Treatment of chronic hepatitis C virus infection in the patient with HIV

INTRODUCTION — The consequences of hepatitis C virus (HCV) infection in patients with HIV are significant and include accelerated liver disease progression, high rates of end-stage liver disease, and shortened lifespan after hepatic decompensation, in particular among those with more advanced immunodeficiency [1-3]. In the era of potent antiretroviral therapy (ART), end-stage liver disease remains a major cause of death among patients with HIV who have HCV coinfection [4,5].

This topic will address the management of patients with HIV/HCV coinfection.

Discussion of recently acquired HCV infection is found elsewhere. (See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

GOALS OF THERAPY — The objective of HCV antiviral treatment is to cure HCV infection, as reflected by a sustained virologic response, which is associated with substantial reductions in liver-related morbidity and mortality.

Sustained virologic response as cure — Successful antiviral therapy is characterized by achievement of a sustained virologic response (SVR), defined as an undetectable HCV RNA 12 to 24 weeks after the end of treatment (ie, SVR12 or SVR24). Since very few patients have rebound viremia between weeks 12 and 24 (or later), SVR12 is increasingly used as a primary endpoint in clinical trials, and in the United States is the recognized endpoint for outcome assessment of the Food and Drug Administration (FDA) [6]. The SVR12 benchmark represents treatment-induced viral eradication, and thus an effective cure [7,8].

Clinical benefits of cure — As in the population with HCV monoinfection, HCV eradication in patients with coinfection has been associated with the following clinical benefits [9-11] (see "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Benefits of treatment'):

●Improvement and/or delayed progression of fibrosis and necroinflammation

●Reduction of morbidity and mortality secondary to liver disease

●Reduced incidence of hepatocellular carcinoma

As an example, one observational study of 711 patients with HIV who had been treated for HCV infection demonstrated that an SVR was associated with a reduced risk of liver-related death (3.7 percent versus 0.5 percent) and liver decompensation (9.1 percent versus 0.5 percent) [12]. In another cohort study of 495 patients with HIV and HCV coinfection and compensated cirrhosis, SVR with all-oral direct-acting antiviral (DAA) was associated with a lower risk of hepatocellular carcinoma (0.35 versus 1.79 cases per 100 person-years) [13].

Another potential benefit of sustained HCV clearance for patients with coinfection may be a reduced risk of drug-induced liver injury associated with antiretroviral therapy (ART) [14].

Patients who do not achieve an SVR remain at risk for further liver disease progression.

EFFECT OF HIV INFECTION ON RESPONSE TO HCV TREATMENT — Although patients with HIV/HCV coinfection traditionally have lower response rates to HCV treatment with peginterferon and ribavirin compared with individuals without HIV, they appear to have comparable sustained virologic response (SVR) rates with direct-acting antiviral-based regimens. Thus, results from trials of direct-acting antiviral regimens performed in patients with HCV monoinfection can be extrapolated to inform expected efficacy of such regimens among patients with HIV/HCV coinfection. (See 'HCV regimen selection' below.)

Nevertheless, the potential for drug interactions between antiretroviral and HCV direct-acting antiviral agents remains an important management issue unique to patients with HIV/HCV coinfection. (See 'Potential drug interactions with ART' below.)

PATIENT EVALUATION

Evaluation to guide management decisions — All patients are better off cured than with chronic HCV infection. Selection of the optimal regimen is based upon several factors, including the infecting genotype in some cases, the stage of the disease, other medical and social priorities, prior treatment history, and drug interactions. Evaluation prior to treatment should focus on these factors and is discussed in greater detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)

Deciding when to treat — A cure of HCV results in improved survival, reduced morbidity, and higher quality of life in the vast majority of patients (see 'Goals of therapy' above). With the growing availability of highly effective interferon-free regimens for HCV, a curative all-oral treatment is a possibility for the vast-majority of patients, including those with HIV coinfection. The very low incidence of adverse events and high efficacy means that almost every patient can benefit from HCV treatment. However, the cost of these new agents complicates universal delivery of antiviral therapy. Because of the more rapid progression to advanced liver disease in the setting of HIV infection, coinfection is one reason to prioritize a patient for HCV antiviral therapy [15-17]. Another reason is cirrhosis or bridging fibrosis. These issues are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Deciding when to treat'.)

