Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Considerations for Antiretroviral Use in Patients with Coinfections

Hepatitis C Virus/HIV Coinfection

Last Updated: October 25, 2018; Last Reviewed: October 25, 2018

Panel's Recommendations Regarding Hepatitis C Virus/HIV Coinfection
Panel's Recommendations
  • All people with HIV should be screened for hepatitis C virus (HCV) infection (AIII). Patients at high risk of HCV infection should be screened annually and whenever incident HCV infection is suspected (AIII).
  • Antiretroviral therapy (ART) may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. For most persons with HCV/HIV coinfection, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Therefore, ART should be initiated in all patients with HCV/HIV coinfection, regardless of CD4 T lymphocyte cell count (AI).
  • Initial ART regimens that are recommended for most patients with HCV/HIV coinfection are the same as those recommended for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, the ART and HCV treatment regimens should be selected with special consideration for potential drug-drug interactions and overlapping toxicities (AIII) (see discussion in the text below and in Table 13).
  • All patients with HCV/HIV coinfection should be evaluated for HCV therapy, which includes having their liver fibrosis stage assessed to inform the length of their therapy and subsequent risk of hepatocellular carcinoma and liver disease complications (AIII).
  • Persons with chronic HCV/HIV coinfection should be screened for active and prior hepatitis B virus (HBV) infection by testing for the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B surface (HBsAb) and core (HBcAb; total or IgG). Persons who are not immune to HBV infection (HBsAb negative) should receive anti-HBV vaccination (AIII).
  • HBV reactivation has been observed in persons with HBV infection during HCV treatment with direct-acting antivirals (DAAs). Accordingly, persons with HCV/HIV coinfection and active HBV infection (HBsAg positive) should receive ART that includes two agents with anti-HBV activity prior to initiating HCV therapy (AIII).
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 treatment of hepatitis C virus (HCV) infection is rapidly evolving. Patients with HCV/HIV coinfection treated with all-oral, direct-acting antiviral (DAA) HCV regimens can achieve sustained virologic response (HCV cure) at rates comparable to those of patients with HCV mono-infection.1-3 This section of the guidelines focuses on hepatic safety and drug-drug interaction issues related to HCV/HIV coinfection and the concomitant use of antiretroviral (ARV) agents and HCV drugs. For specific guidance on HCV treatment, clinicians should refer to the HCV Guidance from the American Association for the Study of Liver Diseases.

Among patients with chronic HCV infection, approximately one-third progress to cirrhosis, at a median time of <20 years.4,5 The rate of progression increases with older age, alcoholism, male sex, and HIV infection.6-9 A meta-analysis found that patients with HCV/HIV coinfection had a three-fold greater risk of progression to cirrhosis or decompensated liver disease than patients with HCV monoinfection.8 The risk of progression is even greater in patients with HCV/HIV coinfection who have low CD4 T lymphocyte cell counts. Although antiretroviral therapy (ART) appears to slow the rate of HCV disease progression in patients with HCV/HIV coinfection, several studies have demonstrated that the rate of disease progression continues to exceed that observed in patients without HIV infection.10,11 Whether HCV infection accelerates HIV progression, as measured by the occurrence of AIDS-related opportunistic infections (OIs) or death,12 is unclear. With older ARV drugs, persons with chronic HCV co-infection experienced higher rates of hepatotoxicity than those seen in persons without HCV.13,14 These higher rates have not been observed with the newer ARV agents that are currently in use.

Assessment of HCV/HIV Coinfection

  • All patients with HIV should be screened for HCV infection using sensitive immunoassays licensed for the detection of antibodies to HCV in blood.15 At-risk HCV-seronegative patients should undergo repeat testing annually or as clinically indicated. HCV-seropositive patients should be tested for HCV RNA using a sensitive quantitative assay to confirm the presence of active infection. Patients who test HCV RNA positive should undergo HCV genotyping and liver disease staging as recommended by the HCV Guidance.
  • Patients with HCV/HIV coinfection should be counseled to avoid consuming alcohol and to use appropriate precautions to prevent transmission of HIV and/or HCV to others.
  • People with chronic HCV/HIV coinfection should be screened for active and prior hepatitis B virus (HBV) infection by testing for the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B surface (HBsAb) and core (HBcAb; total or IgG).
    • Persons with evidence of active HBV infection (as determined by the presence of HBsAg) should be further evaluated and treated with ART that includes agents with anti-HIV and anti-HBV activities (AIII).
    • Those who are not immune to HBV infection (HBsAb negative) should receive anti-HBV vaccination.
  • Patients with HCV/HIV coinfection who are susceptible to hepatitis A virus (HAV) should be vaccinated.
  • All patients with HCV/HIV coinfection are candidates for curative HCV treatment.

Antiretroviral Therapy in HCV/HIV Coinfection

When to Start Antiretroviral Therapy

Initiation of ART for persons with HCV/HIV coinfection should follow the recommendations for all persons with HIV infection, taking into account the need for concurrent HCV treatment with oral DAA regimens, drug-drug interaction potentials, and the individual’s HBV status.

