Managing Hepatitis C in Treatment-Naïve Patients With HIV Coinfection

Hepatitis C is a liver infection caused by the hepatitis C virus (HCV). Transmission of HCV occurs during exposure to contaminated blood and bodily fluids, usually through sharing needles, syringes, or other drug-injection equipment. For some patients, hepatitis C is a short-term illness but for more than half of persons who become infected with HCV, it becomes a long-term, chronic infection, according to the Centers for Disease Control and Prevention.¹ Chronic HCV can lead to severe illnesses such as permanent liver damage and hepatocellular carcinoma; thus, managing the disease is critical. Previous research has shown that coinfection with HIV is common in patients with HCV.^2-4

In 2020, there were 66,700 new cases of acute hepatitis C and 107,300 cases of chronic hepatitis C in the United States.¹ A study by Lo Re et al showed that mortality, morbidity, and hepatic decompensation rates increase with coinfection of HIV and HCV,⁵ which is why adequate and efficient treatment must be provided for both viruses.

The good news is that there are few contraindications for cotreatment of both viruses in infected patients. Since 2013, highly effective, well-tolerated curative treatments known as direct-acting antivirals (DDAs) have been available for hepatitis C; no vaccine for preventing hepatitis C, however, has been developed. In 2014 the World Health Organization (WHO) guidelines began listing persons with HIV/HCV coinfection among those to be prioritized for HCV treatment.⁶ 

Despite this recommendation, barriers to treatment have left a large portion of this population untreated. Barriers to treatment include race, ethnicity, socioeconomic status, sexual and gender minority statuses, and even location. In 2016 Black Americans made up 12% of the US population but, represented 23% of those persons with HCV. Black Americans also had less favorable outcomes compared with other groups.⁷ In 2020, non-Hispanic Black Americans were twice as likely to die from HCV as compared with the White population.⁸

Research has also shown that even with the advancement of DAA treatments, restrictions by insurance companies has resulted in absolute denial of treatment, particularly amongst patients receiving Medicaid.^9,10

Diagnosing Hepatitis C in HIV Patients 

Screening for hepatitis is recommended for all patients living with HIV. The CDC and the American Association for the Study of Liver Disease and Infectious Disease Society of America (AASLD-IDSA) guidelines,^11,12 recommend one-time universal testing for all people over the age of 18 (Table 1). A confirmed diagnosis of HCV is made only when a positive RNA test is received. Although a single detectable HCV RNA result is sufficient to confirm the diagnosis of active HCV infection, a single negative result cannot fully exclude infection. Therefore, repeat testing should be performed if the patient has an abnormal liver function test that cannot be explained by other diagnoses.¹³

Table 1. Recommendations for Hepatitis Testing^11,12

One-Time Testing	Annual and Periodic Testing
At least once in a lifetime for all adults aged ≥18 yearsa	All persons who actively inject drugs or share needles, syringes, or other drug-preparation equipment
All pregnant women during each pregnancya	Sexually active persons about to start PrEP for HIV or taking PrEP
Persons with HIV	All persons with activities, exposures, or conditions or circumstances associated with an increased risk of HCV exposure
Persons with recognized medical conditions such as hemodialysis and abnormal ALTs	HIV-infected men who have unprotected sex with men, and MSM taking PrEP
Persons who ever injected drugs and shared needles, syringes, or other drug preparation equipment, including those who injected once or a few times many years ago	Persons who receive maintenance hemodialysis
Health care, emergency medical, and public safety personnel after needle sticks, sharps, or mucosal exposures to HCV-positive blood
Children born to mothers with HCV infection

Treating Patients With HIV/HCV  

According to the World Health Organization (WHO),⁶ treatment outcomes with DAAs are proven to be comparable in persons with HIV/HCV coinfection to those with only HCV infection. Sustained virologic response (SVR) occurs when hepatitis C virus is not detected in the blood after 12 or more weeks since completing treatment. These agents have few side effects and are used in combinations such as sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, elbasvir/grazoprevir, and glecaprevir/pibrentasvir.

