Hepatitis C Virus Treatment: Simplifying the Simple and Optimizing the Difficult

Abstract

The availability of safe, efficacious, oral direct-acting antivirals (DAAs) have ushered in a new era of hepatitis C treatment with potential to eliminate hepatitis C as a public health threat. To achieve population-level effectiveness of these oral DAAs, hepatitis C treatment by a wide range of providers in different settings will be essential to increase the number of persons treated. We provide a clinical review of hepatitis C treatment with a focus on practical tools for management of hepatitis C in majority of currently infected individuals who can be easily cured and optimization of treatment for those in whom treatment may not be as simple.

There are an estimated 71 million people infected with the hepatitis C virus (HCV), and approximately 400 000 people die of HCV-related causes globally each year [1, 2]. In the United States (US), HCV infection surpassed human immunodeficiency virus (HIV) as a cause of mortality in 2008, and as of 2011 is associated with more deaths than 60 other reportable infectious diseases combined [3, 4]. Although HCV morbidity and mortality is largely driven by disease progression to liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma, extrahepatic manifestations also occur [5–7]. These extrahepatic manifestations occur in multiple systems including renal (membranoproliferative vasculitis), rheumatologic (polyarthritis), neurologic (peripheral neuropathies), cutaneous (purpura and necrotizing vasculitis), and immune (cryoglobulinemic vasculitis and malignant B-cell lymphoma) [8–11]. Chronic hepatitis C viremia is also associated with insulin resistance and diabetes and an increased risk of cardiovascular and renovascular disease [7, 11]. Both hepatic and extrahepatic morbidity and mortality are preventable through treatment and cure of hepatitis C [9, 12–19]. Aside from individual-level benefits of HCV treatment, population-level benefits include reducing the reservoir of those infected with hepatitis C and thus reducing the number of individuals able to transmit the infection to others [20]. This concept of HCV treatment as prevention has potential for particular benefit in subpopulations of HCV-infected individuals such as people who inject drugs, HIV-infected men who have sex with men (MSM), and incarcerated populations [20, 21]. Spurred by the availability of safe, efficacious (>95% cure rate), oral direct-acting antivirals (DAAs) for HCV [1, 22, 23] the World Health Organization made a call for the elimination of hepatitis C as a public health threat in 2016 and subsequently laid out a road map for the achievement of this goal by the year 2030 [1]. Key milestones to achieving this goal include the diagnosis of 90% of persons with HCV infection and treatment of 80% of those eligible for HCV treatment [23, 24]. To achieve these goals, individuals infected with HCV must become aware of their infection through testing and, once diagnosed, should be treated for HCV. This article aims to highlight the simplicity of HCV treatment in the majority of HCV infected patients, describe populations in which HCV treatment may not be as simple, and provide practical tools to optimize HCV treatment in these scenarios.

EVOLUTION OF HEPATITIS C TREATMENT

Discovered in 1989, HCV is an enveloped 9.6 kb positive-sense single-stranded RNA virus classified in the Hepacivirus genus within the Flaviviridae family [25]. Based on virus genetic differences, HCV is classified into 7 genotypes, of which 1–6 are considered clinically relevant. HCV infects and replicates in human hepatocytes, does not integrate into the human host, and, as such, does not have a latent phase. Advances in the understanding of the HCV life cycle have led to tremendous progress in HCV treatments, leading to curative therapy.

Because HCV does not integrate into the human host, viral clearance of HCV is possible [26]. Sustained virologic response (SVR) is equivalent to HCV cure, which leads to reduced risk of cirrhosis, hepatic decompensation, hepatocellular cancer, liver-related mortality, and all-cause mortality [12, 13, 16, 19]. HCV treatment and cure are also associated with improvement of extrahepatic manifestations and quality of life [9, 27–29]. Hepatitis C cure is classically assessed by evaluating HCV RNA in blood at least 12 weeks after the completion of therapy; the absence of detectable HCV RNA at this time is defined as SVR₁₂. Data demonstrating that the majority of patients who achieve SVR₁₂ will have no evidence of active HCV infection for years following therapy led to the acceptance of SVR₁₂ as a surrogate for HCV cure [26, 30].