Considerations When Starting Antiretroviral Therapy

The same regimens that are recommended for initial treatment of HIV in most ART-naive persons are also recommended for persons with HCV/HIV coinfection. Special considerations for ARV selection in persons with HCV/HIV coinfection include the following:

  • When both HIV and HCV treatments are indicated, the ARV regimen should be selected with careful consideration of potential drug-drug interactions with the HCV treatment regimen (see Table 13).
  • In persons with HCV/HBV coinfection, HBV reactivation has been observed during HCV treatment with DAAs.16,17 Therefore, persons with HCV/HIV coinfection and active HBV infection (HBsAg positive) should receive ART that includes agents with anti-HBV activity (such as tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide plus emtricitabine or lamivudine) prior to initiating HCV therapy (AIII).
  • Cirrhotic patients should be evaluated for signs of liver decompensation according to the Child-Turcotte-Pugh classification system. All patients with Child-Pugh class B or C disease should be evaluated by an expert in advanced liver disease and considered for liver transplantation. Furthermore, hepatically metabolized ARV and HCV DAA drugs may be contraindicated or require dose modification in patients with Child-Pugh class B and C disease (see Appendix B, Table 8).

Hepatotoxicity

Drug-induced liver injury (DILI) following the initiation of ART is more common in patients with HCV/HIV coinfection than in those with HIV mono-infection. Individuals with HCV/HIV coinfection who have advanced liver disease (e.g., cirrhosis, end-stage liver disease) are at greatest risk for DILI.18 Eradicating HCV infection with treatment may decrease the likelihood of ARV-associated DILI.19 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored 4 to 8 weeks after initiation of ART and at least every 6 to 12 months thereafter, and more often if clinically indicated. Mild to moderate fluctuations in ALT and/or AST levels (<5 times upper limit of normal [ULN]) are typical in individuals with chronic HCV infection. In the absence of signs and/or symptoms of liver disease or increases in bilirubin, these fluctuations do not warrant interruption of ART, but do warrant monitoring to ensure a return to baseline. Patients with significant elevations in ALT and/or AST levels (>5 times ULN), concomitant increase in total bilirubin, and/or concomitant symptoms (weakness, nausea, vomiting) should be carefully evaluated 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). If these signs and symptoms do not resolve, ART should be discontinued.

Concurrent Treatment of HIV and HCV Infections

Guidance on the treatment and management of HCV in adults with and without HIV can be found in the HCV Guidance . Several ARV drugs and HCV DAAs have the potential for clinically significant pharmacokinetic drug-drug interactions when used in combination. Prior to starting HCV therapy, the ART regimen may need to be modified to reduce the drug-drug interaction potential. Table 13 below provides recommendations on the concomitant use of selected drugs for treatment of HCV and HIV infection. In patients receiving ART that has been modified to accommodate HCV treatment, HIV RNA should be measured within 2 to 8 weeks after changing HIV therapy to confirm the effectiveness of the new regimen. Clinicians should wait at least 2 weeks after ART modification before initiating an HCV DAA regimen. Clinicians should also wait for at least 2 weeks before resuming the original ART regimen after a patient completes the HCV DAA regimen. The prolonged half-life of some HIV and HCV drugs poses a potential risk of drug-drug interactions if a regimen is resumed soon after ART modification or HCV treatment completion.

References

  1. Naggie S, Cooper C, Saag M, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):705-713. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26196665.
  2. Rockstroh JK, Nelson M, Katlama C, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV. 2015;2(8):e319-327. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26423374.
  3. Sogni P, Gilbert C, Lacombe K, et al. All-oral direct-acting antiviral regimens in HIV/hepatitis C virus-coinfected patients with cirrhosis are efficient and safe: real-life results from the prospective ANRS CO13-HEPAVIH cohort. Clin Infect Dis. 2016;63(6):763-770. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27317796.
  4. Alter MJ, Margolis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. N Engl J Med. 1992;327(27):1899-1905. Available at: https://www.ncbi.nlm.nih.gov/pubmed/1280771.
  5. Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284(4):450-456. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10904508.
  6. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825-832. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9121257.
  7. Wiley TE, McCarthy M, Breidi L, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28(3):805-809. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9731576.
  8. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33(4):562-569. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11462196.
  9. Thein HH, Yi Q, Dore GJ, Krahn MD. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS. 2008;22(15):1979-1991. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18784461.
  10. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166(15):1632-1641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16908797.
  11. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815-1826. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19339714.
  12. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet. 2000;356(9244):1800-1805. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11117912.
  13. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283(1):74-80. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10632283.
  14. Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology. 2002;35(1):182-189. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11786975.
  15. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2018. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
  16. Bersoff-Matcha SJ, Cao K, Jason M, et al. Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug Administration adverse event reporting system. Ann Intern Med. 2017;166(11):792-798. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28437794.
  17. Wang C, Ji D, Chen J, et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2017;15(1):132-136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27392759.
  18. Aranzabal L, Casado JL, Moya J, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis. 2005;40(4):588-593. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15712082.
  19. Labarga P, Soriano V, Vispo ME, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis. 2007;196(5):670-676. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17674307.

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