Topic 6. Treatment of HCV in a Correctional Setting

Epidemiology of Acute HCV

In the United States, during the 1980s, an estimated average of 230,000 new hepatitis C virus (HCV) infections occurred each year.[1] After 1989, however, the annual estimated number of new infections steadily declined until 2005, followed by a leveling off between 2006-2010, and then a steady increase from 2011 to 2016 (Figure 1).[1,2] The Centers for Disease Control and Prevention data shows new annual HCV infections in the United States increased approximately 4-fold from 2005 to 2016, with a peak of 41,200 new infections in 2016 (Figure 2).[1] New HCV infections have the highest incidence among persons 20 to 39 years of age. The current opioid epidemic in the United States is the predominant force driving the increase in new HCV infection.[3,4] In addition, an increase in acute HCV infections has been recognized among men who have sex with men, particularly men living with HIV infection who engage in condomless anal intercourse and use methamphetamine.[5]

Definition of Acute HCV Infection

Most experts define acute HCV infection as the 6-month time period following acquisition of HCV.[6,7,8] The definition of acute HCV infection does not depend on the presence or absence of symptoms associated with the acute HCV infection. The preferred accepted laboratory diagnosis of acute HCV infection includes documentation of either of the two following criteria:

• A positive (detectable) HCV RNA in conjunction with a negative HCV antibody, or
• Positive HCV antibody with documentation of a negative HCV antibody in the past 12 months

Risk Factors for Recent Acute HCV Acquisition

All confirmed cases of acute hepatitis C should be interviewed to identify any risk factors for acquiring HCV infection during the 2 weeks to 6 months prior to illness onset. Knowledge of risk factors is important from an epidemiology perspective and can help identify individuals who may be at high risk of transmitting HCV to others. Assessment of ongoing HCV transmission risk may need to be considered in the decision to treat HCV in the acute infection setting.

Differentiating Acute HCV infection from HCV Reinfection

Although reinfection with HCV after SVR is uncommon, it can occur, especially for persons who continue or resume activities that place them at risk for acquiring HCV.[9,10] Individuals with HCV infection who achieve an SVR will have a permanently positive HCV antibody test. Therefore, for persons with HCV who achieved an SVR (at 12 weeks or later after completing HCV treatment), a diagnosis of HCV reinfection is based on the new presence of HCV RNA.[11] It is important to distinguish reinfection from relapse following an undetectable HCV RNA at the end-of-treatment; when relapse occurs, it almost always occurs within the first 12 weeks after completing therapy. Therefore, if an individual has an SVR at 12 weeks or later after completing treatment and subsequently has detectable HCV RNA, a diagnosis of HCV reinfection should be suspected. In this situation, an HCV genotype should be ordered and compared to genotype of HCV in the initial HCV infection. The finding of distinct genotypes confirms reinfection. Note, however, that persons can become reinfected with the same genotype and thus finding the same HCV genotype does not rule out reinfection. Viral sequence analysis can differentiate HCV infections that are the same genotype, but this test is not routinely performed for clinical purposes.[11]

Following acquisition of hepatitis C, an estimated 20 to 35% of persons will have spontaneous clearance of HCV infection.[12,13,14]  Investigators have identified multiple factors that predict a higher likelihood of spontaneous clearance: female sex, IL28B CC genotype, white race, presence of jaundice, and a low peak HCV RNA level during early HCV infection.[12,15,16,17] In contrast, lower rates of spontaneous clearance occur in persons of black race and those coinfected with HIV.[15,18] Studies have shown that if spontaneous clearance occurs, most have clearance within 6 months—failure to clear HCV by 6 months is a strong predictor of chronic HCV infection, except in persons with HIV coinfection, who often have delayed clearance of HCV.[18] 

Additional Laboratory Evaluation

During the initial evaluation for possible acute HCV infection, all persons should also have the following tests performed:

• Testing for HIV infection, (even if previously negative)
• Testing for acute HBV infection (HBsAg, HBcAb IgM, HBcAb IgG), unless previously documented to have a positive and sufficient hepatitis B surface antibody titer
• Comprehensive testing for sexually transmitted diseases if their risk factor for acute HCV was sexual activity

Consideration for HIV Preexposure Prophylaxis

Regardless of whether a patient suspected of acute HCV infection does or does not have HCV, they should be evaluated and considered for HIV preexposure prophylaxis (PrEP), since persons engaging in activities that place them at risk for acquiring acute HCV will also have risk for acquiring HIV infection.

Overall, treatment of acute HCV infection has been shown to result in high sustained virologic response (SVR) rates, even prior to the modern era of treatment with direct-acting antiviral (DAA) medications. Studies of peginterferon alpha-2b monotherapy in intent-to-treat analyses showed SVR rates of 71 to 96%.[19,20] A meta-analysis of 22 studies (n = 1,075) using either standard interferon or peginterferon monotherapy reported an overall SVR rate of 78%.[19] The SVR rates observed with interferon-based therapy of acute HCV are significantly higher than SVR rates observed with interferon- or peginterferon-based treatment of chronic HCV. With interferon-based therapy, the highest SVR rates in the acute infection setting have occurred in persons who received treatment within 12 weeks following acute HCV diagnosis.[20,21] Highly successful outcomes were seen even in typically more challenging populations, including injection drug users and persons with HIV infection. There are limited data at this time on the use of newer DAA regimens for treatment of acute HCV infection. The following summarizes available data regarding the effectiveness of treatment regimens for persons with acute HCV infection.

DAA Regimens for the Treatment of Acute and Recent HCV

• Sofosbuvir plus Ribavirin (DARE-C II): In an open-label trial in Australia and New Zealand, investigators enrolled 19 participants with recent HCV infection (defined duration of infection less than 12 months) to receive a 6-week treatment course of sofosbuvir plus ribavirin.[22] Of those enrolled, (74%) had HIV coinfection and 68% had HCV genotype 1 infection. The median baseline HCV RNA level for participants was 252,000 IU/mL. Only 6 of 19 (32%) subjects achieved an SVR12 and treatment outcome correlated with HIV status and baseline HCV RNA level (Figure 3).[22]
• Sofosbuvir plus Ribavirin (SWIFT-C): This open-label trial enrolled 17 men living with HIV who developed acute HCV infection.[23] All subjects received a 12-week course of sofosbuvir plus ribavirin for treatment of acute HCV.[23] Most subjects (88%) had HCV genotype 1. Overall, only 10 of 17 (59%) subjects achieved an SVR12 and all treatment failures resulted from virologic relapse (Figure 4).[23] Among those enrolled, the median baseline HCV RNA level was 2,280,000 IU/mL.
• Ledipasvir-Sofosbuvir (HepNet Acute HCV IV): This prospective, single-arm study enrolled 20 individuals in Germany with acute HCV genotype 1 monoinfection.[24] All subjects enrolled received ledipasvir-sofosbuvir for 6 weeks and 20 of 20 (100%) achieved an SVR12 (Figure 5).[24] At baseline, 15 of 20 (75%) subjects had HCV RNA levels less than 100,000 IU/mL and only 2 had HCV RNA levels greater than 1 million IU/mL.[24]
• Ledipasvir-Sofosbuvir: In this open-label, single arm study, 26 men living with HIV in Germany or England who were diagnosed with acute HCV genotype 1 or 4 infection were treated with a 6-week course of ledipasvir-sofosbuvir.[25] Overall, 20 of 26 (77%) study participants achieved an SVR12 (Figure 6).[25]
• Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (TARGET-3D): This open-label, single arm study enrolled 30 persons in Australia, England, and New Zealand with recent (duration less than 12 months) HCV infection to receive treatment with an 8-week course of ombitasvir-paritaprevir-ritonavir and dasabuvir.[26] Most (77%) of the participants had HIV coinfection and 93% had genotype 1a HCV infection.[26] Overall, 29 of 30 (97%) persons achieved an SVR12; the one failure occurred in a participant who withdrew from the study after 2 weeks of therapy. The median baseline HCV RNA was approximately 510,200 log IU/mL and 13 of 30 (43%) participants had a baseline HCV RNA greater than 1,000,000 IU/mL.[26]

Clinical Trials for the Treatment of Acute or Recent HCV

• Elbasvir-Grazoprevir (DAHHS-2 II): In this phase 3, open-label trial, Dutch investigators plan to evaluate the efficacy of an 8-week course of elbasvir-grazoprevir in 86 adults living with HIV who develop acute HCV genotype 1 or 4 infection (NCT02600325).
• Elbasvir-Grazoprevir (SAHIV): In this phase 2, open-label trial, French investigators plan to is evaluate the efficacy of an 8-week course of elbasvir-grazoprevir in 30 adults living with HIV who develop acute HCV genotype 1 or 4 infection (NCT02886624).
• Glecaprevir-Pibrentasvir (TARGET-3D Part II): In this phase 3, open-label study, investigators plan to enroll 30 adults with recent HCV infection (acquired within 12 months) to receive treatment with a 6-week course of glecaprevir-pibrentasvir (NCT02634008).
• Glecaprevir-Pibrentasvir (TARGET-3D Part III): In this phase 3, open-label trial, investigators plan to enroll 30 adults with recent HCV infection (acquired within 12 months) to receive treatment with a 4-week course of glecaprevir-pibrentasvir (NCT02634008).
• Sofosbuvir-Velpatasvir (REACT): In this phase 3, randomized, international study, investigators plan to enroll 250 adults who inject drugs who are diagnosed with recent HCV infection to receive treatment with sofosbuvir-velpatasvir for either 6 or 12 weeks (NCT02625909).

Treatment of Acute HCV with Interferon-Based Therapy

• Interferon: In this trial, 44 adults with acute HCV infection were treated with standard interferon alpha-2b, 5 million units subcutaneously, daily for 4 weeks, followed by 3 times per week for 20 weeks.[27] Overall, an SVR occurred in 43 of 44 (98% ) of persons who received treatment (Figure 7).[27] Note that most participants had symptomatic acute HCV, which has been associated with higher spontaneous clearance.[27]
• Peginterferon: In a study involving a 12-week course of peginterferon alfa-2b, SVR rates were higher if treatment was started at week 8 or 12 versus week 20 (Figure 8).[28] The higher SVR12 rate with earlier initiation of therapy may have resulted in part from additional cases of spontaneous clearance that occurred after week 8, but it is possible an enhanced SVR response rate occurs if HCV is controlled through treatment very early following the acute infection.[28]
• Peginterferon and Ribavirin plus Telaprevir: As part of the New York Acute Hepatitis C Surveillance Network, men with HIV infection who developed acute HCV genotype 1 were treated with peginterferon and ribavirin plus telaprevir for 12 weeks, with 16 of 19 (84%) participants achieving an SVR12, as compared to 30 of 48 (63%) in historical controls who were treated with peginterferon and ribavirin.[29]
• Peginterferon and Ribavirin plus Boceprevir: In the Dutch Acute HCV in HIV study (DAHHS), persons with HIV infection who developed acute genotype 1 HCV infection received treatment with a 12-week course of peginterferon and ribavirin plus boceprevir.[30] Preliminary results showed an SVR12 in 21 of 27 (78%) participants; among those with a rapid virologic response at week 4, an SVR12 was achieved in 18 of 19 (95%). 

In the era prior to the new highly effective direct-acting antiviral agents, treatment of acute HCV generated markedly higher SVR12 rates than with treatment of chronic HCV.[27,28,31] With current DAA therapy, however, SVR12 rates are generally greater than 95% in persons with chronic HCV [32,33] Thus, the prior advantage of treating acute HCV infection versus chronic HCV (in terms of SVR12 rates) no longer exists. For these reasons, most experts recommend waiting at least 6 months after HCV acquisition to allow adequate time for spontaneous HCV clearance. The most compelling reason for immediate treatment is to impact HCV transmission risk in a person imminently likely to transmit HCV to others. The American Association for the Study of Liver Diseases and Infectious Diseases Society of America (AASLD-IDSA) Hepatitis C Guidance addresses the approach to treating individuals with acute HCV infection.[8] The following summary highlights key recommendations from the AASLD-IDSA guidance on managing persons with acute HCV infection.[8]

• Monitoring for Spontaneous Clearance: Persons with acute HCV should have HCV RNA monitoring every 4 to 8 weeks for 6 to 12 months to determine if spontaneous HCV clearance occurs. Note that HCV RNA levels may fluctuate in acute HCV infection, and a single negative HCV RNA is not considered adequate to document spontaneous HCV clearance.
• Approach to Persons with Spontaneous HCV Clearance: Persons who spontaneously clear HCV do not require treatment of HCV.
• Treatment Approach to Persons with Acute HCV: The main HCV treatment options for managing persons with acute HCV infection are: (1) defer any HCV treatment decisions until at least 6 months to see if spontaneous HCV clearance occurs, or (2) treat during the acute HCV infection period after monitoring for 12 to 16 weeks to allow time for possible spontaneous HCV clearance. Unless extenuating circumstances exist (as outlined below), the recommended approach is to defer treatment decisions for at least 6 months after HCV acquisition. Treatment should only be initiated in persons with persistently positive HCV RNA levels.
• Circumstances that May Warrant Early Treatment: Situations that may warrant treatment in the acute infection period (prior to 6 months of waiting for possible spontaneous clearance) include: (1) to prevent transmission to others (e.g. person who injects drugs, a surgeon, or a man coinfected with HIV who has sex with other men), (2) to minimize the risk of developing severe hepatic complications from acute infection, as may occur in persons with underlying cirrhosis who become acutely infected with HCV, or (3) to capitalize on the treatment opportunity in a person who may become lost to follow-up.
• Treatment Regimens for Persons with Acute or Recent HCV: If the decision is made to treat a patient in the acute infection period (within 6 months) or in the 6-12 month after HCV acquisition, the recommended DAA regimens and duration of therapy are the same as those recommended for the initial treatment of individuals with chronic HCV.
• Counseling and Referral for Follow-Up: Persons with acute Hepatitis C should receive counseling on how to reduce their risk of transmitting HCV to others, minimize exposure to any agents that are hepatotoxic, and the necessity of follow-up to determine the outcome of their infection. Those with ongoing injection drug use should have a referral to an addiction medicine specialist.