There are 6 hepatitis C virus genotypes and the AASLD-IDSA¹⁴ provides recommendations for treatment regimens based on genotypes, amount of liver damage, and use of prior treatment. Treatment for hepatitis C in patients with HIV coinfection remains remarkably similar to those with HCV monoinfection. Current research suggests modifications in treatment regimens for treatment-naïve patients such as increased duration of treatment for each category (Table 2).¹⁵

Table 2: Alternate Treatment Regimens for HCV With HIV Coinfection¹⁵ 

Treatment-Naïve Patients By Genotypes	Recommended Treatment Duration
Genotypes 1a and 1b without cirrhosis	Ledipasvir-sofosbuvir regimen for 8 weeks for persons with HCV monoinfection (and baseline HCV RNA <6 million IU/mL) For patient with HCV/HIV coinfection, duration of ledipasvir-sofosbuvir therapy is 12 weeks, regardless of their baseline HCV RNA level
Genotypes 1a, 1b, 2, 3, and 4 with compensated cirrhosis	Glecaprevir-pibrentasvir for 8 weeks for those with HCV monoinfection Glecaprevir-pibrentasvir for 12 weeks for those with HCV/HIV coinfection
Genotypes 5 or 6 with and without compensated cirrhosis	Glecaprevir-pibrentasvir for 8 weeks for persons with HCV monoinfection Glecaprevir-pibrentasvir for 12 weeks for those with HCV/HIV coinfection

Diagnostic Labs and Testing Protocols 

As noted, before initiating any treatment for hepatitis C, laboratory testing should be completed to determine genotype and liver damage. Hepatitis C virus genotype testing should be performed in all HIV-infected persons because it is the best predictor of HCV response to treatment and may influence the decision to treat and/or perform a liver biopsy to determine the extent of liver damage. Patients with coinfection should also have their HIV viral loads monitored to avoid possible viral load rebound or virologic failure.^16,17 Generally, studies evaluating the efficacy of HCV treatment in HIV patients have included patients with suppressed HIV levels and CD4 counts greater than 200 cells/mm³.¹⁴ Caution should be taken when trying to initiate therapy in HIV patients who don’t meet these criteria. In these cases, antiretroviral treatment should be initiated first while HCV therapy is deferred until the person is stable on antiretroviral therapy with suppressed HIV RNA levels.  

Patients coinfected with HIV/HCV infection should also be tested for hepatitis B virus (HBV) before initiation of HCV treatment. The reactivation of HBV has been observed during treatment with DAAs.¹⁵ Both hepatitis viruses cause liver damage. In patients with coinfection with HIV and HBV/HCV, providers should ensure that patients receive antiretroviral therapy (ART) that includes agents with anti-HBV activity or receive HBV vaccination. Currently, there are 4 drugs approved by the Food and Drug Administration (FDA) to treat HBV: emtricitabine, lamivudine, tenofovir disoproxil fumarate, and tenofovir alafenamide.¹⁸ 

Monitoring for Hepatotoxicity

Clinicians need to consider the potential hepatotoxicity of ART when prescribing DDAs treatment in this patient population. The Health and Human Services (HHS) website HIV.gov recommends the following monitoring after initiating ART in persons with HIV/HCV coinfection¹⁶:

• Evaluation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should take place 4 to 8 weeks after starting ART and be repeated every 6 to 12 months thereafter.
• Increases in ALT and/or AST can vary significantly. If ALT and/or AST levels are greater than 5 times the upper limit of normal, if there is an increase in total bilirubin, or symptoms of weakness, nausea, or vomiting, the patient should be evaluated for signs and symptoms of liver insufficiency or alternative causes of liver injury.

