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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
Considerations for Antiretroviral Use in Patients with Coinfections
Hepatitis C (HCV)/HIV Coinfection
(Last updated: March 27, 2012; last reviewed: March 27, 2012)
Key Considerations When Managing Patients Coinfected with HIV and Hepatitis C Virus
Key Considerations When Managing Patients Coinfected with HIV and Hepatitis C Virus
All HIV-infected patients should be screened for hepatitis C virus (HCV) infection, preferably before starting antiretroviral therapy (ART).
ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. For most HIV/HCV-coinfected patients, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury (DILI). Therefore, ART should be considered for HIV/HCV-coinfected patients, regardless of CD4 count (BII).
Initial ART combination regimens for most HIV/HCV-coinfected patients are the same as those for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, consideration of potential drug-drug interactions and overlapping toxicities should guide ART regimen selection or modification (see discussion in the text).
Combined treatment of HIV and HCV can be complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be initiated for most HIV/HCV-coinfected patients regardless of CD4 cell count, in ART-naive patients with CD4 counts >500 cells/mm3 some clinicians may choose to defer ART until completion of HCV treatment
In patients with lower CD4 counts (e.g., <200 cells/mm3), it may be preferable to initiate ART and delay HCV therapy until CD4 counts increase as a result of ART.
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
Approximately one-third of patients with chronic hepatitis C virus (HCV) infection 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]. In a meta-analysis, individuals coinfected with HIV/HCV were found to have three times greater risk of progression to cirrhosis or decompensated liver disease than were HCV-monoinfected patients . This accelerated rate is magnified in HIV/HCV-coinfected patients with low CD4 counts. Although 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 , is unclear. If such an increased risk of HIV progression exists, it may reflect the impact of injection drug use, which is strongly linked to HCV infection [10, 11]. The increased frequency of antiretroviral (ARV)-associated hepatotoxicity with chronic HCV infection also complicates HIV treatment [12, 13].
A combination regimen of peginterferon and ribavirin (PegIFN/RBV) has been the mainstay of treatment for HCV infection. In HCV genotype 1-infected patients without HIV, addition of an HCV NS3/4A protease inhibitor (PI) boceprevir or telaprevir to PegIFN/RBV significantly improves the rate of sustained virologic response (SVR) [14, 15]. Clinical trials of these HCV PIs in combination with PegIFN/RBV for the treatment of HCV genotype 1 infection in HIV-infected patients are currently under way. Both boceprevir and telaprevir are substrates and inhibitors of cytochrome P (CYP) 3A4/5 and p-glycoprotein (p-gp); boceprevir is also metabolized by aldo-keto reductase. These drugs have significant interactions with certain ARV drugs that are metabolized by the same pathways. As such, the presence of HCV infection and the treatment of HCV may influence HIV treatment as discussed below.
Assessment of HIV/Hepatitis C Virus Coinfection Before Initiation of Antiretroviral Therapy
All HIV-infected patients should be screened for HCV infection using sensitive immunoassays licensed for detection of antibody to HCV in blood . HCV-seronegative patients at risk for the aquistion of HCV infection should undergo repeat testing annually. HCV-seropositive patients should be tested for HCV RNA using a qualitative or quantitative assay to confirm the presence of active infection .
Patients with HIV/HCV coinfection should be counseled to avoid consuming alcohol and to use appropriate precautions to prevent transmission of HIV and/or HCV to others. HIV/HCV-coinfected patients who are susceptible to hepatitis A virus (HAV) or hepatitis B virus (HBV) infection should be vaccinated against these viruses.
All patients with HIV/HCV coinfection should be evaluated for HCV therapy. HCV treatment is recommended according to standard guidelines [18, 19]. Strong preference should be given to commence HCV treatment in patients with higher CD4 counts. For patients with lower CD4 counts (e.g., <200 cells/mm3), it may be preferable to initiate ART and delay HCV therapy until CD4 counts increase as a result of HIV treatment [17, 20-22].
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, 23, 24]. However, ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation [25-27].Thus, for most coinfected patients, including those with high CD4 counts and those with cirrhosis, the benefits of ART outweigh concerns regarding DILI. Therefore, ART should be initiated for 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 completion of HCV treatment.