• Since 20 to 35% of persons will spontaneously clear HCV in the first year after infection, persons with acute HCV should have monitoring of HCV RNA levels every 4 to 8 weeks for a minimum of 6 to 12 months, unless extenuating circumstances warrant earlier treatment.
• Individuals undergoing workup for acute HCV infection should also be evaluated for acute or new HBV and HIV infection; if their risk for acquiring HCV was through sexual contact, the evaluation should also include comprehensive testing for sexually transmitted infections.
• Persons with ongoing activities that place them at risk for acquiring HCV infection also are at risk of acquiring HIV infection and thus should be carefully considered for HIV PrEP.
• If the decision to treat acute or recent HCV infection is made, the AASLD-IDSA guidance recommends using the same regimens as for initial treatment of chronic HCV infection.
• In the current DAA era, the early initiation of acute HCV treatment provides no real advantage with regard to SVR12 rates.
• The possible efficacy benefits of early acute HCV treatment and the potential public health benefits of reducing transmission must be balanced with the importance of avoiding unnecessary therapy in those individuals who will go on to clear virus spontaneously.
• If the decision to treat acute or recent HCV infection is made, the AASLD-IDSA guidance recommends using the same regimens as for initial treatment of chronic HCV infection.

Impact of HIV Coinfection

In the United States, approximately 5% of adults with chronic hepatitis C (HCV) infection have coinfection with HIV.[1] Among persons living with HIV, an an estimated 15 to 30% have HCV coinfection.[2,3,4] Coinfection with HIV accelerates the progression of hepatic fibrosis and results in a more aggressive course of liver disease (Figure 1).[5,6] Cirrhosis has been observed to occur 12 to 16 years earlier in those coinfected with HCV and HIV compared with those who have HCV monoinfection.[7] For persons living with HIV who have HCV coinfection, liver-related morbidity and mortality is a prominent non-AIDS-defining complication—up to 80 to 90% of liver-related deaths in persons living with HIV are attributable to HCV infection.[8,9] Unfortunately, individuals with HCV and HIV coinfection have decreased access to liver transplantation compared with persons with HCV monoinfection.[10] For these reasons, treatment of HCV in this patient population should have a high priority. Historically, in the interferon era, treatment of HCV in patients coinfected with HIV had limited uptake, largely due to a low response rate with interferon-based therapy, a high rate of adverse effects, concerns for interactions with antiretroviral medications, and high prevalence of comorbidities, such as psychiatric conditions and chemical dependency.[11] The availability of highly effective all-oral direct-acting antiviral (DAA) regimens has generated major enthusiasm and interest for the treatment of HCV in persons with HIV coinfection.

Historic Approach to Treatment

For patients with HCV and HIV coinfection, initial trials with interferon monotherapy or dual therapy with interferon plus ribavirin were associated with very low SVR rates and significant toxicity. Subsequently, studies showed higher SVR rates with peginterferon and ribavirin treatment (Figure 2), but these were still suboptimal, especially in persons with genotypes 1 or 4 (Figure 3).[12,13,14,15] The peginterferon and ribavirin combination regimen had particularly low SVR rates among those with genotype 1 HCV (typically less than 30%). Further, the SVR rates with peginterferon and ribavirin were generally 15 to 25% lower in persons with HCV and HIV coinfection than in those with HCV monoinfection. In 2011, the addition of a first-generation HCV protease inhibitor (telaprevir or boceprevir) to peginterferon and ribavirin improved SVR rates with GT1 to approximately 60% and slightly narrowed the gap in treatment response between persons with HCV-HIV coinfection and HCV monoinfection.[16,17,18,19] This triple therapy regimen, however, proved to be quite complex and challenging due to interactions with antiretroviral medications, greater pill burden, food requirements, and additional adverse effects. With the availability of all-oral DAA regimens that are highly effective, safe, convenient to take, the older regimens of peginterferon and ribavirin or peginterferon and ribavirin plus a first-generation protease inhibitor are no longer recommended for treatment of HCV.[20]

The introduction of direct-acting antiviral agents (DAAs), and in particular, interferon-free combination therapy, has changed the landscape of therapy for persons with HCV and HIV coinfection. Several studies using DAA-based therapy have demonstrated sustained virologic response rates among individuals with HCV-HIV coinfection that are comparable to those with HCV monoinfection (Figure 4), providing convincing evidence that persons with HCV-HIV coinfection no longer require the designation of a special or “treatment refractory” population. It should be noted that these trial participants included primarily individuals without cirrhosis and those with CD4 counts usually well above 200 cells/mm³.[21,22,23,24,25] In addition, several observational cohort studies have shown comparable clinical efficacy in more heterogeneous cohorts of persons with HCV and HIV coinfection, including those with lower CD4 cell counts.[26,27,28] The following provides a summary of key studies (in alphabetical order) involving DAA treatment of HCV infection in persons with HIV coinfection.

• Daclatasvir plus Sofosbuvir (ALLY-2): In the phase 3, randomized, multi-center ALLY-2 trial, investigators enrolled 203 adults with HCV and HIV coinfection to receive treatment of chronic HCV infection with daclatasvir plus sofosbuvir.[29] Hepatitis C treatment-naïve participants were randomized to receive either an 8-week or 12-week treatment course, whereas the treatment-experienced participants received a 12-week course. Individuals with HCV genotype 1, 2, 3, or 4 were eligible. The HIV entry criteria required a CD4 count greater than 350 cells/mm³ if not taking antiretroviral therapy or at least 100 cells/mm³ if on antiretroviral therapy (and an HIV RNA less than 50 copies/mL). Participants receiving a 12-week regimen had excellent SVR 12 rates (96% in treatment-naïve and 98% in treatment-experienced), but only 76% of the treatment-naïve participants receiving 8 weeks of therapy achieved an SVR12.[29]
• Elbasvir-Grazoprevir (C-EDGE Coinfection): In this prospective single-arm, open-label clinical trial, investigators enrolled 218 adults with chronic hepatitis C genotype 1, 4, or 6 and HIV coinfection for treatment with a 12-week course of elbasvir-grazoprevir once daily for 12 weeks.[23] Among those enrolled, 86% had genotype 1a or 1b infection and 35 (16%) had compensated cirrhosis. The overall SVR12 rate was 96% by primary analysis, with the breakdown by genotype showing 96.5% for those with genotype 1a, 95.5% for genotype 1b, and 96.4% for genotype 4. All study participants with cirrhosis achieved an SVR12.[23]
• Glecaprevir-Pibrentasvir (EXPEDITION-2): In this open-label, dual-arm phase 3 trial, 137 noncirrhotic adults with HCV (genotype 1-6) and HIV coinfection were assigned 8 weeks of glecaprevir-pibrentasvir and 16 persons with HCV-HIV coinfection and compensated cirrhosis received 12 weeks of glecaprevir-pibrentasvir.[30] The majority (63%) of participants had genotype 1 HCV infection and 18% were treatment-experienced (16% with an interferon-based regimen and 2% with a sofosbuvir-based regimen).[30] All but 10 participants were taking raltegravir, dolutegravir, or rilpivirine as the antiretroviral therapy anchor drug. The overall SVR12 rate was 98%; one individual with genotype 3 HCV and cirrhosis experienced on-treatment virologic breakthrough.[30]
• Ledipasvir-Sofosbuvir (NIAID ERADICATE): This phase 2 trial investigated the open-label use of ledipasvir-sofosbuvir for 12 weeks in 50 treatment-naïve adults with genotype 1 chronic HCV and HIV coinfection.[31] Among the 50 participants enrolled, 13 were not on antiretroviral therapy and 37 were receiving antiretroviral therapy (antiretroviral medications allowed included tenofovir DF-emtricitabine, efavirenz, and rilpivirine). Overall, 49 (98%) of patients in the study achieved an SVR12.[31]
• Ledipasvir-Sofosbuvir (ION-4): In this phase 3, open-label, multicenter study, investigators enrolled 335 adults with hepatitis C genotype 1 or 4 who were coinfected with HIV to receive a 12-week course of ledipasvir-sofosbuvir.[22] Enrollment included HCV treatment-naïve and treatment-experienced individuals and those without cirrhosis and those with compensated cirrhosis. The HIV enrollment criteria consisted of HIV RNA less than 50 copies/mL and CD4 count greater than 100 cells/mm³; antiretroviral regimens could include tenofovir DF-emtricitabine plus either efavirenz, rilpivirine, or raltegravir. Overall, 321 (96%) of 335 treated study participants achieved an SVR12.[22] The results were similar regardless of prior treatment status or presence of cirrhosis.
• Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir plus Ribavirin (TURQUOISE-I): This open-label study randomized treatment-naïve and treatment-experienced adults with chronic HCV genotype 1 and HIV coinfection to receive a 12- or 24-week course of ombitasvir-paritaprevir-ritonavir and dasabuvir plus ribavirin.[24] Participants were required to have a CD4 count of at least 200 cells/mm³ (or CD4% greater than 13) and an HIV RNA level less than 40 copies/mL while receiving an atazanavir- or raltegravir-based regimen. Enrollment included individuals with compensated cirrhosis (Child-Turcotte-Pugh class A) and those with prior treatment with peginterferon plus ribavirin. The SVR12 rates were 29 (93.5%) of 31 in the 12-week group and 29 (90.6%) of 32 in the 24-week group.
• Sofosbuvir-Velpatasvir (ASTRAL-5): The ASTRAL-5 study was a single-arm, open-label, phase 3 trial of sofosbuvir-velpatasvir for 12 weeks in adults with HCV and HIV coinfection.[25] The study enrolled 106 individuals with HCV genotype 1, 2, 3, 4, or 6; among those enrolled, 18% had compensated cirrhosis and 29% were treatment-experienced.[25] The mean CD4 count was 583 cells/mm³ and all participants had suppressed HIV RNA levels. A variety of antiretroviral regimens, including tenofovir DF and boosting agents (cobicistat or ritonavir), were permitted. The overall SVR12 rate was 95%; two viral relapses occurred, both in persons with genotype 1a HCV; no participants experienced HIV viral rebound during HCV treatment.[25] The presence of cirrhosis or treatment experience did not appear to influence treatment response. Creatinine clearance was lower among people taking a boosting agent and tenofovir DF, but it remained relatively stable over time in all groups.[25]

AASLD-IDSA HCV Guidance

The American Association for the Study of Liver Diseases and Infectious Diseases Society of America (AASLD-IDSA) HCV Guidance addresses treatment of persons with HCV and HIV coinfection in detail.[20] The AASLD-IDSA HCV Guidance recommends using the same general approach for treating HCV in persons with HCV-HIV coinfection as with HCV monoinfection, but notes the importance of recognizing and managing potential drug interactions between HCV medications and HIV antiretroviral medications.[20] In most instances, the recommended HCV treatment regimens are the same persons with HCV monoinfection as in those with HCV-HIV coinfection. One exception is the 8-week regimen of ledipasvir-sofosbuvir, which can be considered for treatment of a select group of persons with HCV genotype 1 monoinfection, but should never be used to treat HCV genotype 1 in persons with HCV and HIV coinfection.[20] As with the treatment of persons with HCV monoinfection, the major factors in selecting a regimen to treat HCV in persons with HIV coinfection include HCV genotype, prior treatment experience, presence of cirrhosis, and potential drug interactions with HIV antiretroviral medications.

Most persons with HIV infection are taking multidrug antiretroviral therapy, which may pose a problem with drug interactions when initiating HCV treatment. For resources on drug interactions that may occur with HIV antiretroviral medications and HCV treatment medications, access the following sites (1) the HHS Adult and Adolescent Antiretroviral Therapy Guidelines Drug-Drug Interactions section, (2) the AASLD-IDSA HCV Guidance Drug Interactions Between Direct-Acting Antivirals and Antiretroviral Drugs tables, (3) the UCSF Center for HIV Information Database of Antiretroviral Drug Interactions tables, and (4) the Liverpool HEP Drug Interactions and HIV Drug Interactions tables. The following provides key points related to drug interactions for HCV DAA medications (and ribavirin).

