Management of the patient with HIV/hepatitis C drug interactions: A guide for nurses and nurse practitioners

We are at a defining moment for hepatitis C virus (HCV) care, when direct acting antivirals (DAAs) can cure HCV in 8 or 12 weeks for most patients, paving a path for HCV elimination (World Health Organization, 2016). We also know that, while one in four people living with HIV (PLWH) are co-infected with HCV (Centers for Disease Control and Prevention, 2016), advances in HCV treatment have not been sufficient to move PLWH to the point of starting and succeeding on DAA therapy. Challenges in the HCV care continuum, including linking patients to care, securing insurance approval for payment, and medication adherence, persist (Cachay et al., 2014; Cope, Glowa, Faulds, McMahon, & Prasad, 2016). In addition, the presence of drug interactions between antiretroviral therapy (ART) and DAAs complicate both HIV and HCV care decisions in this new era (Cope et al., 2015; Patel et al., 2015; Smolders et al., 2017; U.S. Department of Health and Human Services [USDHHS], 2019). HCV treatment guidelines no longer separate patients with HIV/HCV co-infection from those with HCV mono-infection because cure rates (> 93%) are similar in both groups (American Association for the Study of Liver Diseases & Infectious Diseases Society of America [AASLD/IDSA], 2019). The only difference in treatment for HCV in those co-infected with HIV is the need to manage interactions with ART (AASLD/IDSA, 2019).

Multiple studies have demonstrated a high potential for drug interactions in clinical cohorts of HIV/HCV co-infected patients. A cross-sectional examination of medication lists revealed that the prevalence of interactions was as high as 88.4% depending on the HIV and HCV regimens (Patel et al., 2015). In retrospective chart reviews, studies have similarly found that the majority of HIV/HCV co-infected patients in their clinics were prescribed ART regimens that were contraindicated with common DAAs (Cope et al., 2015; Poizot-Martin et al., 2015). Prospectively, researchers have reported that about one-third of HIV/HCV co-infected adults may need to change their ART regimens to safely initiate DAAs, including 27% to start paritaprevir/ritonavir/ombitasvir with or without dasabuvir (Chromy et al., 2018), 31% for ledipasvir/sofosbuvir or simeprevir plus sofosbuvir (Falade-Nwulia et al., 2017), and 68% to 75% to take elbasvir/grazoprevir (Chromy et al., 2018; Smolders et al., 2017).

A considerable number of PLWH who initiate HCV treatment may have to switch their ART regimens to avoid a drug-drug interaction, but stopping ART to accommodate DAAs is not a viable option; interruptions in ART are associated with increased risk of mortality in HCV-co-infected PLWH and not recommended (AASLD/IDSA, 2019). Switching an ART regimen has many clinical and systemic implications for patients who may or may not be virally suppressed. At the individual level, adverse drug reactions, decreased tolerability, and higher symptoms and pill burdens can occur in the setting of switching ART (Cope et al., 2015; Sherr et al., 2007). Switching ART can also take several months, decrease quality of life, deter PLWH from starting HCV treatment, and result in lower HCV cure rates (Falade-Nwulia et al., 2017; Sherr et al., 2007). ART switches require additional follow-up visits, which can be a burden in terms of transportation, caregiving, and finances, and can result in greater than 10% higher mean annual health care costs and higher pharmacy costs compared to patients who do not switch ART (Rosenblatt et al., 2017).

Therefore, identification of ART/DAA drug interactions, including potential ART modifications to minimize barriers to HCV treatment initiation, are urgently needed to smooth the transition for PLWH. The development of DAAs has created a need to educate nurses and nurse practitioners to provide patient support and manage drug interactions with other key medications. The purpose of our paper is to provide a clinical guide for nurses and nurse practitioners, so that they are able to appropriately identify, mitigate and manage ART/DAA drug interactions in patients who are co-infected with HCV/HIV. HIV and HCV treatment guidelines and prescribing information were synthesized to inform this guide.

