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

Considerations for Antiretroviral Use in Patients with Coinfections

Hepatitis C Virus/HIV Coinfection

HCV/HIV Coinfection

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 in 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 and the Infectious Diseases Society of America.

Approximately one-third of patients with chronic HCV infection 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 threefold greater risk of progression to cirrhosis or decompensated liver disease than patients with HCV mono-infection.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.^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, people with HIV and HCV coinfection experienced higher rates of hepatotoxicity than those seen in people with HIV but not 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 people with HIV should be screened for HCV infection using sensitive immunoassays licensed for the detection of antibodies to HCV in blood.¹⁵ Patients who are HCV-seronegative but at risk for HCV infection should undergo repeat testing annually or as clinically indicated. Patients who are HCV-seropositive 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.
• Patients with HCV/HIV coinfection also should be counseled about appropriate precautions to prevent transmission of HIV and/or HCV to others.
• Patients 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 hepatitis B core (HBcAb; total or Immunoglobulin G).
  • Patients with evidence of active HBV infection (HBsAg positive) 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 against HAV.
• 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 patients with HCV/HIV coinfection should follow the recommendations for all persons with HIV infection, considering the need for concurrent HCV treatment with oral DAA regimens, the potential for drug–drug interactions, 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 also are recommended for patients with HCV/HIV coinfection. Special considerations for ARV selection in patients 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 18 below).
• In patients with HCV/HBV coinfection, HBV reactivation has been observed during HCV treatment with DAAs.^16,17 Therefore, before initiating HCV therapy, patients 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) (AIII).
• Patients with cirrhosis 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 12).

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 or symptoms of liver disease or increases in bilirubin, these fluctuations do not warrant interruption of ART, but they do warrant monitoring to ensure a return to baseline. Patients with significant elevations in ALT or AST levels (>5 times ULN), concomitant increase in total bilirubin, or concomitant symptoms (weakness, nausea, vomiting) should be evaluated carefully for signs and symptoms of liver insufficiency and for alternative causes of liver injury (e.g., acute HAV or HBV infection, hepatobiliary disease, 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. Before starting HCV therapy, the ART regimen may need to be modified to reduce the drug–drug interaction potential. Table 18 below provides recommendations on the concomitant use of selected drugs for the 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. After ART modification, initiation of an HCV DAA regimen should be delayed for ≥2 weeks. Resumption of the original ARV regimen also should be delayed until ≥2 weeks after the HCV DAA regimen is completed. 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

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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.
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15. Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. National Institutes of Health, Centers for Disease Control and Prevention, HIV Medicine Association, and Infectious Diseases Society of America. 2023. Available at: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/whats-new
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.
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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.