• Daclatasvir: The NS5A inhibitor daclatasvir is a substrate of CYP3A. When daclatasvir is given with a CYP3A inhibitor, the levels of daclatasvir can increase, particularly with strong inhibitors of CYP3A. The dose of daclatasvir should therefore be reduced to 30 mg when used with either ritonavir-boosted atazanavir or lopinavir. In contrast, when used with efavirenz, a CYP3A inducer, the dose of daclatasvir should be increased to 90 mg daily.
• Elbasvir-Grazoprevir: Grazoprevir is a substrate of the OATP1B1/3 transporters and therefore contraindicated for use with OATP1B1/3 inhibitors such as the HIV protease inhibitors or cobicistat-containing regimens that can increase grazoprevir drug levels and the risk of hepatotoxicity. Both elbasvir and grazoprevir are metabolized by the CYP3A levels and thus levels may decrease if given with CYP3A inducers, such as efavirenz and etravirine. Coadministraton of elbasvir-grazoprevir is not recommended with protease inhibitors, efavirenz, etravirine, or any cobicistat-containing regimen. 
• Glecaprevir-Pibrentasvir: Glecaprevir is a substrate of OATP1B1/3, P-gp and BRCP and inhibitors of these transporters, specifically the HIV protease inhibitors atazanavir, lopinavir or ritonavir can increase levels of glecaprevir. In addition, use of atazanavir with glecaprevir-pibrentasvir has been associated with increased risk of ALT elevation. Cobicistat-containing regimens may also do so but to a lesser extent; 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 contraindicated for use with atazanavir. In addition, glecaprevir-pibrentasvir is not recommended for coadministration with darunavir, lopinavir, ritonavir, efavirenz, or etravirine.
• Ledipasvir-Sofosbuvir: The NS5A inhibitor ledipasvir is not metabolized by the cytochrome p450 system, but is both a substrate and an inhibitor of p-glycoprotein and BCRP transporters. Ledipasvir increases tenofovir AUC levels by 40 to 98% when concomitantly given with tenofovir DF and either rilpivirine or efavirenz. Concurrent use of ledipasvir with tenofovir DF and an HIV protease inhibitor (or cobicistat) has not been adequately studied, but there is concern that tenofovir levels may increase substantially with this combination. Because of this concern and lack of data, the use of ledipasvir with ritonavir-boosted HIV protease inhibitors or cobicistat should, if possible, be avoided. For similar reasons, ledipasvir-sofosbuvir should not be used with cobicistat, 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. Ledipasvir does not have significant drug interactions with tenofovir alafenamide.
• Ombitasvir-Paritaprevir-Ritonavir: The major concern for drug interaction with this regimen is the cytochrome p450 enzyme inhibition generated by ritonavir. This combination regimen should not be used with cobicistat, efavirenz, rilpivirine, darunavir, tipranavir, or lopinavir-ritonavir.
• Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir: The key drug interaction issue with this regimen is the inhibition of cytochrome p450 enzymes by ritonavir. This combination regimen should not be used with cobicistat, efavirenz, etravirine, rilpivirine, darunavir, tipranavir, or lopinavir-ritonavir.
• Ribavirin: Significant and serious toxicities can occur with the simultaneous use of ribavirin and certain HIV nucleoside reverse transcriptase inhibitors. The use of ribavirin with didanosine is strictly contraindicated due to a marked increase in intracellular didanosine levels, which may cause hepatic failure, pancreatitis, and lactic acidosis. This can also occur with stavudine or zidovudine. Thus, simultaneous use of ribavirin with either didanosine, stavudine, or zidovudine should be avoided. In addition, concurrent use of ribavirin and zidovudine should also be avoided because of additive hematologic toxicity and increased risk of severe anemia with this combination.
• Simeprevir: This NS34A HCV protease inhibitor has complex interactions with antiretroviral medications because it is a substrate and an inhibitor of CYP3A4 and p-glycoprotein. In addition, simeprevir inhibits the OATP1B1/3 drug transporter. Simeprevir should not be used concomitantly with any of the following medications: efavirenz, etravirine, nevirapine, any HIV protease inhibitors, or any regimen that contains cobicistat. Simeprevir can be used with reverse transcriptase inhibitors, rilpivirine, dolutegravir, and raltegravir; if used with maraviroc, the dose of maraviroc should be decreased to 150 mg twice daily.
• Sofosbuvir: This NS5B polymerase inhibitor is rapidly converted to a dominant circulating metabolite (GS-331007). Sofosbuvir is not metabolized by the cytochrome p450 system, but is a substrate of p-glycoprotein. The only significant interaction with antiretroviral medications occurs with the p-glycoprotein inducer tipranavir, which may decrease levels of sofosbuvir and the GS-331007 metabolite. Accordingly sofosbuvir should not be used concomitantly with tipranavir, but it can be used with all other antiretrovirals.
• Sofosbuvir-Velpatasvir: Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 have the potential to decrease plasma concentrations of sofosbuvir and/or velpatasvir. For this reason, efavirenz and etravirine, as well as tipranavir, are contraindicated for concurrent use. Velpatasvir, when given with tenofovir DF can increase tenofovir levels so caution is advised when using this combination, especially in persons taking additional medications that may increase tenofovir levels or those who have an increased risk for nephrotoxicity. An increase in tenofovir levels can occur with coadministration of sofosbuvir-velpatasvir and tenofovir alafenamide, although to a lesser extent than with tenofovir DF.
• Sofosbuvir-Velpatasvir-Voxilaprevir: Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 have the potential to decrease plasma concentrations of sofosbuvir and/or velpatasvir. Therefore, efavirenz, etravirine, and tipranavir are not recommended for concurrent use with sofosbuvir-velpatasvir-voxilaprevir. In addition, atazanavir and lopinavir are not recommended for use with sofosbuvir-velpatasvir-voxilaprevir.

The HHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV emphasizes the following key points on treating HIV with antiretroviral therapy for persons with HIV and HCV coinfection:[32]

• Antiretroviral therapy to treat HIV may slow the progression of HCV-related liver disease and reduce the risk of liver-related morbidity.
• For all persons with HIV and HCV coinfection, antiretroviral therapy should be initiated, regardless of the CD4 cell count and fibrosis stage.
• If treatment for both HIV and HCV is indicated, the selected treatment regimens should consider potential drug interactions and overlapping toxicities.
• For individuals living with HIV who have a CD4 counts less than 200 cells/mm³, it may be advisable to first initiate antiretroviral therapy and defer HCV therapy until the person is stable on antiretroviral therapy. It should be noted that the preponderance of clinical trial data on the efficacy of HCV therapy derive largely from patients with suppressed HIV RNA levels on antiretroviral therapy with CD4 counts greater than 200 cells/mm³.
• Antiretroviral therapy-induced liver injury occurs more commonly in persons with HIV and HCV coinfection than in persons with HIV monoinfection.

• In persons with chronic HCV, coinfection with HIV accelerates the progression of hepatic fibrosis. Therefore, treatment of both HIV and HCV should have high priority in persons with HCV-HIV coinfection.
• The availability of highly effective, convenient, and safe DAA regimens has changed the treatment landscape for persons with HCV and HIV coinfection. Multiple studies using DAA HCV treatment regimens have demonstrated comparable SVR12 rates in persons with HCV-HIV coinfection and HCV monoinfection.
• The AASLD-IDSA HCV Guidance recommends using the same HCV treatment approach for persons with HCV-HIV coinfection as with HCV monoinfection, except the 8-week ledipasvir-sofosbuvir regimen is not an option in persons with HCV-HIV coinfection.
• Special consideration should be given to monitoring and managing HIV antiretroviral and HCV DAA drug interactions.
• Antiretroviral therapy may slow liver disease progression in persons with HCV-HIV coinfection and should therefore be considered for all persons with HCV-HIV coinfection, regardless of CD4 cell count.
• For persons with chronic HCV who have HIV coinfection and a CD4 cell count less than 200 cells/mm³, it may be advisable to initiate HIV antiretroviral therapy first and wait for stabilization of the HIV infection prior to initiating HCV therapy.

Interaction of Hepatitis C Infection and Renal Disease

Persons infected with hepatitis C virus (HCV) can develop kidney disease as a result of extrahepatic manifestation of HCV or as a disease process independent of the HCV infection. In addition, hemodialysis has been a risk factor for acquiring HCV infection, as shown by numerous outbreaks and HCV cross-infections that have occurred in hemodialysis units.[1,2,3,4] Earlier studies conducted in western countries have shown an HCV prevalence in hemodialysis patients that ranged from 2.6 to 23%, with higher prevalence correlating with longer duration of hemodialysis.[5,6,7] The risk of HCV transmission in hemodialysis units has declined due to improved testing and infection control practices.[8,9] Several studies have shown that patients on chronic hemodialysis have an increased overall mortality risk if they have chronic hepatitis C infection (when compared with those on dialysis who do not have hepatitis C infection).[10,11] There are also some data showing that chronic hepatitis C may be a risk factor for developing renal cell carcinoma.[12] Chronic hepatitis C infection has also been associated with an accelerated course of renal disease, including in persons with HIV coinfection.[13,14] Extrahepatic manifestations related to HCV, including immune complex-related renal disease, can require urgent HCV treatment to resolve or prevent further organ damage.

Definitions and Classification

As part of evaluating and treating patients with hepatitis C and renal disease, it is important to first determine the stage of the patient’s renal disease, a process that utilizes some of the following definitions.

• Chronic Kidney Disease (CKD): Chronic kidney disease is defined based on the presence of either kidney damage or decreased kidney function for three or more months, irrespective of cause.
• Glomerular Filtration rate (GFR): GFR is generally considered to be the best index of overall kidney function. The GFR varies in normal individuals by age and sex, dietary protein intake, and possibly by race-ethnicity. The normal value for GFR is approximately 130 and 120 mL/min/1.73 m² for men and women, respectively. The widely accepted threshold defining a decreased GFR is less than 60 mL/min per 1.73 m²; kidney failure is defined as a GFR less than 15 mL/min/1.73 m² or treatment by dialysis (Figure 1). The GFR is equal to the sum of the filtration rates in all of the functioning nephrons, but since the GFR cannot be measured directly, it is usually estimated from serum markers. The gold standard for assessment of GFR is the renal inulin clearance test, but this method is highly complex and not practical for routine clinical purposes. Accordingly, several methods, including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD), have been utilized in clinical practice to estimate GFR.[15,16,17]
• Creatinine Clearance (CrCl): The creatinine clearance is a widely used test to estimate the glomerular filtration rate (eGFR). The creatinine clearance, however, overestimates the GFR since creatinine is both filtered by the glomeruli and secreted in the renal tubules. The Cockcroft-Gault formula is commonly used in clinical practice to estimate the creatinine clearance based on the serum creatinine, patient age, body mass in kilograms, and sex (Figure 2).[18] Normal values are 95 to 145 mL/min in men and 75 to 115 mL/min in women. This formula is less accurate in weight extremes. A more accurate, but less practical, determination of creatinine clearance can be made with a 24-hour urine collection. The creatinine clearance is then calculated by dividing the 24-hour urine creatinine by the serum creatinine; the 24-hour urine creatinine is equal to the urine creatinine concentration multiplied by urine volume. There are several limitations to the 24-hour urine creatinine clearance that can cause inaccuracies, such as an incomplete urine collection.
• Staging of Kidney Disease: Guidelines such as the Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease state that among persons diagnosed using the criteria described above, staging of CKD should be done according to the cause of disease, category of eGFR and category of albuminuria.[19] The KDIGO classifies kidney disease based on the cause, patient’s GFR (Figure 3) and albuminuria categories (Figure 4), with an overall prognosis generated based on the both of these categories (Figure 5).[20,21]

Evaluation of Persons with Chronic HCV and CKD

Serum creatinine should be measured and creatinine clearance or GFR should be estimated as part of a pre-treatment assessment for HCV patients. The CKD stage should be determined if renal function is abnormal. Complete blood count should be obtained as well, to assess for pre-treatment anemia.

The availability of direct-acting antiviral agents (DAAs) has sparked major enthusiasm for treating persons with HCV who have chronic renal impairment, especially since many of these individuals historically have not been eligible for treatment given the toxicities associated with interferon and ribavirin-based therapy.[22] The following summarizes key studies involving use of new DAA-based therapy in persons with chronic renal insufficiency. Older studies that used interferon- or peginterferon-based regimens are not reviewed since these agents are no longer recommended for the treatment of HCV infection.