Timing of HCV antiviral therapy in relation to ART initiation in ART-naïve patients is discussed in detail below. (See 'Timing of ART initiation' below.)

Treatment of certain patient populations, such as those with decompensated liver disease, remains associated with increased risk of adverse events and should be undertaken only at centers which have expertise in managing HIV/HCV coinfection.

ANTIRETROVIRAL MANAGEMENT — Antiretroviral management issues in patients with HIV/HCV coinfection for whom HCV treatment is being considered include use of appropriate antiretroviral regimens that do not have serious drug interactions with HCV antiviral agents and the timing of antiretroviral therapy (ART) initiation or switch. Antiretroviral treatment interruption to allow for HCV antiviral therapy is not recommended [18].

ART-naïve patients — ART-naïve patients with HIV/HCV coinfection should be initiated on ART for their HIV disease, regardless of their CD4 cell count [19]. In most instances, it is preferable to start ART first and begin HCV therapy later. (See 'Timing of ART initiation' below.)

Selection of ART regimen — When selecting an ART regimen, potential drug-drug interactions with HCV antiviral medications should be taken into account in addition to the other considerations that inform ART choice. (See 'Potential drug interactions with ART' below and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Timing of ART initiation — We generally initiate ART approximately four to six weeks before starting HCV antiviral therapy. There are two main reasons for this:

●Initiation of ART prior to HCV antiviral therapy allows assessment of tolerability and adverse effects of ART alone.

●Treatment with ART may theoretically translate into better HCV outcomes, either through restoration of immune function or other effects of suppressing HIV viremia [20].

Given the breadth of the antiretroviral armamentarium, there are many good choices that can be safely used with HCV direct-acting antiviral (DAA) regimens and thus HIV therapy can generally be started first.

ART-experienced patients — Patients with HIV/HCV coinfection who have achieved HIV viral suppression on an ART regimen that they tolerate can continue the regimen if it does not have any expected significant drug interactions with the selected HCV treatment regimen. In contrast, a regimen switch may be indicated if components of the ART regimen cannot be used with the HCV antiviral agents. Additionally, if an ART regimen switch is indicated because of failure to suppress HIV or intolerance, potential drug interactions with HCV antivirals should be taken into account in addition to the other considerations that inform ART choice in treatment-experienced patients. (See 'Potential drug interactions with ART' below and "Overview of antiretroviral agents used to treat HIV" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

In cases of ART regimen switches, the prior antiretroviral history and resistance profiles should be carefully studied to ensure that the new regimen includes two to three fully active antiretroviral agents. In general, HCV therapy is started four to six weeks after an ART regimen switch to allow for assessment of tolerability and adverse events of the new ART regimen alone. Additionally, HIV RNA is measured within four to eight weeks after the ART regimen switch to ensure that the new regimen maintains viral suppression. If the new ART regimen is to be switched back to the original ART regimen following HCV treatment, this should be delayed until at least two weeks after the completion of the HCV treatment to ensure clearance of the HCV antivirals [19].

HCV REGIMEN SELECTION

Regimen options — The regimen options for patients with HIV/HCV coinfection are the same as those for patients with HCV monoinfection. Where available, pangenotypic regimens (eg, sofosbuvir-velpatasvir and glecaprevir-pibrentasvir for initial antiviral therapy) are generally preferred options (algorithm 1); they can facilitate therapy because they can be used without prior genotype assessment [15,18]. When several regimens are available for a given genotype, potential drug interactions with the antiretroviral regimen are a critical factor in deciding between them for patients with coinfection. (See 'Potential drug interactions with ART' below.)