In 1991, subcutaneous, recombinant interferon (IFN) alfa was the first agent approved for HCV treatment by the US Food and Drug Administration (FDA). This regimen required thrice-weekly injections for up to 48 weeks and was associated with cure rates <16% [31, 32]. Before the advent of DAAs, the first significant therapeutic advance was the addition of the oral guanosine nucleoside analogue ribavirin (RBV) in 1998, which increased cure rates up to 28% in patients with HCV genotype 1 infection and 66% in genotype 2 and 3 patients [33, 34]. In 2001, the conjugate of recombinant IFN-alfa and polyethylene glycol led to longer-acting (once-weekly) IFN injections, which, in combination with RBV, led to higher rates of SVR of approximately 41% in patients with HCV genotype 1 infection [35, 36]. Unfortunately, IFN therapy was limited by toxicity including influenza-like symptoms (eg, myalgia, arthralgia, and fever), depression, neutropenia, and other side effects affecting nearly all patients and body systems. Additionally, RBV causes hemolytic anemia and is genotoxic and teratogenic. Due to the side-effect profile and contraindications to therapy, the effectiveness of combination therapy was low [37, 38].

In 2011, the first 2 oral DAAs, boceprevir and telaprevir, HCV NS3/4A protease inhibitors, were approved for the treatment of genotype 1 infection in combination with pegylated IFN (peg-IFN)/RBV. In eligible patients, “triple” therapy provided SVR rates up to 75% but also carried the burden of additional side effects including more severe anemia and, for telaprevir, serious rash and gastrointestinal symptoms [39–44].

In 2013, the landscape changed dramatically with the FDA approval of sofosbuvir, a once-daily oral nucleoside analogue with potent antiviral activity against all HCV genotypes (pan-genotypic). Simeprevir, a once-daily NS3/4A protease inhibitor with activity against genotypes 1 and 4, was also approved in 2013. Between 2013 and 2017, additional DAAs targeting HCV nonstructural proteins, including NS3/4A and NS5A, were approved as part of DAA combination regimens, ushering in the era of safe, well-tolerated, efficacious HCV treatment. Two of these DAA regimens, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir, are pan-genotypic, leading to SVR in >95% of treated patients [45–55]. This broad, potent antiviral activity, coupled with minimal side effects and short duration of therapy (8–12 weeks), led to a marked reduction in treatment complexity, particularly compared to first-generation DAA “triple” therapy.

HCV TREATMENT: KEEPING IT SIMPLE

The US has an estimated 2.4–2.7 million individuals chronically infected with HCV [56]. The large number of patients infected with HCV in need of HCV treatment and cure makes the traditional practice of HCV treatment in referral centers by gastroenterology/hepatology and infectious disease specialists impractical in the US and many other global regions. Fortunately, the simplicity of current oral DAA regimens provides an opportunity for a wide range of practitioners to treat hepatitis C in diverse clinical settings, including primary care, prisons, addiction treatment centers, public health clinics, and mobile vans. Indeed, multiple studies have shown the effectiveness of HCV treatment models by nonspecialist providers in different settings [57–65].

Unlike the IFN era, when clinicians weighed the pros and cons of HCV treatment in every patient, the decision on whom to treat for HCV in the oral DAA era is straightforward. As stated by the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) HCV guidance panel, all patients with HCV should be treated for HCV, the only exception being patients with a short life expectancy (<12 months), which cannot be remedied by HCV treatment or liver transplantation [66, 67]. In practical terms, any patient with evidence of active HCV infection, defined as a detectable HCV RNA in the blood, is a candidate for consideration of curative HCV treatment.

Simplified Treatment Algorithms

The most recent update of the AALSD/IDSA HCV management guidance provides a 1-page tool for the use of the simplified HCV treatment algorithm [67].

Pretreatment Evaluation

Important points to note for this algorithm include pretreatment laboratory assessments with HCV RNA to confirm active HCV replication and complete blood count and hepatic/renal function panels. Liver disease stage should also be assessed to determine the presence or absence of cirrhosis. Identification of cirrhosis is essential to select the appropriate curative therapy and to optimize posttreatment clinical outcomes for patients with cirrhosis who are at risk for hepatocellular carcinoma (HCC) despite viral cure. Before treatment, patients with cirrhosis require screening and ongoing surveillance for hepatic decompensation events (eg, ascites, hepatic encephalopathy) and HCC. In the modern DAA era, assessment of liver fibrosis is noninvasive, including measurement of blood tests and liver stiffness; unless there is a need to evaluate the liver for non-HCV conditions, a biopsy is not indicated. Noninvasive blood markers of liver fibrosis include the Fibrosis-4 Score for Liver Fibrosis (FIB-4) and aspartate aminotransferase (AST)–to-platelet ratio index, which are calculated from readily available laboratory tests (alanine aminotransferase, AST, and platelet count) and patient characteristics (eg, age for FIB-4) and have been shown to be accurate in identifying advanced hepatic fibrosis/cirrhosis compared to liver biopsy (Figure 1) [68, 69]. Other blood tests such as the FibroSure®/FibroTest, available through commercial laboratories, have proprietary cutoffs to indicate liver disease stage, including cirrhosis. Office-based measurement of liver stiffness with transient elastography (eg, FibroScan®) allows for the on-demand assessment of cirrhosis status with a fasting (~3 hours) liver stiffness score of 12.5 kPa or higher consistent with cirrhosis [70].