• Elbasvir-Grazoprevir (C-SURFER): In this phase 3, randomized study, investigators enrolled 224 adults with HCV genotype 1 and chronic renal disease, including individuals on hemodialysis, to receive immediate treatment with 12 weeks of therapy with elbasvir plus grazoprevir, or deferred therapy.[23] Subjects in the deferred group received placebo during the first 12 weeks; use of placebo was considered important as a comparator for safety purposes, particularly due to safety concerns in this population with advanced renal disease.[23] Overall, 80% of the participants enrolled in the trial were treatment naïve and 76% were receivinghemodialysis. Among the 116 subjects who completed therapy, 115 (99%) achieved a sustained virologic response 12 weeks after completing treatment (SVR12). Six individuals were excluded from the modified full analysis, but all 6 had HCV RNA levels less than 15 IU/mL at that time of study discontinuation.[23] The safety profile observed in participants who received elbasvir plus grazoprevir was comparable to that seen in the placebo group.
• Glecaprevir-Pibrentasvir (EXPEDITION-4): This phase 3 single-arm open-label trial evaluated the safety and efficacy of 12 weeks of glecaprevir-pibrentasvir in 104 adults with HCV genotype 1-6 infection and advanced renal insufficiency (estimated glomerular filtration rate less than 30 mL/min/1.73m²); 88% had chronic kidney disease stage 5 and 82% were on hemodialysis.[24] Fifty-two percent of participants had HCV genotype 1 infection, 19% had compensated cirrhosis, and 42% were treatment-experienced (all but two with prior interferon-based therapy). The overall SVR rate was 98% by intent-to-treat analysis.[24] The rate of adverse events (pruritus 20%, fatigue 14%, nausea 12%) attributable to glecaprevir-pibrentasvir were comparable to those observed in other glecaprevir-pibrentasvir trials.[24]
• Ledipasvir-Sofosbuvir (ERCHIVES-Renal: Ledipasvir-Sofosbuvir): In an observational cohort study conducted in the Veterans Administration system, investigators used the Electronically Retrieved Cohort of HCV-Infected Persons (ERCHIVES) to analyze HCV treatment responses for 13,663 persons who received ledipasvir-sofosbuvir, with or without ribavirin.[25] This cohort included a total of 1,607 with CKD stage 3, 4, or 5 who completed HCV treatment.[25] The SVR12 rates for individuals with stage 3 CDK who completed treatment was 97.0% (1080 of 1113) in those who received ledipasvir-sofosbuvir and 97.1% (375 of 386) with ledipasvir-sofosbuvir plus ribavirin.[25] For those with stage 4 or 5 CKD, the SVR12 rates were 94.0% (78 of 83) with ledipasvir-sofosbuvir and 100% (25 of 25) with ledipasvir-sofosbuvir plus ribavirin. The ERCHIVES-Renal also included analysis of persons with CKD and HCV treatment responses to ombitasvir-paritaprevir-ribavirin and dasabuvir, with or without ribavirin.
• Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (ERCHIVES-Renal: OPRD): In an observational ERCHIVES cohort study based in the Veterans Administration, investigators analyzed treatment responses to ombitasvir-paritaprevir-ritonavir and dasabuvir, with or without ribavirin in 3,961 persons with chronic HCV infection.[25] The SVR12 rates ranged from 94 to 100% among those treated with ombitasvir-paritaprevir-ribavirin and dasabuvir.[25] The SVR12 rates for individuals with stage 3 CDK who completed treatment was 96.0% (95 of 99) in the group without ribavirin and 95.3% (203 of 213) with ribavirin. With individuals who had stage 4 or 5 CKD, the SVR12 rates were 100% (42 of 42) in the group without ribavirin and 89.1% (41 of 46) with ribavirin.[25] The ERCHIVES-Renal also included analysis of persons with CKD and treatment responses to ledipasvir-sofosbuvir, with or without ribavirin.
• Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (RUBY-I): In the RUBY-1 trial, investigators treated adults with chronic HCV infection and stage 4 or 5 CKD, including individuals on hemodialysis, with a 12-week regimen of ombitasvir-paritaprevir-ribavirin and dasabuvir, with or without ribavirin.[26] All participants had HCV genotype 1, were treatment-naïve, and had noncirrhotic liver disease. Ninety percent (18 of 20) participants achieved an SVR12. Nine of the 13 individuals with HCV genotype 1a had ribavirin therapy interrupted due to anemia and 4 received erythropoietin.[26]
• Sofosbuvir-Based Therapy (HCV Target: Renal Disease): In the HCV TARGET Renal Disease trial, investigators reported findings from a longitudinal cohort study of 1,893 adults with chronic HCV using one of four sofosbuvir-containing regimens: (1) sofosbuvir plus peginterferon plus ribavirin, (2) sofosbuvir plus ribavirin, (3) sofosbuvir plus simeprevir, and (4) sofosbuvir plus simeprevir plus ribavirin.[27] Overall, the SVR12 rates were high (81 to 89%) across different levels of baseline renal insufficiency, with one exception: individuals with cirrhosis who had an estimated GFR less than 30 mL/min/1.73m² had lower SVR12 rates.[27] Rates of treatment-related anemia were higher in persons with more advanced renal disease.

Dosing of DAA Medications in Persons with CKD

The following (in alphabetical order) summarizes recommended dosing information for oral DAA medications (and ribavirin) used to treat HCV in persons with renal impairment. The information provided is based on specific drug prescribing information for persons with renal impairment. The only DAA for which there has been some concern regarding reduced renal clearance and high drug levels has been sofosbuvir; available data on the safety of sofosbuvir for patients with advanced renal disease (i.e. GFR less than 30 mL/min/1.73m²) have been mixed, but more recently several observational reports suggested sofosbuvir is safe in this setting.[27,28,29,30] The AASLD-IDSA HCV Guidance does not recommend using sofosbuvir-containing regimens in persons with advanced (stage 4-5) CKD or on dialysis.[31]

• Daclatasvir: No dosage adjustment of daclatasvir is needed for patients who have mild, moderate, or severe renal impairment. There are no recommendations regarding the use of daclatasvir in patients requiring dialysis (see Daclatasvir Prescribing Information).
• Elbasvir-Grazoprevir: No dosage adjustment of elbasvir-grazoprevir is needed for patients who have mild, moderate, or severe renal impairment, including individuals requiring dialysis (see Elbasvir-Grazoprevir Prescribing Information).
• Glecaprevir-Pibrentasvir: No dosage adjustment of glecaprevir-pibrentasvir is needed for patients who have mild, moderate, or severe renal impairment, including individuals requiring dialysis (see Glecaprevir-Pibrentasvir Prescribing Information).
• Ledipasvir-Sofosbuvir: No dosage adjustment of ledipasvir-sofosbuvir is needed for patients who have mild or moderate renal impairment. There are insufficient data regarding the safety and efficacy of ledipasvir-sofosbuvir in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m²) or end-stage renal disease requiring dialysis (see Ledipasvir-Sofosbuvir Prescribing Information).
• Ombitasvir-Paritaprevir-Ritonavir: No dosage adjustment of ombitasvir-paritaprevir-ritonavir is needed for patients who have mild, moderate, or severe renal impairment. There are insufficient data regarding the safety and efficacy of ombitasvir-paritaprevir-ritonavir in patients requiring dialysis (see Ombitasvir-Paritaprevir-Ritonavir Prescribing Information).
• Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir: No dosage adjustment of ombitasvir-paritaprevir-ritonavir and dasabuvir is needed for patients who have mild, moderate, or severe renal impairment, including individuals requiring dialysis (see Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir Prescribing Information). 
• Simeprevir: No dosage adjustment of simeprevir is needed for patients who have mild, moderate, or severe renal impairment. There are insufficient data regarding the safety and efficacy of simeprevir in patients requiring dialysis (see Simeprevir Prescribing Information).
• Sofosbuvir: No dosage adjustment of sofosbuvir is needed for patients who have mild or moderate renal impairment. There are insufficient data regarding the safety and efficacy of sofosbuvir in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m²) or end-stage renal disease requiring dialysis (see Sofosbuvir Prescribing Information).
• Sofosbuvir-Velpatasvir: No dosage adjustment of sofosbuvir-velpatasvir is needed for patients who have mild or moderate renal impairment. There are insufficient data regarding the safety and efficacy of sofosbuvir-velpatasvir in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m²) or end-stage renal disease requiring dialysis (see Sofosbuvir-Velpatasvir Prescribing Information).
• Sofosbuvir-Velpatasvir-Voxilaprevir: No dosage adjustment of sofosbuvir-velpatasvir-voxilaprevir is needed for patients who have mild or moderate renal impairment. There are insufficient data regarding the safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m²) or end-stage renal disease (see Sofosbuvir-Velpatasvir-Voxilaprevir Prescribing Information).

Dosing of Ribavirin in Persons with CKD

Ribavirin is not a DAA and dosing of ribavirin in persons with CKD requires special consideration independent of recommendations for DAA medication in CKD. In the current era of HCV treatment, ribavirin is recommended for use only in select situations:

• In combination with ledipasvir-sofosbuvir in persons who have decompensated cirrhosis.
• In persons with HCV genotype 1a who are receiving treatment with elbasvir-grazoprevir and who have baseline NS5A resistance-associated substitutions (RASs) for elbasvir.

Ribavirin is manufactured by multiple companies and is available as a generic preparation. In general, concern exists with the use of ribavirin in patients with renal impairment since ribavirin levels will increase as renal function decreases. Several ribavirin company package inserts, including Rebetol and Ribasphere recommend not using ribavirin in patients with an estimated glomerular filtration rate less than 50 mL/min. The package insert for Copegus permits the use of ribavirin in patients with an estimated glomerular filtration rate less than 50 mL/min if the dose is reduced and careful monitoring occurs. The AASLD-IDSA HCV Guidance recommends adults with a creatinine clearance of 30 to 50 mL/min should have the ribavirin dose reduced to alternating doses of 200 and 400 mg every other day (for example, 200 mg on Monday, 400 mg on Tuesday, 200 mg on Wednesday, etc.). In addition, these guidelines recommend reducing the dose of ribavirin to 200 mg once daily in adults who have severe renal disease (creatinine clearance less than 30 mL/min), end-stage renal disease, or hemodialysis.

The AASLD-IDSA HCV Guidance provides the following specific recommendations for treatment of HCV in persons with renal impairment, with the guidance stratified based on the degree of renal impairment.[31] 

Mild-to-Moderate Renal Impairment: Any DAA Regimen

For persons with chronic HCV infection and mild-to-moderate renal impairment (CKD stage 1, 2, or 3), any of the DAA regimens recommended in the AASLD-IDSA HCV Guidance can be used without the need for dose adjustment. Interactions between DAA medications and other medications may require dose adjustment.

Severe Renal Impairment: Glecaprevir-Pibrentasvir or Elbasvir-Grazoprevir

For persons with severe renal impairment (CKD stage 4 or 5, with eGFR less than 30 mL/min or end-stage renal disease), the AASLD-IDSA HCV Guidance recommends using standard doses of a 12-week course of elbasvir-grazoprevir (for HCV genotypes 1a, 1b, or 4) and an 8 to 16 week course of glecaprevir-pibrentasvir (for HCV genotypes 1-6); the duration of glecaprevir-pibrentasvir is based on prior treatment history and presence of cirrhosis. Interactions between DAA medications and other medications may require dose adjustment.

Hepatitis C Treatment Prior to Renal Transplantation

Most experts recommend that persons with chronic HCV infection who are renal transplantation candidates receive treatment of HCV prior to renal transplantation, if possible.[32,33] In some circumstances, however, it may not be possible to treat HCV prior to renal transplantation. Historically, HCV treatment was recommended pretransplant, given the potential for graft dysfunction in patients who received interferon-based therapy post-transplant and the improved clinical outcomes in those who underwent HCV clearance prior to transplantation.[34,35,36] Pretransplant treatment of HCV has also been shown to prevent some HCV-related renal complications, such as glomerulonephritis in the kidney transplant population. When treating HCV in a person waiting for renal transplant, the DAA regimens are the same as those recommended to treat persons with chronic severe renal impairment.[31]

HCV Treatment Studies in Renal Transplant Recipients

In recent years, multiple HCV treatment studies have been conducted using DAAs in renal transplant recipients. Most of these studies have involved a small number of participants, typically 25 or less.[37,38,39,40] In these studies, DAA therapy was safe and highly effective. Several larger studies also support the efficacy of HCV treatment in renal transplant recipients.[41,42] In a phase 2, open-label trial, investigators in Europe enrolled 114 treatment-naïve or treatment-experienced kidney transplant recipients with chronic HCV genotype 1 or 4 infection to receive either a 12- or 24-week course of ledipasvir-sofosbuvir.[41] All 114 (100%) of study participants achieved an SVR12.[41] In the observational HCV-TARGET study, 55 renal transplant recipients had treatment of HCV with DAA therapy, most often ledipasvir-sofosbuvir, with or without ribavirin.[42] Overall, 94.5% (52 of 55) renal transplant recipients achieved an SVR12 with DAA therapy for chronic HCV infection.[42]

AASLD-IDSA Guidance for HCV Treatment after Renal Transplant

The following summarizes the AASLD-IDSA HCV Guidance for the treatment of renal transplant recipients, which are stratified based on HCV genotype.[43] Note that consideration for drug interactions is extremely important in the post-transplantation period, particularly with regard to immunosuppressant calcineurin inhibitors, particularly cyclosporine and tacrolimus.

• Genotypes 1 and 4, with or without Compensated Cirrhosis: The recommended regimens are a 12-week course of glecaprevir-pibrentasvir or a 12-week course of ledipasvir-sofosbuvir.
• Genotypes 2, 3, 5 or 6, with or without Compensated Cirrhosis: The recommended regimen is a 12-week course of glecaprevir-pibrentasvir. The alternative regimen is a 12-week course of daclatasvir plus sofosbuvir plus low initial dose of ribavirin (starting at 600 mg per day and increasing to standard dosing as tolerated).