What antiretroviral to start and what antiretroviral not to use: Initial ARV combination regimens for most HIV treatment-naive patients with HCV are the same as those for patients without HCV infection. Special considerations for ARV selection in HIV/HCV-coinfected patients include:
When both HIV and HCV treatments are indicated, the choice of ARV regimen should be guided by the HCV treatment regimen selected with careful consideration of potential drug-drug interactions and overlapping toxicities (as discussed below).
Cirrhotic patients should be carefully assessed for signs of liver decompensation according to the Child-Turcotte-Pugh classification system because hepatically metabolized ARV drugs may require dose modification or avoidance in patients with Child-Pugh class B and C disease. (See Appendix B, Table 7.)
Hepatotoxicity: DILI following 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 or end-stage liver disease) . Eradication of HCV infection with treatment may decrease the likelihood of ARV-associated DILI .]
Given the substantial heterogeneity in patient populations and drug regimens, comparison of DILI incidence rates for individual ARV agents across clinical trials is difficult. In such studies, the highest incidence rates of significant elevations in liver enzyme levels (>5 times the upper limit of the laboratory reference range) have been observed during therapy with ARV drugs that are no longer commonly used in clinical practice, including stavudine (d4T) (with or without didanosine [ddI]), nevirapine (NVP), or full-dose ritonavir (RTV) (600 mg twice daily) . Additionally, certain ARV agents should be avoided if possible because they have been associated with higher incidence of serious liver-associated adverse effects, such as fatty liver disease with nucleoside reverse transcriptase inhibitors (NRTIs) such as d4T, ddI, or zidovudine (ZDV) , noncirrhotic portal hypertension associated with ddI , and hepatotoxicity associated with RTV-boosted tipranavir .
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored at 1 month after initiation of ART and then every 3 to 6 months. Mild to moderate fluctuations in ALT and/or AST are typical in individuals with chronic HCV infection. In the absence of signs and/or symptoms of liver disease these fluctuations do not require interruption of ART. Significant ALT and/or AST elevation should prompt careful evaluation for signs and symptoms of liver insufficiency and for alternative causes of liver injury (e.g., acute HAV or HBV infection, hepatobiliary disease, or alcoholic hepatitis); short-term interruption of the ART regimen or of the specific drug suspected to be responsible for the DILI may be required .
Treating Both HIV and Hepatitis C Virus Infection
Concurrent treatment of HIV and HCV is feasible but may be complicated by high pill burden, drug interactions, and overlapping drug toxicities.In this context, the decision to treat chronic HCV should also include consideration of the medical need for such treatment on the basis of an assessment of 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 PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (boceprevir or telaprevir) is initiated, the 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.
Considerations for using certain nucleoside reverse transcriptase inhibitors and hepatitis C virus treatments:
ddI should not be given with RBV because of the potential for drug-drug interactions leading to life-threatening ddI-associated mitochondrial toxicity including hepatomegaly/steatosis, pancreatitis, and lactic acidosis (AII).
Combined use of ZDV and RBV is associated with increased rates of anemia, making RBV dose reduction necessary. Therefore, this combination should be avoided when possible . Because the risk of anemia may further increase when boceprevir or telaprevir is combined with PegIFN/RBV, ZDV should not be given with this combination (AIII).
Abacavir (ABC) has been associated with decreased response to PegIFN/RBV in some, but not all, retrospective studies; current evidence is insufficient to recommend avoiding this combination [37-39]
Considerations for the use of HCV NS3/4A protease inhibitors (boceptrevir or telaprevir) and antiretroviral therapy:
Boceprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. After 4 weeks of PegIFN/RBV therapy, boceprevir is added to the regimen for 24, 32, or 44 additional weeks of HCV therapy. Data on the use of an HCV regimen containing boceprevir together with ART in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with boceprevir plus PegIFN/RBV (64 patients) than with PegIFN/RBV alone (34 patients). In this study, patients received ART that included HIV-1 ritonavir-boosted atazanavir (ATV/r), darunavir (DRV/r), or lopinavir (LPV/r) or raltegravir (RAL) plus dual NRTIs .