Figure 1.

Noninvasive liver fibrosis assessment with Fibrosis-4 Score for Liver Fibrosis or aspartate aminotransferase (AST)–to-platelet ratio index. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FIB-4, Fibrosis-4 Score for Liver Fibrosis.

Due to shared modes of transmission, patients should be tested for HIV and hepatitis B virus (HBV) infection. Patients coinfected with hepatitis B and C are at risk for HBV reactivation with or without HBV flare during or after curative HCV therapy. As such, patients should be tested for HBV with anti–hepatitis B surface (HBs), anti–hepatitis B core (HBc), and hepatitis B surface antigen (HBsAg) as part of HCV treatment evaluation. Patients who are HBsAg positive require further evaluation for hepatitis B prior to HCV treatment initiation and/or monitoring for HBV reactivation during treatment. Patients who are anti-HBs negative (nonimmune) should undergo vaccination, as should patients who are hepatitis A nonimmune.

For women of childbearing potential, pregnancy testing is recommended before HCV treatment, as well as education regarding the risk of pregnancy. Alcohol and substance use disorder (SUD) screening with appropriate counseling and brief intervention is also indicated. Patients with active SUD, including injection drug use, are candidates for curative treatment and should not be denied treatment due to ongoing substance use. Rather, knowledge of ongoing substance use should guide linkage to appropriate harm reduction services such as SUD treatment including opioid agonist treatment, syringe service programs, and naloxone prescription for overdose prevention in opioid users.

Given that oral DAAs have drug interactions with drugs from multiple other drug classes, medication reconciliation of all medications the patient is currently taking should be done and evaluation for drug interactions conducted. Many centers have had success in working with clinical pharmacists for managing drug interactions. Alternatively, online tools such as the University of Liverpool hepatitis drug interaction checker (https://www.hep-druginteractions.org/checker) are excellent resources to investigate and manage potential drug interactions.

On-Treatment Support and Posttreatment Follow-up

The level of support required to help patients adhere to treatment and achieve SVR is variable and should be assessed before therapy. Strategies to enhance adherence may include provider visits during treatment, laboratory monitoring with feedback, and telephone check-ins by members of the care team, including nurses, pharmacists, and peer advocates. However, it is essential to recognize that for some patients, the best strategy may be to provide HCV medications, the means to engage the team if needed, and a laboratory test 12 weeks after completion of HCV treatment (minimal monitoring). For all patients, HCV RNA should be measured in the blood at or after posttreatment week 12 to assess for cure. While most patients who complete therapy will achieve HCV cure, patients who have an active infection posttreatment should be evaluated for retreatment.

Patients without advanced liver fibrosis (Metavir stage F2 or lower) who achieve cure do not require liver disease-specific follow-up. For those at risk of HCV reinfection either due to ongoing SUD or high-risk sexual practices, HCV reinfection surveillance should be done with HCV RNA testing at least annually [67].

Other Considerations in Patients With Cirrhosis

Assessment of Clinical Status

Patients with cirrhosis should be assessed for signs and symptoms of hepatic decompensation with calculation of the Child-Turcotte-Pugh score, which includes levels of albumin, international normalized ratio, and total bilirubin and the clinical assessment of ascites and hepatic encephalopathy. Patients with a Child-Turcotte-Pugh score ≥7 or a history of clinical hepatic decompensation including ascites, hepatic encephalopathy, and variceal bleeding should be classified as having decompensated cirrhosis for the purpose of HCV treatment and should ideally be managed at medical centers with access to liver transplant to facilitate access to appropriate care in the case of clinical worsening during or after HCV treatment. The HCV NS3/4A protease inhibitors grazoprevir, glecaprevir, and voxilaprevir are contraindicated in this patient population due to the risk of drug-induced liver injury.

Screening for Esophageal Varices

Portal hypertension and varices with an attendant risk of variceal bleeding may develop as a complication of liver cirrhosis. As such, patients with cirrhosis should undergo esophagogastroduodenoscopy (EGD) and appropriate management of varices if identified. Based on Baveno VI criteria, patients with a liver stiffness score of <20 kPa and a platelet count of >150 000/μL can avoid an EGD due to a low risk of varices requiring treatment [71, 72]. Platelet count and transient elastography should be performed yearly to assess if an EGD is indicated. The frequency of EGD testing after the initial EGD is dependent on findings from the initial EGD, absence or presence of ongoing liver injury (eg, alcohol use), and co-factors (eg, obesity) [71, 72].