Selection and administration of antiviral regimens for chronic HCV infection are discussed in detail elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

Several studies have demonstrated that patients with coinfection achieve high sustained virologic response (SVR) rates with direct-acting antiviral (DAA) regimens that are comparable to those seen in patients with monoinfection [21,22]. Examples include:

●Glecaprevir-pibrentasvir – Glecaprevir-pibrentasvir is a potent, highly effective pangenotypic regimen. In a study of patients with HIV/HCV coinfection treated with glecaprevir-pibrentasvir, an eight-week course resulted in SVR in all of the patients with genotype 1 (n = 87), genotype 2 (n = 9), and genotype 3 (n = 22) infection and no cirrhosis [23]. Patients with cirrhosis received a 12-week course in that study; none of the 10 patients with genotype 1 and only one of the four patients with genotype 3 infection experienced virologic failure. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Glecaprevir-pibrentasvir'.)

●Sofosbuvir-velpatasvir – Sofosbuvir-velpatasvir is a potent, highly effective pangenotypic regimen. In a study of patients with HIV/HCV coinfection treated with sofosbuvir-velpatasvir for 12 weeks, SVR rates were 95 percent for genotype 1 (n = 78), 100 percent for genotype 2 (n = 11), and 92 percent for genotype 3 (n = 92 percent) [24]. Some patients failed to achieve SVR because of loss to follow-up (rather than known virologic failure); SVR rates were high regardless of the presence of cirrhosis or treatment history. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Sofosbuvir-velpatasvir'.)

●Sofosbuvir-velpatasvir-voxilaprevir – This regimen is generally reserved for patients who have previously failed contemporary DAA-based regimens (although in Europe there is an approved eight-week option for initial treatment). Its efficacy has not been directly studied in populations with HIV/HCV coinfection but is thought to be comparable to that in patients with HCV monoinfection.

●Daclatasvir plus sofosbuvir – This combination is used in locations where pangenotypic regimens are not accessible, and it is highly effective in coinfection with genotypes 1, 2, 3, and 4 [25-31]. In a study of over 200 patients with coinfection, 83 percent of whom had genotype 1 infection, 12 weeks of daclatasvir plus sofosbuvir resulted in SVR rates of 97 and 98 percent among treatment-naïve and treatment-experienced patients, respectively [25]. All of 10 patients with genotype 3 infection achieved SVR. SVR rates were lower (76 percent) when given for only eight weeks. Allowed antiretroviral agents included darunavir, atazanavir, or lopinavir (each ritonavir-boosted), efavirenz, nevirapine, rilpivirine, raltegravir, and dolutegravir. Daclatasvir dose was adjusted when used with certain antiretrovirals (30 mg with protease inhibitors and 90 mg with efavirenz and nevirapine).

●Ledipasvir-sofosbuvir – This is an option for patients with genotypes 1, 4, 5, and 6 infection. It is highly effective in patients with coinfection [32,33]. As an example, in the ION-4 study, which included over 300 treatment-naïve and treatment-experienced patients with genotype 1 coinfection, ledipasvir-sofosbuvir for 12 weeks resulted in a high sustained virologic response (SVR) rate overall (96 percent) and even among patients with cirrhosis (94 percent) or prior treatment failure (97 percent) [33]. Analysis of data from patients with monoinfection has suggested that ledipasvir-sofosbuvir for 8 weeks is equally effective as 12 weeks for HCV treatment-naïve patients without cirrhosis who also have an HCV viral load <6 million international units/mL. Although this abbreviated course in the setting of coinfection is not routinely recommended [18], observational data evaluating use of this eight-week course in patients with coinfection are reassuring [34].

●Elbasvir-grazoprevir – This is a potential option for patients with genotype 1 and 4 infection and is highly effective in patients with coinfection [35-37]. In a study of 189 treatment-naïve patients with HIV/HCV genotype 1 coinfection, SVR with 12 weeks of elbasvir-grazoprevir was 94 percent [36]. SVR rates were comparably high among the 16 percent who had cirrhosis. Analysis of outcomes among patients with monoinfection has suggested an association between lower SVR rates and pre-existing variations in the NS5A inhibitor sequence of genotype 1a virus. Therefore, American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) guidelines recommend that if elbasvir-grazoprevir is considered for patients with genotype 1a, they undergo testing for resistance-associated substitutions (RASs) and, if RASs are present, receive a different regimen [18]; European Association for the Study of the Liver (EASL) guidelines recommend elbasvir-grazoprevir for genotype 1b patients only [15].