• Chronic kidney disease is a major potential comorbidity in people living with chronic HCV infection.
• Renal function, including an estimation of CrCl or GFR, must be assessed before initiating any hepatitis C treatment. Based on the estimated CrCl or GFR value, individuals with renal impairment are classified as having mild (50 to 80 mL/min), moderate (30 to 50 mL/min), or severe (less than 30 mL/min) disease
• For persons with mild-moderate renal impairment (CKD stage 1, 2, or 3) no dose adjustments are needed for DAA medications.
• For persons with severe renal impairment (CKD stage 4 or 5, including those with end-stage renal disease), the AASLD-IDSA HCV Guidance recommends using standard doses of a 12-week course of elbasvir-grazoprevir (for HCV genotypes 1a, 1b, or 4) or an 8- to 16-week course of glecaprevir-pibrentasvir (for HCV genotypes 1-6); the duration of glecaprevir-pibrentasvir is based on prior treatment history and presence of cirrhosis.
• Ribavirin is required in limited situations in persons with chronic renal failure; these include in combination with ledipasvir-sofosbuvir with extended duration of 24 weeks for persons with decompensated cirrhosis and in combination with elbasvir-grazoprevir in those with HCV genotype 1a who have presence of NS5A resistance-associated substitutions prior to treatment.
• For individuals with severe renal impairment who require ribavirin, the recommended ribavirin dose is 200 mg/day (typically starting at 200 mg three times weekly and titrating up to 200 mg/day as tolerated). Caution should be exerted when using ribavirin in persons with renal failure because of the risk of severe hemolysis.
• Persons with chronic HCV infection who require renal transplantation should undergo prompt evaluation for HCV treatment; the treatment of hepatitis C prior to renal transplantation is strongly preferred over treatment of hepatitis C post renal transplantation.

Introduction

Individuals with chronic hepatitis C virus (HCV) infection and cirrhosis have an increased risk of developing severe liver-related complications, including hepatic decompensation, hepatocellular cancer, and death. Accordingly, any person with chronic HCV infection who is diagnosed with compensated cirrhosis should be considered at a high priority for HCV treatment. For persons with chronic HCV infection and decompensated cirrhosis, the treatment plans and goals may need modifying if the patient is planning to undergo liver transplantation.

Distinguishing Compensated and Decompensated Cirrhosis

One important step in treating HCV in persons with cirrhosis is to determine whether the cirrhosis is compensated or decompensated.[1,2] The treatment approach and goals are divergent based on the classification of compensated versus decompensated cirrhosis. In particular, HCV protease inhibitor-based regimens are not recommended for use in persons with decompensated cirrhosis, due to the risk of hepatotoxicity with some medications and lack of data with the others.[3] In general, individuals with compensated cirrhosis have mild hepatic impairment (Child-Turcotte-Pugh class A) (Figure 1) and do not have jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy. In contrast, individuals should be considered to have decompensated cirrhosis if they have moderate or severe liver disease (Child-Turcotte-Pugh class B or C). Individuals are defined as having decompensated cirrhosis if they have experienced one or more of the following: ascites, jaundice, variceal hemorrhage, or hepatic encephalopathy.[1,4] Patients who have significant clinical improvement after experiencing one feature of hepatic decompensation should be evaluated on a case-by-case basis to determine whether they could be considered for treatment similar to patients with compensated cirrhosis.

Multiple studies, most from the interferon era, have shown that successful treatment of HCV in persons with compensated cirrhosis will decrease subsequent cirrhosis-related complications (Figure 2), including lowering the risk for hepatic failure, hepatocellular carcinoma (Figure 3), and liver-related deaths.[5,6,7] Concern was raised when several European studies reported treatment of HCV with direct-acting antiviral (DAA) medications appeared to increase the risk of hepatocellular carcinoma, particularly with recurrent hepatocellular carcinoma in persons who had received prior ablative therapy for their hepatocellular carcinoma.[8,9] A subsequent meta-analysis and national cohort study did not find this association, and the investigators underscored that post-treatment risk assessment of hepatocellular carcinoma is instead more closely tied to patient factors, such as age and liver disease severity; these variables need to be controlled when performing any post-treatment risk for hepatocellular carcinoma.[10,11] Multiple studies have shown that persons with chronic HCV and cirrhosis have significant improvement in inflammatory grade and have improvement in fibrosis following HCV therapy and achievement of a sustained virologic response (SVR).[5,12] The improvement in hepatic inflammation and fibrosis was initially shown with several studies involving interferon- or peginterferon-based treatment studies.[13,14,15] More recently, several investigators have shown substantial improvements in hepatic fibrosis following achievement of an SVR with DAA-based treatments.[16,17,18,19]

HCV Treatment Goals in Persons with Compensated Cirrhosis

The most important immediate goal of treatment is to achieve an SVR, which is required before observing the subsequent benefit in liver-related and other outcomes. The next intermediate-term priority with therapy is to decrease the patient’s risk of developing hepatic decompensation. The long-term goals are to diminish the risk of developing HCV-related hepatocellular carcinoma and death.

Response to HCV Treatment

The impact of cirrhosis on the response to therapy has changed over time with evolving treatment regimens. The following summary illustrates a significant improvement in SVR rates among patients with cirrhosis with regimens that include new direct-acting agents.

• Elbasvir-Grazoprevir: In this study, investigators performed an integrated analysis of six elbasvir-grazoprevir phase 2/3 clinical trials to determine SVR12 treatment responses in 402 subjects with HCV genotype 1, 4, or 6 and compensated cirrhosis.[20] Participants received treatment with elbasvir-grazoprevir, with or without weight-based ribavirin; the treatment duration was 12 weeks for treatment-naïve participants (n=169) and 12, 16, or 18 weeks for treatment-experienced subjects (n=233).[20] Prior treatment regimens consisted of peginterferon and ribavirin, with or without a first-generation protease inhibitor (boceprevir, telaprevir or simeprevir). Notably, platelet counts less than 100,000 cells/mm³ and serum albumin less than 3.5 g/dL were present in only 25% and 6% of participants respectively. Overall, using an intent-to-treatment analysis, SVR12 occurred in 96% of treatment-naïve participants and ranged from 89 to 100% among treatment-experienced subjects.[20] Genotype 1a patients were most likely to experience viral relapse with the strongest predictor for treatment failure being the presence of baseline NS5A resistance-associated substitutions. Asymptomatic grade 3-4 increases in hepatic aminotransferase levels were observed in 2.3%.
• Glecaprevir-Pibrentasvir: The efficacy of glecaprevir-pibrentasvir for 12 or 16 weeks was evaluated in a pooled analysis of 308 adults with HCV genotypes 1-6 and compensated cirrhosis.[21] Cirrhosis status was determined by FibroScan in 70% of the study subjects and 41% were treatment-experienced with prior peginterferon-based therapy. Child-Turcotte-Pugh score was 5 in 86% of those enrolled. Using an intent-to-treat analysis, SVR12 was achieved in 96% (297/308) of the study participants.[21] The SVR12 rates by HCV genotype showed 94% with HCV genotype 1, 97% with genotype 3, and 100% with genotypes 2, 4, 5 or 6.[21] There were no DAA-associated serious adverse events and no grade 3-4 elevations in hepatic aminotransferase levels. Grade 3 hyperbilirubinemia developed in 3 study participants; this occurred without associated abnormalities in other liver parameters and it resolved without treatment discontinuation.
• Ledipasvir-Sofosbuvir: The ION-1 trial enrolled HCV treatment-naïve adults, with and without compensated cirrhosis, to receive 12 or 24 weeks of ledipasvir-sofosbuvir.[22] Among the subjects enrolled with compensated cirrhosis, 97% (63 of 65) achieved an SRV12; the results were similar with 12 or 24 weeks of therapy (Figure 4).[22] The ION-2 trial enrolled treatment-experienced adults, and those with cirrhosis had lower SVR12 rates if they received ledipasvir-sofosbuvir for 12 weeks (86%) versus 24 weeks (100%) (Figure 5).[23] In these studies, the addition of ribavirin did not significantly improve SVR12 rates. In the SIRIUS trial, 155 treatment-experienced adults with HCV genotype 1 and compensated cirrhosis received 12 weeks ledipasvir-sofosbuvir plus ribavirin or 24 weeks of ledipasvir-sofosbuvir; the SVR12 rates were 96% for participants in the 12-week group and 97% in the 24-week group (Figure 6).[24] In a post-hoc analysis of 7 clinical trials, investigators analyzed data from 513 adults with HCV genotype 1 and compensated cirrhosis who received ledipasvir-sofosbuvir, with or without ribavirin.[25] The treatment-naïve subjects did equally well with a 12- or 24-week treatment course, but treatment-experienced individuals had lower response rates with 12 versus 24 weeks; ribavirin did not significantly improve SVR rates.[25]
• Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir plus Ribavirin: In the TURQUOISE II trial, 380 adults with chronic HCV genotype 1 infection and Child-Turcotte-Pugh class A cirrhosis were randomized to receive either 12 or 24 weeks of ombitasvir-paritaprevir-ritonavir and dasabuvir plus ribavirin.[26] The study included HCV treatment-naïve and treatment-experienced participants. In the 12-week group, 191 of 208 (92%) achieved an SVR12; for those in the 24-week group, SVR12 was achieved in 165 of 172 (96%) (Figure 7).[26] The treatment responses were similar in the treatment-naïve and treatment-experienced participants. Only 2% of the participants discontinued therapy due to adverse effects.
• Sofosbuvir-Velpatasvir: The main sofosbuvir-velpatasvir registration trials (ASTRAL 1, 2 and 3) included 14 to 30% of adults with compensated cirrhosis as part of the overall study population.[27,28] In the ASTRAL-1 trial of treatment-naïve and treatment-experienced adults with genotype 1, 2, 4, 5 or 6, the SVR12 rates with 12 weeks of sofosbuvir-velpatasvir treatment in participants with cirrhosis was 99% (120 of the 121).[27] Similarly, all 19 participants with cirrhosis and HCV genotype 2 in ASTRAL-2 achieved an SVR12.[28] In contrast, in the ASTRAL-3 study, which enrolled persons with HCV genotype 3, among the 80 patients with cirrhosis who received sofosbuvir-velpatasvir, the SVR12 rates were 93% for treatment-naïve and 89% for treatment-experienced participants.[28] Additional data suggest that persons with HCV genotype 3 and cirrhosis should undergo baseline NS5A resistance testing and those with pretreatment NS5A resistance-associated substitutions may benefit from the addition of ribavirin to reduce the risk of viral relapse.[29]

Recommended HCV Treatment with Compensated Cirrhosis

For individuals with compensated cirrhosis (Child-Turcotte-Pugh Class A), including those with hepatocellular carcinoma, the American Association for the Study of Liver Diseases and Infectious Diseases Society of America (AASLD-IDSA) HCV Guidance provides recommendations for initial treatment and retreatment (when prior therapy has failed).[30,31] Although the treatment recommendations for persons with and without cirrhosis have significant overlap, there are, in some instances, key differences in the recommended regimens, duration of therapy, or inclusion of ribavirin.[30,31] Thus, when treating HCV in persons with compensated cirrhosis, it should not be assumed the treatment is the same as those without cirrhosis and AASLD-IDSA treatment guidelines should be closely checked and followed.[30,31]

HCV Treatment Goals in Persons with Decompensated Cirrhosis

Individuals with cirrhosis are considered to have decompensated cirrhosis if they develop any of the following complications: ascites, jaundice, variceal hemorrhage, or hepatic encephalopathy.[1,2,4] The treatment of persons with decompensated cirrhosis (Child-Turcotte-Pugh class B or C) can be potentially challenging given the high rate of clinical events and complications that may occur in persons with decompensated cirrhosis. The immediate treatment goal for individuals with decompensated cirrhosis differs based on candidacy for liver transplantation. For those who are not a candidate for liver transplantation, the short-term goal of therapy is to achieve an SVR, with the hope that some degree of liver fibrosis will reverse as a result of therapy, which could then stabilize or improve their clinical condition. For persons with chronic HCV infection and decompensated cirrhosis who are candidates for liver transplantation, the short-term or intermediate goal of HCV therapy is to achieve virologic clearance of HCV prior to the liver transplantation. Individuals with detectable HCV at the time of liver transplantation will uniformly infect their new liver with HCV, which can reduce the life of the liver graft. The primary rationale for pretransplantation treatment of HCV is therefore to reduce the risk of HCV reinfection of the new liver and thus improve post-transplantation outcomes. In addition, for some pretransplantation individuals with decompensated cirrhosis, HCV treatment may prevent the need for a liver transplant. In a European study that enrolled 103 persons with chronic HCV who were on an active liver transplant list due to decompensated cirrhosis, treatment with DAA therapy resulted in delisting of 19% at 60 weeks after treatment.[32]

Response to HCV Treatment

Limited data exist for hepatitis C treatment in patients with decompensated cirrhosis, primarily because of concerns related to treatment-related toxicity.