Counseling

Alcohol use abstinence should be recommended for all patients with liver cirrhosis.

Surveillance for Hepatocellular Carcinoma

The AASLD/IDSA HCV guidelines panel recommends ongoing semiannual surveillance with liver ultrasound with or without α-fetoprotein [67, 73]. Many experts also recommend HCC screening for patients with advanced fibrosis (Metavir stage F3). Oral DAA treatment reduces but does not eliminate the risk of HCC [74]. Compared to the IFN era, oral DAA treatment has dramatically increased the number of patients being treated for HCV and of older patients in particular [75, 76]. The annual incidence of HCC after DAA treatment in a retrospective analysis from the Veterans Health Administration was 0.90 (95% confidence interval [CI], 0.77–1.03/100 person-years) in those that achieved cure compared to 3.45 (95% CI, 2.73–4.18/100 person-years) among those that did not achieve cure [74].

CURRENT HCV TREATMENT REGIMENS AND APPROACHES TO CHOICE OF REGIMEN

As depicted in Table 1, multiple HCV treatment regimens demonstrating high efficacy across HCV genotypes and in different population groups are available [22, 77]. There is also guidance easily accessible through the relevant society guidelines, including the AASLD/IDSA [67]. The latest generation of DAAs, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir, are active against all of the most common HCV genotypes (pan-genotypic). Glecaprevir/pibrentasvir is dosed as 3 tablets taken once daily for 8 weeks in all treatment-naive patients, including those with cirrhosis. Similarly, sofosbuvir/velpatasvir is 1 tablet taken once daily for 12 weeks for all genotypes in patients with and without cirrhosis. Ledipasvir/sofosbuvir and elbasvir/grazoprevir are both dosed at 1 tablet daily but only active against HCV genotypes 1, 4, 5 and 6. Given the range of regimen choice for HCV treatment, characteristics of the patient and their virus often drive the selection of a specific HCV regimen. However, given the similarity of HCV outcomes, treatment options may be restricted for some patients by payors. Critical factors in selecting the regimen include the following:

Table 1.

Recommended Combinations of Oral Direct-Acting Antiviral Agents and Hepatitis C Virus Genotype Coverage

Oral DAA Class			Formulation and Dosing
Protease NS3/4A Inhibitors	NS5A Inhibitors	NS5B Polymerase Inhibitors
Grazoprevir	Elbasvir	…	100 mg GZR, 50 mg EBR 1 tablet daily
Glecaprevir	Pibrentasvir	…	GLE 100 mg, PIB 40 mg 3 tablets daily
…	Ledipasvir	Sofosbuvir	400 mg SOF, 90 mg LDV 1 tablet daily
…	Velpatasvir	Sofosbuvir	400 mg SOF, 100 mg VEL 1 tablet daily
Voxilaprevir	Velpatasvir	Sofosbuvir	400 mg SOF, 100 mg VEL, 100 mg VOX 1 tablet daily

Abbreviations: DAA, direct-acting antiviral; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; LDV, ledipasvir; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.

HCV Treatment History

Patients can be classified as having no prior treatment (treatment naive) or prior, ineffective treatment (treatment experienced). Among treatment-experienced patients, the recommended DAA regimens take into account the type of drugs in the previous HCV treatment regimen, particularly the use of DAAs. The options for HCV treatment are different for treatment-naive and treatment-experienced patients. Of note, patients who previously received peg-IFN plus RBV or IFN with a first-generation DAA have SVR rates similar to those seen in treatment-naive patients when treated with modern oral DAA regimens.

Cirrhosis and Clinical Status

Recommended HCV treatment regimen and duration may vary by the absence or presence of cirrhosis (Tables 2 and 3).

Table 2.

Recommended Hepatitis C Virus Regimen for Treatment-Naive Patients With and Without Compensated Cirrhosis

Table 3.

Recommended Hepatitis C Virus Regimen Choice for Second-Generation Direct-Acting Antiviral Treatment–Experienced Patients

HCV Genotype

Despite the high efficacy of all recommended regimens, HCV genotype 3 infection, especially in patients with cirrhosis, may warrant additional consideration. Furthermore, the use of DAA regimens that are not pan-genotypic require knowledge of HCV genotype for selection of an optimal HCV regimen. Based on these considerations, HCV genotype testing is recommended but not required if using a pan-genotypic regimen.