Direct Acting Antiviral Mechanisms of Action

HCV is a positive, single-stranded, enveloped RNA virus with extremely high genetic variability (Khan, Miller, & Marcotrigiano, 2015). HCV is comprised of structural and nonstructural proteins; structural proteins E1 and E2 play a major role in viral attachment, entry, and fusion, and account for most of the variability of HCV, while nonstructural (NS) proteins are far less variable and, consequently, have been the targets of anti-HCV drug development (Khan et al., 2015). Four classes of DAAs targeting NS proteins are available: NS3/4A protease inhibitors (PIs), nucleoside and nucleotide NS5B polymerase inhibitors, non-nucleoside NS5B polymerase inhibitors, and NS5A inhibitors (Table 1). Largely tolerable and effective NS3 and NS4A PIs, including grazoprevir, simeprevir, paritaprevir, glecaprevir, and voxilaprevir, play a critical role in HCV posttranslational processing (AASLD/IDSA, 2019; Kim & Chang, 2013). Recent advances have also introduced NS5B nucleotide polymerase inhibitors (sofosbuvir and dasabuvir) and NS5A protein inhibitors (daclatasvir, elbasvir, ledipasvir, ombitasvir, velpatasvir, and pibrentasvir) with a greater ability to inhibit the HCV lifecycle. The NS5B protein is key in HCV RNA translation and replication, while NS5A is involved in HCV replication, assembly, and release (Kim & Chang, 2013).

Table 1.

Four Classes of Direct Acting Antivirals

DAA Class	Suffix	Medications
NS3/4A protease inhibitors	-previr	grazoprevir
		paritaprevir
		simeprevir
		glecaprevir
		voxilaprevir
NS5B polymerase inhibitors	-buvir
Nucleoside and nucleotide		sofosbuvir
Non-nucleoside and nucleotide		dasabuvir
NS5A inhibitors	-asvir	daclatasvir
		elbasvir
		ledipasvir
		ombitasvir
		velpatasvir
		pibrentasvir

Note. DAA = direct acting antiviral.

The goal of HCV therapy is sustained virologic response (SVR). SVR is defined as maintaining an undetectable HCV RNA viral load 12 weeks after completing DAA treatment. SVR is considered a cure; 5-year relapse rates after achieving SVR are as low as 0.4% in HCV mono-infected patients and 0.01% in HIV/HCV co-infected patients (Simmons, Saleem, Hill, Riley, & Cooke, 2016). In clinical trials of DAAs administered to HIV co-infected patients, SVR was achieved in 93–100% of study participants (Naggie et al., 2015; Sulkowski et al., 2015; Wyles et al., 2017; Wyles et al., 2015).

HCV Treatment Guidelines

The AASLD-IDSA guidelines for the treatment of HCV are continuously updated and are available at www.hcvguidelines.org. Table 2 outlines the approved and recommend first-line treatments for HCV as of April 2019. Aside from drug interactions, there is no difference in the recommended course of treatment for HIV/HCV co-infected patients compared to HCV mono-infected patients. Modifications are instead made to accommodate genotype, prior HCV treatment, severity of liver disease, and presence of renal disease. The guidelines do not recommend a different course of treatment based on sex or gender. In 2016, the first pan-genotypic drug, elbasvir/grazoprevir, was approved, although all regimens have been approved to treat genotype 1a, the most common strain in the United States. Additionally, all regimens may be used in naïve and PEGylated interferon/ribavirin treatment-experienced patients without cirrhosis (i.e., metavir score ≤ 3). Special considerations must be made for patients with compensated and, especially, decompensated cirrhosis; as described in Table 2, these patients may require adding ribavirin and/or extending treatment to 24 weeks (AASLD/IDSA, 2019).

Table 2.