Other direct-acting antivirals are available in certain other locations. Clinicians in those locations are advised to check local guidelines on the optimal use of such agents.

Potential drug interactions with ART — Several important drug interactions between antiretroviral therapy (ART) and HCV antiviral agents should be considered when assessing a patient with HIV/HCV coinfection for HCV treatment (table 1).

Sofosbuvir-velpatasvir — Sofosbuvir-velpatasvir is available in a fixed-dose combination (table 1). In relatively small clinical studies of patients with HIV/HCV coinfection who were treated with sofosbuvir-velpatasvir, antiretroviral agents that were concurrently used without evidence of decreased efficacy or adverse effect included abacavir, atazanavir, cobicistat, darunavir, elvitegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, ritonavir, and TDF [24]. Pharmacokinetic studies in healthy volunteers have also not shown clinically relevant drug level changes when sofosbuvir-velpatasvir is used with any of these, dolutegravir, bictegravir, or tenofovir alafenamide [38-40]. No clinically relevant drug interactions with cabotegravir or doravirine are expected.

Coadministration of sofosbuvir-velpatasvir with some antiretroviral regimens containing TDF results in elevated levels of tenofovir in pharmacokinetic studies, although the clinical significance of these levels is uncertain. If these agents are used together, monitoring for renal toxicity is warranted, as for coadministration with ledipasvir-sofosbuvir (see 'Ledipasvir-sofosbuvir' below). These changes in tenofovir levels are not seen with tenofovir-alafenamide-containing regimens.

Both sofosbuvir and velpatasvir are substrates of P-glycoprotein transporter. Thus, concomitant use of tipranavir, which is a P-gp inducer, is not recommended because it is expected to decrease velpatasvir and sofosbuvir levels. However, a small pharmacokinetic study suggests that P-gp inhibition by ritonavir, with which tipranavir is always coadministered, may negate this effect [41].

Velpatasvir is CYP2B6 substrate. Coadministration with efavirenz, a CYP2B6 inducer, is also not recommended because of significant decreases in velpatasvir levels.

Other important drug interactions with sofosbuvir-velpatasvir are discussed elsewhere and can be queried in the drug interactions program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Sofosbuvir-velpatasvir'.)

Glecaprevir-pibrentasvir — Glecaprevir and pibrentasvir are available only as a fixed-dose combination. They are substrates and inhibitors of P-glycoprotein, breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Thus, coadministration with several antiretrovirals is not advised (table 1).

Use with efavirenz is not recommended because of the potential for decreased levels of glecaprevir and pibrentasvir.

Use with atazanavir is contraindicated because of the risk of aminotransferase elevations. Use with other protease inhibitors (including darunavir, lopinavir, and ritonavir) is not recommended because of the potential for increased levels of glecaprevir and pibrentasvir.

In clinical studies of patients with HIV/HCV coinfection who were treated with glecaprevir-pibrentasvir, antiretroviral agents that were concurrently used without evidence of decreased efficacy or adverse effect included tenofovir (both TDF and TAF), abacavir, emtricitabine, lamivudine, raltegravir, dolutegravir, elvitegravir with cobicistat, and rilpivirine [23]. No clinically relevant drug interactions with bictegravir, cabotegravir, or doravirine are expected. However, the European product label for bictegravir-emtricitabine-tenofovir alafenamide notes caution when used with glecaprevir-pibrentasvir because levels of bictegravir, a P-glycoprotein and BCRP substrate, may be elevated with coadministration [42].

Other important drug interactions with glecaprevir-pibrentasvir are discussed elsewhere and can be queried in the drug interactions program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

Voxilaprevir — Voxilaprevir is only available as a combination pill with sofosbuvir and velpatasvir. Its use is generally reserved for patients who have failed prior treatment with certain DAA-containing regimens. Voxilaprevir is a substrate and inhibitor of P-glycoprotein, BCRP, and OATP 1B1 and 1B3. It is also slowly metabolized by CYP34A. Thus, coadministration with several antiretrovirals is not advised (table 1).