HIV Infection Status

Recommended DAA regimens for HIV/HCV-coinfected and monoinfected individuals are, for most patients, identical given similar efficacy and adverse event profiles [51, 78–80]. Patients with HIV infection not on antiretroviral therapy should be initiated on antiretroviral therapy to reduce the independent HIV-related risk of progression to end-stage–related liver disease. Special attention should be given to potential drug interactions between HIV antiretrovirals and HCV oral DAA agents being prescribed.

Drug-Drug Interactions

Oral DAAs have drug interactions with drugs from multiple other drug classes. Evaluation for and management of potential drug interactions is a core component of HCV treatment.

HCV TREATMENT IN SPECIFIC POPULATIONS

Persons With No Prior HCV Treatment (Naive) and No Evidence of Cirrhosis

The approach to persons who are HCV treatment naive is relatively simple, with 4 safe, well-tolerated recommended DAA regimens that deliver HCV cure in >95% of patients treated for 8–12 weeks (Table 2) [22, 77]. In clinical trials of modern oral DAAs, <1% of patients discontinued oral DAAs due to an adverse event [45, 52, 81–89]. Adverse events reported were similar among participants who received oral DAA and placebo with the most common side effects being fatigue, headache, nausea, and diarrhea (Table 4). The safety and tolerability of these drug regimens allow for the delivery of HCV treatment by both specialists and generalists, including those in nontraditional medical practices such as addiction treatment centers.

Table 4.

Adverse Reactions Observed in ≥5% of Subjects in Oral Direct-Acting Antiviral Clinical Trials

Drug and AE	Oral DAA (% of Participants With AE)	Placebo (% of Participants With AE)
Glecaprevir/pibrentasvir (8–12 weeks) [45, 89]
Fatigue	10–16	10
Headache	5–17	12
Nausea	6–12	3
Diarrhea	3–7	2
Ledipasvir/sofosbuvir (8–12 weeks) [85]
Fatigue	13–16	…
Headache	11–16	…
Nausea	6–7	…
Diarrhea	3–4	…
Insomnia	3–5	…
Elbasvir/grazoprevir (12 weeks) [81, 86]
Fatigue	5–15	8–17
Headache	7–17	5–18
Nausea	5–11	8
Diarrhea	5	7
Insomnia	1–5	6
Arthralgia	6	6
Sofosbuvir/velpatasvir (12 weeks) [52, 87]
Fatigue	15–22	20
Headache	10–29	28
Nausea	7–12	11
Nasopharyngitis	13	10
Diarrhea	8	7
Asthenia	5–7	8
Insomnia	5–9	9
Sofosbuvir/velpatasvir/voxilaprevir (12 weeks) [82, 88]
Headache	21–23	14–23
Fatigue	17–19	15–23
Diarrhea	13–14	3–9
Nausea	10–13	3–7
Asthenia	4–6	4–6
Insomnia	3–6	1–3

Abbreviations: AE, adverse event; DAA, direct-acting antiviral.

Use of Pan-Genotypic DAA Regimens

Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir are active against genotypes 1–6. This broad antiviral activity, coupled with once-daily dosing, minimal side effects, and excellent safety, supports the use of these regimens in community settings with minimal monitoring.

Use of Genotype-Specific DAA Regimens

The AASLD/IDSA HCV guidance panel recommends the use of ledipasvir/sofosbuvir and elbasvir/grazoprevir in persons with HCV genotypes 1 and 4.

Genotype 1

Ledipasvir/sofosbuvir is active against genotype 1 infection, with SVR rates of >95% with 12 weeks of treatment demonstrated in patients with or without cirrhosis in the ION-1 trial [84]. The ION-3 trial evaluated 8 vs 12 weeks of ledipasvir in patients without cirrhosis and demonstrated SVR rates of 93%–95%, with a higher rate of virologic relapse in patients who received 8 weeks of therapy [90]. The higher rate of relapse in patients who received 8 weeks of ledipasvir/sofosbuvir was found in post hoc analyses to be associated with a baseline HCV RNA >6 million IU/mL, providing initial data to support a recommendation of 8 weeks of ledipasvir/sofosbuvir in HCV genotype 1 patients with an HCV RNA <6 million IU/mL. The efficacy of the 8-week regimen of ledipasvir/sofosbuvir has subsequently been borne out in multiple real-world studies [91–93]. However, this shorter course of ledipasvir/sofosbuvir is not recommended in persons with HIV coinfection due to limited data and lower SVR rates observed with an 8-week course of a similar regimen in the ALLY-2 study [94].