Boceprevir is primarily metabolized by aldo-keto reductase, but because the drug is also a substrate and inhibitor of CYP3A4/5 and p-gp enzymes, it may interact with ARVs metabolized by these pathways. Based on drug interaction studies in healthy volunteers, boceprevir can be coadministered with RAL . However, coadministration of boceprevir with ATV/r, DRV/r, LPV/r, or efavirenz (EFV) is not recommended because of bidirectional drug interactions (see Table 18a and 18b) [42, 43] . Importantly, the pharmacokinetic (PK) interactions of HIV PIs with boceprevir were not identified before the approval of boceprevir and before participant enrollment in the HIV/HCV-coinfection trial; consequently, some coinfected patients have received HIV PIs and boceprevir during HCV treatment. Patients who are currently receiving these drug combinations should be advised not to stop any medication until contacting their health care providers. If therapy with HIV PIs and boceprevir is continued, patients should be closely monitored for HIV and HCV responses and consideration should be given to switching the HIV PI or EFV to RAL during boceprevir therapy. Additional clinical trial data are needed to determine if other ARVs may be coadministered with boceprevir.
Telaprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. Telaprevir is administered in combination with PegIFN/RBV for the initial 12 weeks of HCV therapy followed by 12 or 36 weeks of additional treatment with PegIFN/RBV. Data on the use of this regimen in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with telaprevir plus PegIFN/RBV (38 patients) than with PegIFN/RBV alone (22 patients). In this study, patients received ART containing EFV or ATV/r plus tenofovir/emtricitabine (TDF/FTC) or no ART during the HCV therapy .
Because telaprevir is a substrate and an inhibitor of CYP3A4 and p-gp enzymes, the drug may interact with ARVs metabolized by these pathways. On the basis of drug interaction studies in healthy volunteers and data on responses in coinfected patients enrolled in the small clinical trial noted above, telaprevir can be coadministered with ATV/r  and RAL  at the standard recommended dose of telaprevir (750 mg every 7–9 hours) and with EFV at an increased dose of telaprevir (1125 mg every 7–9 hours) (see Table 18b); however, coadministration of telaprevir with DRV/r, fosamprenavir/ritonavir (FPV/r), or LPV/r is not recommended because of bidirectional drug interactions . Data on PK interactions of telaprevir with other ARVs including non-nucleoside reverse transcriptase inhibitors (NNRTIs) other than EFV and with maraviroc (MVC) are not available; therefore, coadministration of telaprevir with other ARVs cannot be recommended.
Following are preliminary recommendations for the use of boceprevir or telaprevir in HIV patients coinfected with HCV genotype 1 based on current ART use. These recommendations may be modified as new drug interaction and clinical trial information become available.
Patients not on ART:
Use either boceprevir or telaprevir
Patients receiving RAL + 2-NRTI:
Use either boceprevir or telaprevir
Patients receiving ATV/r + 2-NRTI:
Use telaprevir at standard dose. Do not use boceprevir.
Patients receiving EFV + 2-NRTI:
Use telaprevir at increased dose of 1125 mg every 7–9 hours. Do not use boceprevir.
Patients receiving other ARV regimens:
If HCV disease is minimal (i.e., no or mild portal fibrosis), consider deferring HCV treatment given rapidly evolving HCV drug development.
If good prognostic factors for HCV treatment response are present—IL28B CC genotype or low HCV RNA level (<400,000 International Unit [IU]/mL)—consider use of PegIFN/RBV without HCV NS3/4A PI.
On the basis of ART history and HIV genotype testing results, if possible, consider switching to the ART regimens listed above to permit the use of boceprevir or telaprevir.
For patients with complex ART history or resistance to multiple classes of ART, consultation with experts regarding the optimal strategy to minimize the risk of HIV breakthrough may be needed. In such patients, telaprevir may be the preferred HCV NS3/4A PI because its duration of use (12 weeks) is shorter than that of boceprevir (24 to 44 weeks).
In summary, HCV coinfection and use of PegIFN/RBV with or without HCV NS3/4A PIs (telaprevir or boceprevir) to treat HCV may impact the treatment of HIV because of increased pill burden, toxicities, and drug-drug interactions. Because ART may slow the progression of HCV-related liver disease, ART should be considered for most HIV/HCV-coinfected patients, regardless of CD4 count. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (telaprevir or boceprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug-drug interactions and/or drug toxicities that may develop during the period of concurrent HIV and HCV treatment. The science of HCV drug development is evolving rapidly. As new clinical trial data on the management of HIV/HCV-coinfected patients with newer HCV drugs become available, the Panel will modify its recommendations accordingly.
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