• Daclatasvir plus Sofosbuvir: In the ALLY-1 trial, daclatasvir in combination with sofosbuvir and low-dose ribavirin was used to treat adults with HCV genotypes 1-6 and advanced cirrhosis or who had a post-transplantation HCV recurrence.[33] The advanced cirrhosis cohort included 48 participants with advanced cirrhosis (Child-Turcotte-Pugh class B or C).[33] An SVR12 was achieved in 22 of 24 (92%) participants with Child-Turcotte-Pugh class B and in 5 of 10 (50%) in those with Child-Turcotte-Pugh class C.[33]
• Ledipasvir-Sofosbuvir plus Ribavirin: In Cohort A of the phase 2, SOLAR-1 study, investigators prospectively enrolled 108 adults with hepatitis C genotype 1 or 4 infection and decompensated liver disease (Child-Turcotte-Pugh class B or C).[34] A total of 108 participants were randomized to receive either a 12-week or 24-week course of ledipasvir-sofosbuvir plus ribavirin; the ribavirin dose started at 600 mg per day and then was titrated up as tolerated.[34] Overall 65% of patients were HCV treatment experienced. Patients receiving the 12-week regimen had an SVR12 rate of 87%, which was similar to the SVR12 rate of 89% in the 24-week regimen; these data excluded 6 patients who underwent liver transplantation (Figure 8).[34] The results were similar in the Child-Turcotte-Pugh class B and C groups. Overall, the regimen of ledipasvir-sofosbuvir plus ribavirin was safe and well tolerated. In a similar phase 2 trial (SOLAR 2), investigators evaluated 12 or 24 weeks of ledipasvir-sofosbuvir plus ribavirin in adults with HCV genotype 1 or 4 and advanced liver disease.[35] The study cohort A included adults with Child-Turcotte Pugh class A, B, and C who had not undergone liver transplantation.[35] In participants with Child-Turcotte Pugh class B, the SVR12 rates were 87% with 12 weeks of treatment and 96% with 24 weeks. For those with Child-Turcotte-Pugh class C, the SVR12 rates were 85% with 12 weeks of treatment and 78% with 24 weeks (Figure 9).[35]
• Sofosbuvir-Based Regimens: In an open-label, nonrandomized, phase 2 trial, 50 adults with Child-Turcotte-Pugh cirrhosis and portal hypertension were randomized to receive immediate or deferred HCV treatment with sofosbuvir 400 mg once daily plus weight-based ribavirin 1000 to 1200 mg once daily.[36] The immediate group received treatment for 48 weeks; the deferred group was observed during the first 24 weeks after 24 weeks and then received 48 weeks of therapy.[36] Overall, 33 of 46 (72%) of the participants achieved an SVR.  The results were better in those with Child-Turcotte-Pugh class A (78%) than in those with Child-Turcotte-Pugh class B (68%). For the 37 participants who had paired baseline and end-of-treatment hepatic venous gradient measurements, there was a mean decline of 1.0 mmHg.[36]
• Sofosbuvir-Velpatasvir: The ASTRAL-4 trial was a randomized, open-label phase 3 trial designed to examine the safety and efficacy of the fixed-dose combination of sofosbuvir-velpatasvir with or without ribavirin in adults with genotype 1, 2, 3, 4, or 6 chronic HCV infection and decompensated cirrhosis.[37] Treatment-naïve and treatment-experienced individuals with Child-Pugh-Turcotte (CTP) class B disease were randomized to one of three arms: (1) sofosbuvir-velpatasvir for 12 weeks (n=90), (2) sofosbuvir-velpatasvir plus ribavirin for 12 weeks (n=87), or (3) sofosbuvir-velpatasvir for 24 weeks (n=90). All three regimens were highly efficacious among genotype 1 patients (88%, 96%, and 92% respectively) and genotypes 2, 4 and 6 patients (100%, 100%, and 86% respectively) (Figure 10).[37] Notably among participants with HCV genotype 3, the treatment groups without ribavirin had lower SVR12 rates. The Model for End-Stage Liver Disease (MELD) scores improved over baseline in those with a baseline MELD score less than 15 (Figure 11) and in those with a baseline MELD score of 15 or greater (Figure 12).[37] A total of 22 study subjects experienced virologic failure; most (n=18) had NS5A variants at the time of failure with the Y93H/N occurring most frequently.

Guidance for HCV Treatment with Decompensated Cirrhosis

The AASLD-IDSA Hepatitis C guidance address this group of patients in the section Unique Patient Populations: Patients with Decompensated Cirrhosis.[3] The key recommendation from the AASLD/IDSA guidance is that general management and treatment of all patients with decompensated cirrhosis should be performed by a medical practitioner highly experienced in managing persons with chronic HCV infection and decompensated cirrhosis. Accordingly, referral of these patients to an expert, ideally at a transplant center, is strongly recommended. Patients with decompensated cirrhosis include patients who may or may not be a candidate for liver transplantation and may include patients with hepatocellular carcinoma.

• Treatment of HCV in persons with compensated cirrhosis (Child-Turcotte-Pugh class A) is a high priority because of the risk of developing severe liver-related complications. 
• For persons with HCV-related cirrhosis, treatment of HCV is associated with significant reversal in hepatic fibrosis and reduced risk of developing hepatocellular carcinoma when an SVR occurs with therapy.
• For persons with HCV and compensated cirrhosis, the regimen choice and duration is generally generally similar to those without cirrhosis, except for longer duration and in select circumstances, the addition of ribavirin.
• With use of HCV DAA treatment, individuals with HCV and compensated cirrhosis can have comparable SVR12 rates as those without cirrhosis, especially with adjustments in therapy duration when indicated.
• Treatment of HCV is recommended in persons with decompensated cirrhosis who are eligible for liver transplantation, since the transplanted liver will become infected with HCV in all patients who have detectable HCV RNA levels at the time of liver transplantation. In addition, post-transplantation HCV infection is associated with an accelerated course of liver disease.
• Treatment of hepatitis C in patients with decompensated cirrhosis should be performed only by highly experienced hepatitis C medical providers.

The availability and effectiveness of direct-acting antiviral (DAA) medications has radically changed the assessment and consideration of substance use in HCV treatment decisions. Recommendations issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) HCV Guidance state that in the modern DAA treatment era recent or active injection-drug use should not be considered a contraindication to HCV treatment and requirements for pretreatment screening for illicit drug or alcohol use should be discontinued.[1] The general approach to considering initiation of treatment of HCV for individuals with a prior history of substance use, including injecting drugs, should be the same as in patients with no history of drug use. Nevertheless, for persons with chronic HCV infection, substance use, either past or present, which encompasses the use of opioids, amphetamines, cannabis, cocaine, alcohol, and other drugs, may still be relevant to the individual's overall health and medication access. Substance use disorders are common in the United States, with 2015 data indicating that among persons 18 years of age or older, approximately 10% had used illicit drugs in the past month and approximately 51% had used illicit drugs in their lifetime.[2] The following discussion will address the potential impact of substance use on HCV disease and HCV treatment.

Potential Impact of Substance Use on Adherence

Earlier studies that examined adherence with interferon-based therapy in persons who inject drugs (PWID) found a modest decrease in adherence among persons with active injection drug use compared to others without active substance use.[3] In one review that included adherence data from 6 studies, the overall rate of nonadherence with interferon-based therapy was 6.8% among PWID with HCV treatment, compared with 4.9% of patients without drug use.[3] Multiple studies that have enrolled persons with active or recent injection drug use have shown excellent adherence with DAA therapy (Figure 1).[4,5,6] Persons with opioid use disorder who receive opioid agonist maintenance therapy (e.g. methadone, buprenorphine, or buprenorphine-naloxone) during HCV treatment have excellent rates of adherence, treatment completion, and sustained virologic response (SVR) rates, all comparable to results of other study participants.[7,8] In a large study that examined the impact of alcohol use on treatment outcomes with interferon-based therapy, recent alcohol use was associated with a slightly higher treatment discontinuation rate and a slightly lower SVR rate; past alcohol use did not impact these outcomes.[9] A separate study investigated different levels of alcohol intake and the impact on interferon-based therapies and found that low-moderate alcohol consumption did not impact SVR rates, but alcohol intake of 24 grams daily or higher reduced SVR rates. There are insufficient data related to the impact of past or recent alcohol use on outcomes with DAA therapy. One study examined the impact of past or active methamphetamine use in persons with chronic HCV treated with interferon-based regimens and methamphetamine use did not appear to significantly impact treatment completion or SVR rates. There are no published studies on the impact of methamphetamine use on DAA therapy.[10]

Duration of Abstinence to Maximize Treatment Outcome

Although some payers require 6 months or more of abstinence prior to HCV treatment, studies of both injection drug use and alcohol use have found no impact of duration of abstinence on likelihood of SVR.[3] There is no medical reason to ensure any duration of abstinence prior to HCV treatment. Current AASLD-IDSA Hepatitis C guidance recommendations do not consider substance use a contraindication to HCV treatment.[1] Institutional and provider-level stigma related to drug use can be a barrier for a client to initiate HCV treatment and this should be addressed with careful attention through the patient-provider relationship.

Impact of Treating People with Active Drug Use on HCV Transmission

Mathematical modeling, even assuming a reinfection rate equal to initial infection rates, has demonstrated that HCV treatment among persons with active injection drug use would result in a significant reduction in HCV transmission.[11,12,13,14] Several recent studies utilizing mathematical modeling based on DAA regimens concluded that scaling up HCV treatment in PWIDs would have a major impact in reducing HCV incidence and prevalence in this patient population, even more so in the setting of robust access to sterile injection equipment and opioid agonist maintenance services.[13] Further, scaling up and widespread treatment of HCV in PWID as a prevention tool, akin to treating HIV to reduce community viral load, has become a more realistic goal with the short-course, well-tolerated, interferon-free regimens.

Impact of Comorbidities in Persons with Substance Use Disorder

In clinical practice, treating persons with an active substance use disorder may be complicated by coexisting social problems and barriers erected by payers, but clinical experience suggests that, with appropriate infrastructure and patient support including the treatment of substance use disorders, HCV treatment is feasible in this population.[15,16,17,18,19] Examples of patient support include directly-observed therapy and related approaches, patient navigation, and group treatment models, particularly in substance use disorder treatment settings.

HCV Treatment Outcomes with Interferon-Based Therapy in PWID

Treatment success rates with peginterferon and ribavirin have historically been comparable among current and former PWID, with the exception that frequent drug use during treatment was associated with lower SVR rates than drug abstinence or occasional drug use during treatment (Figure 2).[17,20,21] In a meta-analysis, investigators evaluated HCV treatment outcomes in studies that included approximately 50% of participants with active injection drug use during the HCV treatment; all studies in this meta-analysis were conducted prior to DAA-based therapy.[22] Overall, they concluded that persons with active injection drug use had SVR rates similar to reported rates among among persons who did not inject drugs (when receiving HCV treatment outside of a clinical trials setting).[22] In a recent retrospective analysis from the University of California at San Diego,[23] the HCV treatment SVR rates were evaluated across three different HCV treatment eras in persons coinfected with HIV who were seen in a clinic where active barriers to care, including drug or alcohol use were common.[23] The SVR rates markedly increased in the DAA treatment era in this patient population (Figure 3).[23]

HCV Treatment Outcomes with DAA Therapy in PWID

Despite the extensive data that have been generated with DAA-based therapies, relatively little data exists with the use of DAAs in patients with active injection drug use. The following summarizes several key studies that have analyzed HCV treatment responses with DAA-based therapy in persons who inject drugs or who have previously injected drugs and were receiving opioid agonist therapy. Multiple studies clearly show that use of DAA-based therapy in persons with past or current injection drug use results in high SVR rates, comparable to those seen in persons who do not use drugs.[6]

• Elbasvir-Grazoprevir (C-EDGE CO-STAR): In this phase 3, multinational study (C-EDGE CO-STAR), investigators evaluated HCV treatment with elbasvir-grazoprevir in 301 PWID who had also been receiving opioid agonist therapy (e.g. methadone, buprenorphine, or buprenorphine-naloxone maintenance) for at least 3 months prior to enrollment.[4] Participants with chronic HCV genotype 1, 4, or 6 were randomized to immediately receive a 12-week course of elbasvir-grazoprevir (immediate treatment group) or to receive the 12-week course of elbasvir-grazoprevir after a 16-week delay (deferred treatment group). On day 1 of the study, 58% of the subjects had a positive urine drug screen (excluding opiate agonist therapy). Overall, when excluding participants who discontinued for non-treatment reasons, 91.5% in the immediate treatment group and 89.5% in the deferred treatment group achieved an SVR12; the treatment responses were excellent regardless of cirrhosis status and baseline drug screening results (Figure 4).[4]
• Ledipasvir-Sofosbuvir (ION Trials): In the ION trials, participants with chronic HCV genotype 1 infection received 8, 12, or 24 weeks of ledipasvir-sofosbuvir.[24] Investigators performed a pooled data analysis to compare HCV treatment response in participants receiving opioid substitution therapy during treatment (n = 70) with participants not receiving opioid substitution therapy (n = 1882).[24] The two groups had similar treatment completion, adherence, and SVR12 rates (Figure 5).[24] Among those receiving opioid substitution therapy, 66 (94%) of 71 achieved an SVR12.[24]
• Sofosbuvir-Based Treatment in Phase 3 Trials: In a pooled analysis of data from phase 3 trials using sofosbuvir-based regimens, investigators compared HCV treatment responses in participants receiving opioid substitution therapy during treatment (n = 194) with participants not receiving opioid substitution therapy (n = 4549).[8] There were no significant differences in SVR12 rates (94% in those receiving opioid substitution therapy versus 97% for those not receiving opioid substitution therapy).[8]
• Sofosbuvir-Velpatasvir (SIMPLIFY): In this single-arm, open label, phase 4 study, 103 participants with chronic HCV infection genotype 1-6 and recent (within 6 months) injection drug use were treated with a 12-week course of sofosbuvir-velpatasvir.[5] During the treatment course, 61 (59%) of the participants were receiving opioid substitution therapy and 76 (74%) had used injection drugs in the month prior to starting treatment.[5] A total of 100 (97%) of the 103 participants completed treatment; 2 were lost to follow-up and one person died from an accidental overdose. Overall, 97 (94%) of participants achieved an SVR12.[5]
• Sofosbuvir-Velpatasvir (ASTRAL Trials): In a subset analysis of the phase 3 ASTRAL trials, investigators compared treatment response to sofosbuvir-velpatasvir in persons receiving opioid substitution therapy during treatment (n = 51) compared with those where were not receiving opioid substitution therapy (n = 984).[7] Receipt of opioid substitution therapy did not impact treatment responses— 96% of participants receiving opioid substitution therapy achieved an SVR12.[7]