The use of elbasvir/grazoprevir for patients with HCV genotype 1a infection requires testing for NS5A resistance-associated substitutions (RASs) at amino acid positions 28, 30, 31 or 93, which are detected in approximately 15% of treatment-naive patients [95]. In patients with genotype 1a, but not 1b, infection, the presence of these RASs are associated with a significantly lower SVR rate (58%) compared to patients without RASs (99%) [81]. Accordingly, AASLD/IDSA guidelines recommend NS5A resistance testing for persons with HCV genotype 1a infection if treatment with elbasvir/grazoprevir is planned. If the patient has HCV genotype 1a infection without NS5A RASs or HCV genotype 1b infection, elbasvir/grazoprevir is recommended as 1 tablet daily for 12 weeks. For patients with HCV genotype 1a infection with detected NS5A RASs, the FDA approved the use of elbasvir/grazoprevir plus RBV for 16 weeks. However, given the safety concerns associated with RBV, the AASLD/IDSA HCV guidelines panel does not endorse this approach and recommends an alternative DAA regimen.

Genotype 4

Studies demonstrate consistently high SVR rates with 12 weeks of elbasvir/grazoprevir [78, 81, 96] or ledipasvir/sofosbuvir [97, 98]. A recent study from Rwanda demonstrated the potential for lower SVR with HCV subtype 4r compared with other genotype 4 subtypes [99].

Persons With No Prior HCV Treatment (Naive) and With Evidence of Cirrhosis

Except for patients with HCV genotype 3 infection, the presence of compensated cirrhosis does not affect the likelihood of SVR following HCV treatment [45, 50, 52, 53, 55, 81, 84, 97, 98, 100–102]. Among treatment-naive patients with cirrhosis, patients with genotype 3 infection achieve modestly lower SVR rates compared to other HCV genotypes, and they have fewer treatment options compared to genotype 1, which was considered difficult to cure in the IFN era. The ASTRAL 3 study examined the efficacy of sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 3 infections. It demonstrated an SVR rate of 93% in treatment-naive patients with cirrhosis compared to 98% in those without cirrhosis [53]. In a post hoc analysis, patients with evidence of an NS5A RAS at position 93 (Y93H) were less likely to achieve SVR (21 of 25 patients [84%]). Although debate remains among experts, the AASLD/IDSA HCV guidelines panel recommends testing for NS5A RASs in patients with cirrhosis and HCV genotype 3 infection with consideration of adding a third drug, RBV or the HCV protease inhibitor voxilaprevir, if the Y93H RAS is detected [67]. On the other hand, the SVR rate for 63 patients with compensated cirrhosis and HCV genotype 3 infection treated with glecaprevir/pibrentasvir for 8 weeks was 95% [50]. Accordingly, if NS5A RAS testing is not available, glecaprevir/pibrentasvir is recommended for this patient group for an 8-week duration unless the patient is HIV coinfected, in which case a 12-week course of therapy is preferred [67]. Additionally, ledipasvir/sofosbuvir is not recommended for 8 weeks for patients with HCV genotype 1 or 4 infection and cirrhosis.

OTHER SPECIAL POPULATIONS

Patients With HIV/HCV Coinfection

HCV treatment recommendations for patients with HIV infection are similar to those for patients without HIV infection given equivalent efficacy, safety, and tolerability in patients with and without HIV coinfection. There are 3 notable exceptions: (1) The 8-week regimen of ledipasvir/sofosbuvir is not recommended in HIV-infected treatment-naive patients with genotype 1 infection regardless of the HCV RNA level; (2) patients with HIV infection and cirrhosis should be treated with glecaprevir/pibrentasvir for 12 weeks rather than 8 weeks; and (3) patients with HIV and HCV genotype 5 or 6 infection regardless of cirrhosis status should be treated with glecaprevir/pibrentasvir for 12 weeks rather than 8 weeks [67].

Patients With Renal Impairment

Recommended regimens for patients with renal impairment including those with end-stage renal disease are identical to those for patients without renal impairment, with no dosage adjustments for oral DAA agents [67]. Sofosbuvir-based regimens are also recommended in patients with end-stage renal disease [67]. However, due to the heightened risk of severe anemia, RBV should be avoided in patients with renal impairment. If used, the RBV dose should be lowered in patients with an estimated glomerular filtration rate of ≤50 mg/dL.