Experts from AASLD-IDSA¹⁴ suggest that a greater than 10-fold increase in ALT values from baseline at any time during DAA treatment should indicate discontinuation of therapy. Hepatitis C treatment should also be discontinued if there is an increase in ALT less than 10 times from baseline accompanied by symptoms such as weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or international normalized ratio (INR). If the patient is asymptomatic, he/she should be closely monitored with repeat testing at 2-week intervals. If levels are persistently high, consideration should be given to discontinuing DAA therapy and primary providers may seek consultation from specialists.¹¹ 

HIV-HCV Medication Interactions 

With the introduction of ART, precautions should be taken to prevent harmful medication interactions, especially in patients being treated for both HIV and HCV. HIV medication must never be stopped. If the patient is compromised from HIV, then the patient should be given ART therapy until they are stable enough to tolerate HCV treatment, at which time liver disease progression should be frequently monitored.

Some medication interactions to consider include¹⁵: 

• Elbasvir-grazoprevir
  • Coadministration is contraindicated with all protease inhibitors
  • Coadministration is contraindicated with non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz, etravirine, nevirapine
  • Coadministration is contraindicated with any cobicistat-containing regimen to prevent hepatotoxicity.
  • Elbasvir-grazoprevir taken with fostemsavir should be avoided, if possible, due to increased grazoprevir levels. 
• Glecaprevir-pibrentasvir
  • Use of HIV protease inhibitors atazanavir, lopinavir, or ritonavir can increase levels of glecaprevir.
  • The use of atazanavir with glecaprevir-pibrentasvir has been associated with an increased risk of ALT elevation; thus, coadministration should be avoided.
  • Cobicistat-containing regimen may also increase ALT levels; monitoring for hepatotoxicity is advised.
  • Coadministration of glecaprevir-pibrentasvir with inducers of CYP3A, such as efavirenz or etravirine, may result in lower plasma concentrations of glecaprevir and pibrentasvir.
  • Glecaprevir-pibrentasvir is not recommended for coadministration with darunavir, tipranavir, or nevirapine. 
• Tenofovir DF and Tipranavir
  • There is concern that tenofovir levels may increase substantially with the use of ledipasvir-sofosbuvir. This combination with tenofovir DF, HIV protease inhibitor (or cobicistat) and/or ritonavir-boosted HIV protease inhibitors should, if possible, be avoided.
  • Ledipasvir-sofosbuvir should not be used with elvitegravir or tipranavir.
  • Monitoring for tenofovir DF nephrotoxicity or switching to tenofovir alafenamide should be considered.
  • Ledipasvir-sofosbuvir should not be used in persons with HIV infection on tenofovir DF if the baseline creatinine clearance is less than 60 mL/min.
  • Sofosbuvir should not be used concomitantly with tipranavir, but it can be used with all other antiretrovirals 
  • Efavirenz and etravirine, as well as tipranavir, are contraindicated for concurrent use with sofosbuvir-velpatasvir because they have the potential to decrease plasma concentrations of sofosbuvir and/or velpatasvir.
  • Velpatasvir, when given with tenofovir DF, can increase tenofovir levels, especially in people taking other medications that can increase tenofovir levels or in persons with an increased risk for nephrotoxicity. 

Efavirenz, etravirine, and tipranavir are not recommended for concurrent use with sofosbuvir-velpatasvir-voxilaprevir because of the same concerns discussed previously. In addition, atazanavir and lopinavir are not recommended for use with sofosbuvir-velpatasvir-voxilaprevir. The use of elbasvir-grazoprevir with fostemsavir should be avoided, if possible, due to increased voxilaprevir levels. 

Summary 

The use of DAAs has provided overall excellent efficacy in the treatment of hepatitis C while patients are actively being treated for HIV. The presence of HIV does not prevent the treatment of hepatitis C in these patients. The increased risk of adverse outcomes and poor prognosis make HIV patients a high priority for treatment. When managing and treating hepatitis C in this population, special consideration should be taken to avoid medication interactions, hepatotoxicity, and other adverse events. Liver function should be monitored closely when appropriate and when necessary; discontinuation of treatment may be warranted. 

Claudine Lejuste, BSN, currently works as a medical/surgical nurse and emergency room nurse. She holds a Bachelor of Science in Biology from the University of Florida and a Bachelor of Science in Nursing from the University of North Florida. She is currently a BSN-DNP family nurse practitioner student with an interest in acute care practices.

References

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