Impact on Natural History of HCV

Opioid use by injection is a major driver of HCV transmission, but opioid use itself, either orally or by injection, does not appear to speed progression of liver disease in persons with chronic HCV.[25] Opioid analgesic use disorder is also a risk factor for HCV acquisition and transmission, particularly as some users transition from oral ingestion of prescribed opioids to illicit opioids, and potentially to higher risk modes of administration, such as injection.[26,27]

Pretreatment Requirements

The AASLD-IDSA Hepatitis C guidance does not have a requirement for abstinence from opioids prior to HCV treatment.[1] Indeed, active injection drug use in an individual with chronic HCV is considered by many to be a direct indication for HCV treatment, due to the potential benefit of reducing secondary HCV transmission.[28,29] In contrast to these expert recommendations, some payers may require abstinence from non-prescribed opioids. There are three FDA-approved treatments for opioid use disorder – buprenorphine, methadone, and extended-release naltrexone. While methadone access is limited to designated Outpatient Treatment Programs, the other medications can be prescribed in the context of routine medical care.

Management Strategies

For persons with a past or current history of opioid use disorder, treatment of HCV infection would ideally be performed in a multidisciplinary setting whereby HCV treatment and opioid use disorder can be addressed, as well as other comorbidities that may exist.[1] Multiple treatment options exist for opioid use. Agonist maintenance therapy is the most effective known treatment and has been shown to reduce the risk of new HCV infection.[30] Data from interferon-based regimens demonstrate that patients receiving methadone, buprenorphine, or buprenorphine-naloxone for opioid agonist therapy respond to HCV treatment similar to populations not using drugs.[31,32,33] Injectable extended-release naltrexone is also approved for opioid dependence, although access can be challenging and uptake can be limited. There are no known clinically significant interactions between opioid agonist therapies or naltrexone and currently approved DAA medications.[34,35] A detailed discussion of opioid agonist therapy is beyond the scope of this topic review.

Potential Reinfection with HCV among Persons who Inject Drugs

Multiple other studies have shown significant risk of HCV reinfection in persons cured with HCV therapy. Thus, it is essential that persons with past or active injection drug use be counseled that they can become reinfected with HCV after achieving an SVR; this risk is significant in persons who inject drugs and it also can occur through sexual contact, particularly among men who have sex with men. In one study that clearly evaluated reinfection among treated PWIDs, the reinfection rate for those reporting ongoing injection after SVR was 5.3 per 100 person-years, suggesting a small ongoing risk comparable to that reported in one meta-analysis of late relapse or reinfection.[36] It is important that programs for HCV treatment provide access to counseling for safe injection practices and opioid agonist therapy. Although unstudied, detailed guidance on safer injection techniques may mitigate this risk (i.e. ensuring a source of sterile syringes and other injection equipment, as well as reviewing possible sources of HCV transmission such as cottons, cookers, water, alcohol pads, or any syringes used to divide, prepare, or inject drugs).[37]

Impact on HCV

Injection of cocaine or methamphetamine is another major driver of HCV transmission.[38,39,40] Other routes of administration of stimulants, such as intranasal, may also be associated with HCV transmission.[41] In addition, prolonged stimulant use may result in cardiac and cerebrovascular toxicity.

Pretreatment Requirements

There is no requirement for abstinence from stimulant use prior to HCV treatment. However, some payers may require abstinence from methamphetamine prior to starting treatment.

Management Strategies

Stimulant use is often more intermittent than opioid or alcohol use but can also be associated with periods of poor adherence to medical care. Pharmacologic options are limited, with multiple current trials underway for both methamphetamine and cocaine dependence.[42] In a double-blind, placebo-controlled, randomized trial conducted from 2012 to 2015, a 12-week course of extended-release naltrexone did not appear to reduce amphetamine use among dependent persons.[43] In a similar randomized, controlled trial, a 12-week course of aripiprazole, when given over a 12-week period, did not significantly reduce methamphetamine use.[44] Mirtazapine and possibly bupropion or modafinil have demonstrated some efficacy for reducing methamphetamine use among dependent persons, but there is no current standard of therapy for methamphetamine dependence at this time.[45,46,47]

Impact on Liver Fibrosis in Patients with Chronic HCV

Several studies have shown that heavy alcohol consumption (at least 60 grams/day in men and 40 grams/day in women) accelerates the progression of HCV-related hepatic fibrosis (Figure 6).[48,49] A typical alcohol drink (12 ounces of beer, 5 ounces of wine, and 1.5 ounces of whiskey) contains 12 grams of alcohol. An estimated one-third of patients with chronic HCV infection have cirrhosis attributable to heavy alcohol consumption.[50] In a study in Alaska, investigators compared outcomes in persons who recovered from HCV with those who had chronic HCV and found heavy alcohol use (at least 50 grams of alcohol daily) was associated with the highest incidence of end-stage liver disease, regardless of whether the individual had recovered from HCV or had chronic HCV infection.[51] In addition, separate studies have shown that progression of liver disease may continue among heavy alcohol users even if SVR is achieved with treatment of HCV. Taken together, the available data suggest reducing alcohol use is critical to liver health. The effects of low or moderate alcohol consumption on liver health are not well characterized for persons with chronic HCV infection.

Pretreatment Requirements

Although abstinence from alcohol is strongly encouraged for patients with chronic HCV infection, a requirement for abstinence from alcohol prior to HCV DAA treatment is no longer recommended.[1] Some payers may still require abstinence.

HCV Treatment Outcomes Among Persons With Alcohol Use

The literature is mixed on whether alcohol use impacts treatment outcomes. Among a privately insured cohort, pretreatment alcohol consumption patterns were unrelated to SVR attainment or HCV relapse after interferon-based treatment.[52] A Swiss retrospective study also found no difference in SVR among 554 patients stratified by alcohol use.[53] In contrast, some studies suggest that active or heavy alcohol use during treatment with peginterferon plus ribavirin diminishes treatment responses.[9,19,54] In one French prospective study, investigators enrolled 73 patients with chronic hepatitis C who were treated with peginterferon and ribavirin and had varying degrees of alcohol consumption: abstinence, low-risk consumption, and excessive consumption.[19] Abstinence referred to patients off alcohol during the entire treatment period. Low-risk consumption was defined as weekly consumption of no more than 21 standard drinks (10 g of pure ethanol) for men and no more than 14 drinks for women, and no more than 4 by drinking occasion. Excessive consumption was defined as drinking more than the limits defined for low-risk consumption on at least two occasions during the treatment period. Overall, patients with excessive alcohol use had lower SVR rates than those who were abstinent or had low-risk ingestion (Figure 7).[19] There are insufficient data to determine how alcohol consumption impacts DAA outcomes.

Management Strategies

Although abstinence from alcohol prior to HCV DAA treatment is no longer required, efforts should be made to ensure that ongoing alcohol use does not interfere with adherence or medical follow-up. Alcohol consumption is discouraged in patients with chronic HCV infection due to the hepatotoxic effects of alcohol. Multiple pharmacologic agents are available for alcohol use disorder, including naltrexone, acamprosate, and topiramate.[55] Among these, the most promising results have been seen with naltrexone given as a monthly injection. Brief counseling on alcohol has also shown reductions in use among patients with HCV infection. A multidisciplinary approach, involving personalized addiction care and case management, may provide further benefit in managing alcohol dependence.[19] One study reported reduced alcohol use following treatment with peginterferon-based regimens for HCV infection.[56] It is unclear whether reduced alcohol intake would occur after treatment with DAA-based therapy.

There is mixed evidence regarding cannabis use and HCV-related hepatic fibrosis progression.[57,58,59] Two separate longitudinal cohort studies found no association between cannabis use and progression of liver fibrosis among patients coinfected with HCV and HIV.[57,60] In addition, one study found a positive association between cannabis use and good adherence with HCV treatment.[61] Although individuals living with HCV are generally advised to abstain from regular cannabis use, ongoing cannabis use is not considered a contraindication for initiating HCV therapy.

• Active substance use or use disorder is not a contraindication to HCV treatment.

• Treatment of HCV in persons with active injection drug use may have public health benefits in terms of reduced secondary HCV transmission.

• It is important to talk to patients about their substance use not insofar as to determine treatment eligibility but to understand how best to support them through treatment and prevent reinfection.
• Treatment of persons actively injecting drugs may have public health benefits in terms of reduced secondary transmission.
• Patients should be aware that heavy use of alcohol may reduce the benefits of HCV treatment.
• Therapeutic approaches to substance use disorders are generally more effective when including a pharmacologic agent.
• Care should be taken to ensure that PWIDs are aware of specific drug use techniques to avoid reinfection, particularly in the ways the drug are divided or prepared for injection.

The burden of hepatitis C virus (HCV) infection is much higher in corrections compared to the general community.  In the late 1990’s, the Centers for Disease Control and Prevention (CDC) estimated that 16 to 41% of prison inmates had serologic evidence for HCV infection (HCV antibody positive), with extrapolated estimated rates of chronic hepatitis C infection ranging from 12 to 35%.[1] Subsequent estimates based on 12 state prisons in the United States showed an HCV seroprevalence that ranged from 9.6% to 41.1% in 2001 to 2012 (Figure 1).[2] In a review of pooled published studies during 2003-2010, the HCV seroprevalence among incarcerated persons in the United States was 23.3%.[3] In a comprehensive review, investigators estimated an HCV seroprevalence in prisons of 18% in 2015.[4] Regardless of which seroprevalence data is examined, the HCV seroprevalence rate in prisons is clearly markedly higher than in the overall United States population, which has a seroprevalence of approximately 1%. [5] Seroprevalence data only account for the numbers of individuals incarcerated on any given day and do not account for the movement in and out of correctional facilities. Approximately 30% of individuals with hepatitis C infection in the United States pass through the correctional system in a given year.[6,7]

HCV Screening Policies

In the United States, different HCV screening policies are used in correctional facilities. The following summarizes the various types of HCV screening policies: 

• Upon Request: HCV testing upon request is offered only to those individuals who ask for testing to be performed.
• Risk-Based: Using the risk-based approach, HCV screening is offered only to those individuals who self-identify as belonging to a group considered at risk for acquiring HCV infection.
• Opt-In:With an opt-in approach, all individuals are offered HCV testing, but testing is performed only if the person agrees.
• Opt-Out: With the opt-out approach, individuals are offered HCV testing and the testing is routinely performed unless the person declines.
• Mandatory Testing: For mandatory testing, the test is performed regardless of whether the individual being tested approves of the test.

Rationale for HCV Testing in Corrections

Multiple reasons exist why HCV testing should be emphasized and offered as an opt-out strategy for jails and prisons in the United States. First, the yield of testing is high since the proportion of persons in jails and prisons who have chronic HCV infection is approximately 5-10-fold higher than in the general United States population.[2,3,5,8] Second, performing routine opt-out testing reduces the stigma associated with risk-based screening.[9] Third, using a strategy of only testing persons in corrections who were born between 1945 to 1965 misses approximately 50% of persons with HCV in jails and prisons.[10,11,12,13] Fourth, testing in correctional facilities can lead to earlier identification and treatment of persons with HCV, which results in behavior change related to HCV transmission and liver-associated benefits. Last, testing and treating the large population of persons with HCV in correctional facilities is essential in an overall population strategy to eliminate HCV infection in the United States.[6,14,15]

Recommendations for HCV Testing in Corrections

The United States Preventive Services Task Force (USPSTF) recommends screening for HCV in all persons at risk for infection and all adults born between 1945 and 1965; in these recommendations, incarceration is categorized as a risk factor for HCV acquisition.[16] The 2018 Federal Bureau of Prisons Guidance on the Evaluation and Management of Chronic HCV Infection recommends using an opt-out strategy of voluntary testing for HCV infection at the prevention baseline visit for all people who are sentenced.[17] The American Association for the Study of Liver Diseases and Infectious Diseases Society of America (AASLD-IDSA) HCV Guidance recommends implementing HCV opt-out testing in jails and in prisons.[18] In addition, multiple experts have also recommended universal opt-out testing in jails and prisons.[6,9,19] 

Understanding the Difference Between Jails and Prisons

A person is jailed upon arrest for allegedly committing a crime. Jails are confinement facilities typically operated and funded by local cities or counties under the authority of a police chief, sheriff, or city or county administrator. Most individuals placed in jail are awaiting a trial or have received a conviction and are serving a brief sentence.[7] Thus, jails house innocent people as well as people who have committed misdemeanors and felonies. Once sentenced, the length of the sentence is the predominant factor that determines if a person transfers to prison. Most states hold individuals in jail for sentences up to 1 year.[20] Since prisons generally house persons who have received a sentence of at least one year, most people in prison are convicted felons. Prisons are part of either a state or federal system housing people depending on the type of crime committed. A few states have created a unified system that integrates the state correctional system and local jail network.