OPTIMIZING HCV OUTCOMES IN PATIENTS FOR WHOM SIMPLIFIED GUIDELINES DO NOT APPLY

Patients With Previous HCV Treatment Experience

For patients previously treated with peg-IFN/RBV with or without a first-generation protease inhibitor, the recommended approaches to treatment are similar to those described for treatment-naive patients. However, the approach to retreatment in persons who have failed multiple previous DAA regimens is more complicated due to the presence of NS5A RASs in most patients who did not achieve HCV cure following these regimens. Such patients should either be referred to or managed in consultation with an infectious diseases or hepatology specialist.

Role of Resistance Testing

Unlike HIV infection, resistance testing is not routinely recommended in the management of HCV infection, including for patients who did not achieve HCV cure with prior treatment. Resistance testing is recommended in situations in which the presence of RAS will affect the efficacy of the intended oral DAA regimen. The AASLD/IDSA guidelines panel recommends NS5A RAS testing when considering the use of elbasvir/grazoprevir in patients with HCV genotype 1a infection, and when considering the use of sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 3 infection and cirrhosis or in those who did not respond to prior treatment. Of note, NS3/4A and NS5B RAS testing is not routinely recommended but may be considered in patients for whom the optimal HCV treatment regimen for retreatment is not known (eg, treatment nonresponse following sofosbuvir/velpatasvir/voxilaprevir). However, for most patients for whom first-line DAA therapy did not lead to HCV cure, retreatment can lead to HCV cure despite the presence of RASs that confer decreased susceptibility to the second regimen [103].

Patients Who Did Not Achieve HCV Cure With Prior second-generation Oral DAAs

Among patients who do not achieve cure with an NS5A-containing oral DAA regimen including sofosbuvir-based regimens, sofosbuvir/velpatasvir/voxilaprevir for 12 weeks is recommended for retreatment and does not require RAS testing before retreatment (Table 3). This is supported by data from the POLARIS-1 and POLARIS-4 studies among patients who had previously received an NS5A inhibitor–containing DAA regimen. The rate of SVR was 96% in POLARIS-1 and 98% in POLARIS-4 [82]. Among genotype 1–infected patients, SVR rates were similar among those with baseline RAS (98%) and those without RAS (97%). Attention should be given to factors that may have played into nonresponse to the prior NS5A-containing regimen, including drug-drug interactions and nonadherence, and any issues identified should be addressed before retreatment.

Among genotype 1 patients who fail a sofosbuvir-based regimen not inclusive of an NS3/4 protease inhibitor, glecaprevir/pibrentasvir for 16 weeks is an alternative regimen [67, 104–106].

Among patients who fail glecaprevir/pibrentasvir, sofosbuvir/velpatasvir/voxilaprevir is an option for retreatment [107]. Due to historically lower SVR rates in patients with cirrhosis, addition of RBV should be considered in patients with cirrhosis. In a study of patients without cirrhosis who failed treatment with glecaprevir/pibrentasvir, retreatment with sofosbuvir plus glecaprevir/pibrentasvir plus RBV for 16 weeks led to SVR in 22 of 23 patients [108].

The number of patients who do not achieve HCV cure following 2 courses of HCV DAA therapy is quite small. For persons who are adherent to treatment, the likelihood of not achieving HCV cure with first-line therapy is approximately 3%; as such, for every 1000 treatment-naive patients who are treated with DAAs, approximately 30 patients will require retreatment. Of 30 patients who are retreated with sofosbuvir/velpatasvir/voxilaprevir, approximately 97% are expected to achieve HCV cure, leaving only 1 patient with active HCV infection.

The best approach to the management of patients who do not respond to treatment with sofosbuvir/velpatasvir/voxilaprevir is not known. Several strategies may be considered, including testing for HCV drug resistance to help guide the next treatment course. Other considerations include the following:

1. Use of sofosbuvir as the backbone: In studies of thousands of patients treated with this nucleoside analogue inhibitor of NS5B, the emergence of specific RASs that confer decreased susceptibility to sofosbuvir are rare; as such, this drug is useful for the retreatment of patients despite prior exposure [103, 109].

2. Longer duration of therapy: Studies suggest low rates of HCV relapse after treatment durations as long as 24 weeks since this may decrease the likelihood of persistence of HCV in the liver [103].

3. Addition of RBV to the DAA regimen [103]: As a nonspecific antiviral drug, RBV may have a role in overcoming resistant HCV and has been associated with decreased HCV relapse in multiple clinical trials and the prevention of the emergence of HCV drug resistance.