Use with efavirenz is not recommended because of potentially decreased levels of voxilaprevir.

Use with atazanavir or lopinavir is not recommended because of potentially increased levels of voxilaprevir. For similar reasons, use of other DAA regimens is recommended for patients on fostemsavir.

In pharmacokinetic studies of sofosbuvir-velpatasvir-voxilaprevir, there were no concerning drug levels when given with tenofovir (both TDF and TAF), emtricitabine, rilpivirine, dolutegravir, bictegravir, and raltegravir [39,40]. No clinically relevant drug interactions with doravirine or cabotegravir are expected. Voxilaprevir levels were higher when coadministered with boosted regimens (ie, elvitegravir with cobicistat and darunavir with ritonavir or cobicistat), but these levels were not thought to be clinically relevant.

Coadministration of sofosbuvir-velpatasvir-voxilaprevir with some antiretroviral regimens containing TDF is expected to result in elevated levels of tenofovir (as with sofosbuvir-velpatasvir), although the clinical significance of these levels is uncertain. If these agents are used together, monitoring for renal toxicity is warranted, as for coadministration with ledipasvir-sofosbuvir (see 'Ledipasvir-sofosbuvir' below).

Ledipasvir-sofosbuvir — Ledipasvir is only available as a fixed-dose combination with sofosbuvir (table 1). Coadministration of ledipasvir-sofosbuvir with tenofovir disoproxil fumarate (TDF) results in elevated levels of tenofovir in pharmacokinetic studies, and levels are even higher when measured intracellularly or in the setting of concurrent use with certain other antiretrovirals [43-45]. The clinical significance of such levels of tenofovir is uncertain. Nevertheless, given the paucity of safety data in individuals with HIV and the lack of clear correlation between drug levels and toxicity, conservative management is warranted until there is greater experience.

●Because coadministration with tenofovir alafenamide (TAF) does not result in elevated plasma levels of tenofovir and TAF is associated with less renal and bone toxicity than TDF [46,47], we switch patients from a TDF- to a TAF-containing regimen when planning to use ledipasvir-sofosbuvir.

●When TAF is not an option, management depends on the precise TDF-containing antiretroviral regimen and the renal function of the patient; consultation with an HIV pharmacologist can be useful in this setting. Some TDF-based regimens can be used with ledipasvir-sofosbuvir. If that is undertaken, we check a baseline creatinine, urinalysis, and phosphate level and monitor for tenofovir-associated renal toxicity (eg, with creatinine and phosphate at least monthly). If there is evidence of significant renal toxicity, consultation with a renal expert is warranted. Specific options for different TDF-containing antiretroviral regimens are as follows:

•Concomitant use of ledipasvir-sofosbuvir with the combination regimen of elvitegravir, cobicistat, TDF, and emtricitabine (ECF-TDF) is not recommended because of the uncertainty of the safety of tenofovir levels reported in this setting [43]. Combination of elvitegravir, cobicistat, TAF, and emtricitabine (ECF-TAF), however, is possible. If this formulation is not available, a different antiretroviral regimen or a different HCV regimen should be chosen.

•For patients who are on TDF plus a ritonavir-boosted protease inhibitor (eg, atazanavir, darunavir), we use ledipasvir-sofosbuvir cautiously and with increased renal monitoring if their baseline renal function is normal. However, for patients with some renal impairment at baseline (that does not preclude ledipasvir-sofosbuvir use), we are more likely to change either the backbone to abacavir-lamivudine, or the third drug to raltegravir, dolutegravir, or rilpivirine prior to using ledipasvir-sofosbuvir, provided that the new antiretroviral regimen is expected to be effective based on baseline genotype and prior treatment history.

