for treatment of HCV and HIV infection). In some patients, alternative HCV or ARV drugs should be considered to avoid increases in TDF exposures. If the drugs are co-administered, the patient should be monitored for potential TDF-associated renal injury by assessing measurements of renal function (i.e., estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein) before HCV treatment initiation and periodically during treatment.
The fixed-dose drug combination of ombitasvir (a NS5A inhibitor), paritaprevir (an HCV PI), and RTV (a pharmacokinetic enhancer) is co-packaged and used in combination with dasabuvir, an NS5B inhibitor.38 Paritaprevir is a substrate and inhibitor of the CYP3A4 enzymes and therefore may have significant interactions with certain ARVs that are metabolized by, or may induce or inhibit the same pathways. Dasabuvir is primarily metabolized by the CYP2C8 enzymes. Furthermore, ombitasvir, paritaprevir, and dasabuvir are inhibitors of UGT1A1 and also substrates of P-gp and BCRP. Paritaprevir is also a substrate and inhibitor of OATP1B1/3. Co-administration with drugs that are substrates or inhibitors of these enzymes and drug transporters may result in increased plasma concentrations of either the co-administered drug or the HCV drugs. Given that several CYP enzymes and drug transporters are involved in the metabolism of dasabuvir, ombitasvir, paritaprevir, and RTV, complex drug-drug interactions are likely. Therefore clinicians need to consider all coadministered drugs for potential drug-drug interactions. No significant drug-drug interactions have been found when dasabuvir, ombitasvir, paritaprevir, and RTV are used in conjunction with ATV or RAL. When either RTV or COBI is used in conjunction with ATV, the boosting agent should be discontinued during HCV therapy and ATV should be taken in the morning at the same time as ombitasvir, paritaprevir/r, and dasabuvir. RTV or COBI should be restarted after completion of HCV treatment. See Table 12 for other recommendations for concomitmant use of HCV drugs with ARVs. HIV-infected patients not on ART should be placed on an alternative HCV regimen because RTV has activity against HIV.
Simeprevir is a HCV NS3/4A PI that has been studied in HIV/HCV-coinfected patients.39 Simeprevir is a substrate and inhibitor of CYP3A4 and P gp enzymes, and therefore may have significant interactions with certain ARVs that are metabolized by the same pathways. Simeprevir is also an inhibitor of the drug transporter OATP1B1/3. On the basis of drug-drug interaction studies in healthy volunteers, simeprevir can be coadministered with RAL, DTG, RPV, and TDF.40 However, coadministration of simeprevir with EFV, ETR, HIV PIs, COBI, or EVG/c/TDF/FTC is not recommended. (See Table 12 for recommendations on the concomitant use of selected drugs for treatment of HCV and HIV infection.)
Given that the treatment of HCV is rapidly evolving, this section will be updated when new HCV drugs are approved that may have an impact on the treatment of HIV. For guidance on the treatment of HCV infection, refer to http://www.hcvguidelines.org/.
Table 12. Concomitant use of Selected HIV Drugs and FDA-approved HCV Drugs for Treatment of HCV in HIV-Infected Adults
Recommendations in this table are based on available pharmacokinetics interaction data or predictions based on the known metabolic pathways of the HIV and HCV drugs. Whenever HIV and HCV drugs are used concomitantly, patients should be closely monitored for HIV and HCV virologic efficacy and potential toxicities. Given that the field of HCV therapy is rapidly evolving, clinicians should also refer to the latest drug product labels and HCV guidelines (http://www.hcvguidelines.org) for updated information.
|HCV DAA Drugs||HCV Non-DAA Drugs
|Selected HIV Drugs||NS5B Inhibitor||Coformulated NS5A/NS5B Inhibitor||CoformulatedNS5A/HCV PI Plus NS5B Inhibitor||HCV Protease Inhibitora|
|Sofosbuvir||Ledipasvir/Sofosbuvir||Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvirb||Simeprevir||Ribavirin||Pegylated Interferon alpha|
Monitor for TDF toxicity
Reduce ATV dose to 300 mg and take in AM at same time as (ombitasvir/paritaprevir/r plus dasabuvir).
If RTV cannot be used, choose an alternative HCV regimen.
If PI/r [or ATV/c, DRV/c] is used with TDF, ↑TDF concentrations are expected. If coadministration necessary, monitor for TDF-associated toxicities (see footnotee)
Take ATV 300mg in AM at same time as (ombitasvir/paritaprevir/r plus dasabuvir); discontinue RTV or COBI in HIV regimen until HCV therapy completed.
If EFV used with TDF/FTC, monitor for TDF toxicity due to ↑ TDF concentrations
|EVG (plus PI/r Without COBI)||Refer to recommendations specific to each PI/r.|
√ = ARV agents that can be used concomitantly
a Boceprevir is no longer recommended for HCV treatment and telaprevir is no longer available in the United States; therefore, these products have been removed from this table.
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; AM = morning; ART = antiretroviral therapy; ATV/r = atazanavir/ritonavir; ATV/c = atazanavir/cobicistat; COBI = cobicistat; DAA = direct-acting antiviral agents; DRV/r = darunavir/ritonavir; DRV/c = darunavir/cobicistat; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; HCV = hepatitis C virus; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NVP = nevirapine; PI/r = ritonavir-boosted protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SQV/r = saquinavir/ritonavir; TDF = tenofovir disoproxil fumarate; TPV/r = tipranavir/ritonavir; ZDV = zidovudine