Decompensated Cirrhosis

Given the risk of worsening liver disease during HCV treatment of patients with decompensated liver disease, HCV specialists should treat these patients at centers with access to liver transplantation services. The use of the HCV protease inhibitors glecaprevir, grazoprevir, and voxilaprevir is contraindicated in persons with decompensated liver disease due to an increased risk of liver injury, likely due to higher drug concentrations in the setting of hepatic impairment. Treatment with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir is recommended. Interestingly, this patient population is one of the few for whom RBV is recommended based on randomized controlled trials demonstrating improved outcomes [110–112]. However, the use of RBV is often complicated by anemia and intolerance in this patient group, leading to its discontinuation [110]. If RBV is added to the sofosbuvir plus NS5A regimen, the recommended duration of treatment is 12 weeks whereas if RBV is not used, the treatment duration is prolonged to 24 weeks [66]. The timing of treatment relative to liver transplantation is another important consideration. Given the complexity of decision-making and patient management, specialists with expertise in this population best serve persons with decompensated liver disease.

Patients With Coexisting Hepatitis B Infection

Patients who are coinfected with chronic hepatitis B and C virus are at increased risk for liver disease, and the presence of each virus may suppress the replication of the other pathogen [113, 114]. Some coinfected patients are at risk for HBV reactivation with or without HBV flare during or after curative HCV therapy [115]. The risk of HBV reactivation varies by HBV serological status. In a recent meta-analysis of 17 studies, including 1621 patients (n = 242 with chronic and n = 1379 with resolved HBV infection), the incidence was 24% among patients with chronic untreated HBV (HBsAg positive) and 1.4% among patients with resolved HBV (HBsAg negative and anti-HBc positive) [115]. Among patients with chronic HBV 9% had evidence of hepatitis with reactivation. None of the patients with resolved hepatitis B had hepatitis with HBV reactivation. Overall, there were significant clinical events related to HBV reactivation in 3 patients with chronic HBV, 1 hepatic decompensation, and 2 liver failure events, 1 of whom required liver transplantation. Patients with active HBV infection, defined as positive HBsAg, should have HBV DNA testing and consideration of HBV treatment before starting HCV therapy. If HBV treatment is not initiated before HCV treatment, patients should be monitored with liver function tests or HBV DNA at 4-week intervals until 12 weeks after HCV treatment completion. If the HBV DNA level increases >10-fold or to >1000 IU/mL from a previously undetectable HBV DNA, HBV treatment should be initiated.

HCV Reinfection

HCV reinfection is an expected outcome as HCV treatment is expanded to populations with the highest risk of incident HCV infection, such as people who inject drugs and HIV-infected MSM with high- risk sexual practices. Classically, HCV reinfection is ascertained with phylogenetic analyses comparing the similarity of pretreatment and posttreatment HCV or a switch in pre- and posttreatment HCV genotype. Due to the limited availability of viral sequencing, clinical definitions of reinfection have been proposed. Given the extremely low rate of viral relapse with currently available oral DAA, patients with detectable HCV viremia after completion of an effective oral DAA regimen with proven efficacy of 95% or greater with probable or definitive risk factors for reinfection, or who have a genotype switch in pre- and posttreatment virus, should be considered to be reinfected [30, 116]. Patients with HCV reinfection should be treated with oral DAA regimens recommended for treatment-naive patients. Additional counseling and linkage to harm reductions services should be provided to reduce the risk of subsequent reinfection.

CONCLUSIONS

The rapidity of development, efficacy, and tolerability of current HCV treatments represent a modern miracle of medicine of this era. Despite the availability of these agents, a large number of HCV-infected individuals remain unaware of their infection, and the majority remain untreated. Oral DAA treatment for the majority of infected individuals is straightforward. The more complex multilevel barriers to HCV treatment and cure will need to be addressed to unleash the true population-level effectiveness potential of these potent oral DAA regimens.

Notes

Financial support. M. S. S. received support through a National Institutes of Health (NIH) Mid-Career Mentor Award (award number K24 DA034621). O. F.-N. was supported by an NIH Mentored Patient-Oriented Research Career Development Award (award number K23 DA041294).

Supplement sponsorship. This supplement is sponsored by educational grants from Gilead Sciences Inc. and Abbott Laboratories.

Supplement sponsorship. This supplement is sponsored by educational grants from Gilead Sciences Inc. and Abbott Laboratories.

Potential conflicts of interest. M. S. S. has been the principal investigator for research grants, with funds paid to Johns Hopkins University, from AbbVie, Assembly Bio, Gilead Sciences, and Janssen; and has served as a scientific advisor and consultant for AbbVie, Arbutus, Assembly Bio, and Gilead (the terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflicts of interest policies). O. F.-N. reports no potential conflicts of interest.

Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.