Management of Hepatitis C in Jails

Some jails screen incoming newly arrested persons for HCV infection and then ideally attempt to link individuals with diagnosed HCV infection to care upon release. Although jails can be a place to identify a large number of individuals with HCV infection, there has been a reluctance to systematically perform HCV testing if treatment for HCV cannot be offered in the jail system. Since the average length of incarceration in a jail is usually only days to weeks, most jail systems currently do not offer treatment for HCV. As treatment options for HCV expand and include shorter courses with newer combinations of direct-acting antiviral (DAA) medications, it will likely become more feasible to treat some individuals in the jail system, especially if they have advanced liver disease and/or they have an expected jail stay of at least 3 to 4 months. Given the high cost of DAA therapies and the limited budget of most jails, either major funding changes or significant price reductions for HCV DAA-based therapies would need to occur before HCV treatment can be made widely available in the jail setting.

Management of Hepatitis C in Prisons

In contrast with the situation in jails, the average prison sentence is usually a couple of years, and treatment for HCV can easily be completed during incarceration for many individuals. In addition, prison systems are larger in size than most jails and usually have larger budgets to provide health services. Most prisons offer HCV treatment, but historically only a small fraction of patients with chronic HCV infection have received the treatment. In a study performed at the Connecticut Department of Corrections during 2002 to 2006 (in the interferon era), investigators characterized major reasons for deferral of therapy, and inability to complete therapy before a person is released was the most common reason for deferral; other major reasons included lack of indication for treatment, patient refusal, and unstable clinical conditions (Figure 2).[21] With the advent of DAAs, many  of the clinical barriers to treatment have been eliminated, but some significant barriers to care remain, including cost of therapy, limited clinician capacity, and lack of perceived expertise among clinicians. These barriers are magnified by the size of the population living with HCV infection in the prison setting.

Impact of Cost of Therapy

Given the high prevalence of HCV in corrections, even with the decreasing cost of DAAs, cumulative cost of HCV treatment can be astronomical for correctional systems. The expense of HCV therapy continues to force many facilities to prioritize treatment for those individuals in whom it is most medically necessary. The prioritization of treatment for the patients with advanced liver disease has been ongoing for years in the correctional systems, but the issue was amplified with the availability of expensive DAA medications as more patients desired and had fewer contraindications for treatment.[7,22,23,24] Despite the high cost of therapy, correctional systems have a constitutional obligation to provide adequate healthcare based on a United States Supreme Court decision [Estelle v Gamble].[25,26] It has been difficult to precisely define what this means in regards to HCV infection. Regardless of the order in which persons in correctional facilities are treated, there are several class action lawsuits currently challenging the blanket restriction of treatment of persons with little to no fibrosis in whom treatment is deemed not medically necessary.

Prioritization Based on Medical Necessity

Different correctional systems vary in how they decide who and when to treat for hepatitis C infection. Similar to the decision-making process for persons living with HCV in the community, medical necessity typically dictates whom to treat first in the correctional setting, with medical necessity usually determined by the degree of liver fibrosis or by the presence of significant HCV-related extrahepatic manifestations. Methods used to estimate the degree of liver fibrosis, whether by aspartate aminotransferase (AST) to platelet ratio index (APRI) score, FibroSure, transient elastography (FibroScan), liver biopsy, or a combination of these tests, are highly variable as are the cutoffs used for determining treatment eligibility. Many state prison systems have used the Federal Bureau of Prison Clinical Guidance on the Evaluation and Management of Chronic Hepatitis C Virus Infection or a similar protocol to guide prioritization for HCV treatment.[17]

Release Date

Correctional systems have historically taken a patient’s release date into account when deciding whether to treat them for HCV while they are incarcerated. The slow progression of disease that occurs with chronic HCV infection has allowed for the deferral of treatment for many patients until they are released to the community. In the states that have expanded Medicaid programs, individuals who are incarcerated will have good access to HCV care and treatment in the community through their medical insurance plan upon release. Although a short delay in initiating HCV treatment (until a patient is released) will likely have no significant clinical consequences, prolonged treatment postponement can eventually lead to worse outcomes, especially if the patient has already developed cirrhosis. With current 8- to 12-week DAA treatment courses, most patients can start and complete an HCV treatment course prior to release from prison and for those who are unable to complete the course, it will become increasingly important to establish linkages to care for treatment completion. Some systems have managed to establish relationships with community providers to allow smooth transitions while on treatment and avoiding any gaps in care. The New York State Hepatitis C Continuity Program is an important model to assist with the transition of patients with HCV upon release to the community: patients who have initiated HCV treatment are transitioned to a community-based provider for completion of treatment and patients who have not yet been started on treatment are given a referral to a community-based provider in order to be evaluated in a timely manner upon release.

Treatment Models

In the correctional setting, a variety of different types of treatment models have been utilized to provide specialty care for HCV treatment.[17] Some systems evaluate the patient for HCV treatment eligibility based on local protocols or guidelines, with those patients considered appropriate treatment candidates then sent to a community HCV specialist for treatment. Other systems contract with a community HCV specialist to provide consultation at the corrections facility and the HCV specialist participates in the entire evaluation and treatment process. Some systems provide their own HCV evaluation and treatment on-site with the assistance of consultation and mentoring, such as that provided by the Project ECHO (Extension of Community Health Outcomes) model.[27] Project ECHO utilizes regular teleconferencing sessions to link medical care providers on-site at a correctional facility with an HCV specialist panel, with the goal that the specialists will help co-manage HCV evaluation and treatment with the on-site medical provider.[27] In some instances, correctional facilities have a medical provider working within the system who has HCV expertise and this individual can supervise evaluation and treatment plans carried out by primary medical providers within the correctional system. In addition, excellent sustained virologic response (SVR12) rates with DAA therapy have been documented in the corrections setting with the assistance of telemedicine.[28]

Treatment Outcomes

The correctional setting can be the ideal environment to provide hepatitis C treatment. Medication adherence levels within corrections can usually exceed those in the community for several reasons. First, incarcerated persons have limited access to drugs and alcohol that could diminish adherence or treatment follow-up. Second, nurses working together with medical practitioners are able to frequently monitor patients during treatment for side effects and support patients throughout the treatment course. Third, the structure of the daily routine in corrections usually leads to improved adherence. Whether medications are dispensed for patient self-administration or by staff-distributed individual doses, it is easier to monitor adherence to the treatment protocol and quickly address issues that arise in a timely manner.

Treatment Regimens

The Federal Bureau of Prisons Clinical Guidance recommends using the AASLD-IDSA Hepatitis C Treatment Guidance for initial treatment options.[17,29] Since multiple options typically exist, factors such as cost often determine the choice of regimen.

Preventing Reinfection

Patients who achieve an SVR with HCV therapy can potentially become reinfected with HCV. The following summarizes some of the key issues related to HCV reinfection on persons succesfully treated for HCV in a correctional setting. 

• Risk of Reinfection: Persons achieving an SVR12 with treatment for HCV while incarcerated remain at risk for reinfection, particularly upon release when there is higher risk for relapse of intravenous drug use.[30,31,32] Some correctional systems deny patients treatment based on their drug use history or risk of future relapse, which is contrary to the goal from a public health perspective as these individuals are the most likely to transmit HCV to others. In general, limited data exist regarding hepatitis C reinfection rates and these data are often biased as surveys and studies frequently only follow those individuals who become reincarcerated, which often serves as a marker for ongoing high-risk behaviors and inherent higher risk for reinfection. Although the risk for HCV reinfection clearly exists, the actual risk of reinfection will vary depending on the prevalence of HCV in the community of release, the injecting behavior after release, the availability of needle exchange programs in the community, and sexual practices.
• Reinfection during Incarceration: The risk of reinfection also exists during incarceration. A cohort of 119 patients in Spain were followed for an average of 1.4 years after successful treatment while they remained in prisons that had needle exchange and/or methadone programs and found an overall reinfection rate of 5.27 cases per 100 person-years.[33] Among 53 patients with chronic HCV who achieved an SVR while in an Australian prison, 5 were reinfected and 5 had late relapse.[34] Comparable data from the United States do not exist, but presumably some risk for reinfection during incarceration exists after successful treatment, especially considering the high prevalence of HCV in correctional facilities. Between 1998 and 2000 at the Rhode Island Adult Correctional Institute, the incidence of HCV among 446 treatment-naïve persons incarcerated for a year or more was 0.4 per 100 person-years.[35] The prevalence of hepatitis C was 23.1% at the time.[35]
• Patient Education Related to Reinfection: The risk for reinfection, even if low, highlights the importance of providing hepatitis education and prevention services during and after incarceration, including adequate chemical dependency treatment and harm reduction strategies. Several correctional facilities have implemented effective peer-led programs. Education and prevention services should ideally be part of any hepatitis C treatment program and should continue long after an SVR has been achieved.  Unfortunately, most correctional systems in the United States have chosen not to adopt effective harm reduction strategies that have been utilized in other countries during incarceration and upon release, such as mechanisms for safe tattooing, needle exchange programs, medication-assisted therapy, and access to condoms. These recommendations would equally apply to cirrhotic patients who are incarcerated as to those in the community, highlighting the advantages of treating patients earlier in the course of disease.

Management of Persons with Cirrhosis

Although the risk of developing complications of end-stage liver disease and hepatocellular carcinoma decrease after successful HCV treatment, these risks are not eliminated. Unfortunately, clearance of the hepatitis C virus does not always reverse the amount of preexisting scarring present in the liver. Accordingly, all patients with hepatitis C-related cirrhosis, even those who have successful treatment for HCV, need ongoing medical care. Specifically, those patients who have cirrhosis at the time of HCV treatment should have routine medical follow-up every 6 months for evaluation of symptoms and to monitor laboratory values. In addition, the AASLD guidelines for the Treatment of Hepatocellular Carcinoma recommends that cirrhotic patients successfully treated for hepatitis C continue regular surveillance (every 6 months) for hepatocellular carcinoma using hepatic ultrasound, with or without alfa-fetoprotein levels.[36] These recommendations would apply equally to cirrhotic patients who are incarcerated as to those in the community, highlighting the advantages of treating patients earlier in the course of disease.

Given the high prevalence of HCV in correctional settings, a public health opportunity exists in corrections to combat HCV infection and its complications. More than 90% of persons who are incarcerated release back out into the community and these individuals often do not engage in medical care following release from incarceration, due to a number of factors.[23] Effectively screening and treating patients with HCV infection during incarceration has individual benefit, but it also has societal advantages.[6] One modeling study demonstrated that (1) incarceration and the elevated transmission risk following prison release can contribute significantly to ongoing HCV transmission and (2) scaling up DAA treatment in these settings can have a major impact on reducing HCV incidence and prevalence in communities.[37] To achieve a goal of HCV eradication in the United States, prison and jail populations will need to be included as a primary target group for treatment.[6,14,15] Therefore, it will become increasingly important for correctional systems to partner with public health systems when determining standards of medical treatment and prevention of HCV.

• The prevalence of hepatitis C is much higher in corrections than in the general community.
• Jails are an ideal setting for identifying individuals with HCV infection, but not generally well-suited for DAA treatment of persons with HCV.
• Incarceration can be an ideal time to treat HCV infection, given the high level of structure and oversight that enhance high treatment completion and SVR rates.
• The high cost of HCV therapy and limited capacity of the workforce has forced most correctional facilities to prioritize treatment based on disease severity, but many facilities are quickly expanding the population receiving treatment based on changing standards and external pressures.
• Because the risk for reinfection exists, education and prevention services should be part of any hepatitis C treatment program and should continue long after a sustained virologic response has been achieved. The services should include effective harm reduction strategies, such as mechanisms for safe tattooing, needle exchange programs, medication-assisted therapy, and access to condoms.
• All patient with hepatitis C-related cirrhosis, even those who have successful treatment for HCV, need ongoing medical care.
• To achieve a goal of hepatitis C eradication in the United States, jail and prison populations will need to be included as a primary target group for treatment and as such it will become increasingly important for correctional systems to partner with public health systems.