•The expected increase in tenofovir levels when TDF and ledipasvir-sofosbuvir are coadministered is lower for nonnucleoside reverse transcriptase inhibitor- or integrase inhibitor-containing regimens, and in such cases, we use ledipasvir-sofosbuvir cautiously and with increased renal monitoring. In clinical studies of patients with HIV/HCV coinfection who were treated with ledipasvir-sofosbuvir, antiretroviral agents that were concurrently used without evidence of decreased efficacy or adverse effect included TDF plus emtricitabine with efavirenz, rilpivirine, or raltegravir [32,33]. In one study of over 300 patients who received ledipasvir-sofosbuvir plus one of those antiretroviral regimens, only four patients had an increase in the serum creatinine level ≥0.4 mg/dL; two remained on TDF, one had the TDF dose reduced, and one discontinued TDF [33].

Clinically significant interactions are not expected or have not been observed in healthy individuals with abacavir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, bictegravir, doravirine [48], and lamivudine. Although dolutegravir and cabotegravir may not have been explicitly studied with ledipasvir-sofosbuvir, based on metabolism pathways, it is appropriate to extrapolate that they can be safely used concomitantly.

Other important drug interactions with ledipasvir-sofosbuvir are discussed elsewhere and can be queried in the drug interactions program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Ledipasvir-sofosbuvir'.)

Elbasvir-grazoprevir — Elbasvir and grazoprevir are available only as a fixed-dose combination. Both are primarily metabolized through CYP3A metabolism, and grazoprevir is a substrate of OATP1B1/3 as well. Thus, coadministration with several antiretrovirals is not advised (table 1).

Use with efavirenz is contraindicated because of the potential for decreased levels of elbasvir and grazoprevir. Use with etravirine is not recommended for similar reasons.

Use with protease inhibitors (including darunavir and atazanavir) is contraindicated because of the risk of elevated levels of grazoprevir. Use with cobicistat-containing regimens and fostemsavir is not recommended for similar reasons.

In clinical studies of patients with HIV/HCV coinfection who were treated with elbasvir-grazoprevir, antiretroviral agents that were concurrently used without evidence of decreased efficacy or adverse effect included tenofovir, abacavir, emtricitabine, lamivudine, raltegravir, dolutegravir, and rilpivirine [36]. No clinically relevant drug interactions with doravirine have been observed in pharmacokinetic studies [48], and none are expected with bictegravir or cabotegravir.

Other important drug interactions with elbasvir-grazoprevir are discussed elsewhere and can be queried in the drug interactions program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Elbasvir-grazoprevir'.)

Sofosbuvir — Overall, sofosbuvir has few drug interactions with antiretroviral agents (table 1), as it is not metabolized by and has no effect on the hepatic P450 enzyme complex, of which many antiretroviral agents are inducers or inhibitors. The main exception is ritonavir boosted tipranavir, which is not recommended for use with sofosbuvir because it is expected to decrease sofosbuvir levels since tipranavir is an inducer of the P-glycoprotein transporter. (See 'Sofosbuvir-velpatasvir' above.)

In clinical studies of patients with HIV/HCV coinfection who were treated with sofosbuvir, antiretroviral agents that were concurrently used without any evidence of decreased efficacy or adverse effect included tenofovir disoproxil fumarate-emtricitabine (TDF-FTC), efavirenz, ritonavir boosted atazanavir, ritonavir boosted darunavir, raltegravir, and rilpivirine [49]. Although other commonly used antiretroviral agents, such as abacavir, dolutegravir, bictegravir, cabotegravir, and elvitegravir, may not have been explicitly studied with sofosbuvir, based on the metabolism pathway, it is appropriate to extrapolate that these agents can be safely used with sofosbuvir.

There are potential interactions between sofosbuvir and other agents from different drug classes, and thus consideration of drug interactions is essential. As an example, sofosbuvir-containing regimens should not be used with amiodarone because of reported cases of severe bradycardia with concomitant use. Other important drug interactions with sofosbuvir are discussed elsewhere and can be queried in the drug interactions program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Sofosbuvir'.)

Less commonly used agents

●Daclatasvir — Daclatasvir may be used in combination with sofosbuvir to treat HCV infection. It is metabolized by the CYP3A subfamily, which consists mainly of hepatic and intestinal CYP3A4 metabolism, thus significant inducers or inhibitors of CYP3A4 are expected to alter the concentrations of daclatasvir (table 1). The typical dose is 60 mg once daily. An increase in the daclatasvir dose to 90 mg daily is indicated when used with efavirenz, and a dose reduction to 30 mg daily is indicated when used with ritonavir- or cobicistat-boosted atazanavir. Of note, boosted lopinavir or darunavir require no dose adjustment. Pending further data, we avoid use with etravirine because of the potential for lower daclatasvir levels.

In a clinical trial of daclatasvir plus sofosbuvir in patients with coinfection, the following antiretroviral agents were allowed: darunavir, atazanavir, and lopinavir (each ritonavir-boosted), efavirenz, nevirapine, rilpivirine, raltegravir, dolutegravir, TDF, abacavir, emtricitabine, lamivudine, zidovudine, maraviroc, and enfuvirtide [25]. No clinically relevant drug interactions with bictegravir, cabotegravir, or doravirine are expected.

Other important drug interactions with daclatasvir are discussed elsewhere and can be queried in the drug interactions program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Daclatasvir'.)

●Ribavirin — Important drug interactions between antiretroviral agents and ribavirin include direct interactions as well as combinations that potentiate adverse effects.

Patients on atazanavir-containing ART may develop jaundice due to an increase in total serum bilirubin levels following initiation of ribavirin [50]. The mechanism leading to this observation may be related to increased ribavirin-associated hemolysis in combination with decreased physiologic clearance of bilirubin due to atazanavir use. Clinicians should discuss this potential side effect with patients who are taking atazanavir. Patients who develop jaundice should have assays for indirect hyperbilirubinemia to be certain that the total increase in serum bilirubin is consistent with the drug effect of atazanavir. An increase in direct bilirubin, which suggests hepatic disease rather than drug effect, would be of much greater concern.

PATIENT MONITORING — Patients should be monitored for adherence and side effects, and, in some cases, viral load responses on therapy. This depends on the regimen used. As an example, for patients using ledipasvir-sofosbuvir while using a tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimen, monitoring creatinine and urinalysis during HCV treatment to evaluate for renal toxicity is prudent. (See 'Ledipasvir-sofosbuvir' above.)

BARRIERS TO CARE — Comorbidities and underlying psychiatric and substance abuse issues can complicate delivery of care for this complex patient population [51-53]. However, dedicated programs with case management and stabilization of psychiatric and addiction care can increase the success of treatment [54].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Hepatitis C (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – The objective of hepatitis C virus (HCV) antiviral treatment is to cure the HCV infection, as reflected by a sustained virologic response, which is associated with substantial reductions in liver-related morbidity and mortality. Although patients with HIV/HCV coinfection traditionally had lower response rates to HCV treatment with peginterferon and ribavirin compared with individuals without HIV, they appear to have comparable sustained virologic response rates with all oral, direct-acting antiviral (DAA) combination therapy. (See 'Goals of therapy' above and 'Effect of HIV infection on response to HCV treatment' above.)

●Prioritization of patients with coinfection – With the availability of highly effective interferon-free, direct-acting antiviral combination regimens for HCV, a curative all-oral treatment is becoming a possibility for the vast-majority of patients, even those with HIV. Because of the more rapid progression to advanced liver disease in the setting of HIV infection, coinfection is one reason to prioritize a patient for HCV antiviral therapy. (See 'Patient evaluation' above and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Deciding when to treat'.)

●Timing of ART and HCV antiviral initiation – In antiretroviral therapy (ART)-naïve patients with HIV/HCV coinfection, we generally initiate ART at least four to six weeks before starting HCV antiviral therapy. (See 'Antiretroviral management' above and 'Potential drug interactions with ART' above.)

●Regimen selection and drug interactions – HCV antiviral regimen selection for patients with HIV/HCV coinfection is generally the same as for patients with HCV monoinfection, and most of the supporting evidence for these regimens is from studies in patients with monoinfection (algorithm 1). Where available, pangenotypic DAA combinations can facilitate therapy because they can be administered without genotype assessment. Regimen selection should take into account potential drug interactions between ART and HCV antiviral agents (table 1). (See 'HCV regimen selection' above.)