Recommended Direct Acting Antiviral Regimens (in Ascending Order by Date of FDA Approval)

DAA (Commercial Name)	Dose/Duration	Recommended Use
Simeprevir (Olysio™) plus sofosbuvir (Sovaldi®)	150 mg + 400 mg PO daily with food 12 weeks	Alternative regimen only GT 1 No cirrhosis
Ledipasvir/sofosbuvir (Harvoni®)	90 mg/400 mg PO daily 12 to 24 weeks	GT 1, 4, 5, 6 No cirrhosis Compensated cirrhosis (GT 1, 4) Decompensated cirrhosis (+RBV or 24 weeks; GT 1, 4, 5, 6)
Paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekira Pak®) plus Ribavirin	150 mg/100 mg/25 mg and 600 mg dasabuvir PO daily or 250 mg dasabuvir twice daily + weight-based RBV 12 weeks	Alternative regimen only GT 1, 4 No cirrhosis Compensated cirrhosis (GT 1b, 4)
Daclatasvir (Daklinza™) plus sofosbuvir (Sovaldi®)	60 mg + 400 mg PO daily 12 to 24 weeks	Alternative regimen only GT 1, 2, 3 No cirrhosis Compensated cirrhosis (GT 2, 3) Decompensated cirrhosis (+RBV or 24 weeks; GT 1, 2, 3, 4)
Elbasvir/grazoprevir (Zepatier®)	50 mg/100 mg PO daily 12 to 16 weeks	GT 1, 4 No cirrhosis Compensated cirrhosis ESRD (GT 1, 4)
Sofosbuvir/velpatasvir (Epclusa®)	400 mg/100 mg PO daily 12 to 24 weeks	GT 1, 2, 3, 4, 5, 6 No cirrhosis Compensated cirrhosis Decompensated cirrhosis (+RBV or 24 weeks; GT 1, 2, 3, 4, 5, 6)
glecaprevir/pibrentasvir (Mavyret™)	300 mg/120 mg PO daily 8 to 16 weeks	GT 1, 2, 3, 4, 5, 6 No cirrhosis Compensated cirrhosis ESRD
Sofosbuvir/velpatasvir/voxilaprevir (Vosevi®)	400 mg/100 mg/100 mg daily 12 weeks	Alternative regimen only GT 3 Compensated cirrhosis

Note: GT = Genotype; PO = by mouth; ESRD = end stage renal disease; PI = protease inhibitor; +RBV = add ribavirin; P/R = peginterferon/ribavirin

Source: American Association for the Study of Liver Diseases & Infectious Diseases Society of America, 2019

HIV/HCV Drug Interactions

Co-prescribing DAAs and ART requires diligence to avoid potentially toxic drug interactions. Drug-drug interactions depend on the classes of DAAs and ART involved. Table 3 provides a summary of the ART-DAA interactions by prescribed DAA regimen. Simeprevir administration is the most problematic with ART, because 76% to 88% of PLWH may encounter a contraindicated drug-drug interaction. Similarly, elbasvir/grazoprevir is contraindicated with all ritonavir or cobicistat boosted HIV PIs as well as efavirenz, etravirine, elvitegravir/cobicistat, and nevirapine (AASLD/IDSA, 2019).

Table 3.

Drug Interactions Between HCV Direct Acting Antivirals and HIV Antiretroviral Therapy

DAA	Contraindicated ART	Mechanism of Interaction	Additional Considerations
High ART interaction risk
elbasvir/grazoprevir (Zepatier®)	all protease inhibitors	increases grazoprevir concentration 5–11-fold via OATP1B inhibition and potential CYP3A inhibition
	cobicistat	may increase grazoprevir exposure due to OATP1B inhibition and potential CYP34 inhibition
	efavirenz	decreases elbasvir and grazoprevir concentrations via CYP3A/P-gp induction
	etravirine	may decrease elbasvir and grazoprevir concentrations via CYP3A induction
	nevirapine	may decrease elbasvir and grazoprevir concentrations via CYP3A induction
glecaprevir/pibrentasvir (Mavyret™)	ritonavir-containing regimens	increases glecaprevir/pibrentasvir concentrations via OATP1B inhibition	Additional monitoring for hepatic toxicity with elvitegravir/cobicistat
	atazanavir	increases risk for ALT elevation and increases glecaprevir concentration due to OATP1B inhibition
	efavirenz	decreases glecaprevir/pibrentasvir concentrations
	etravirine	may decrease glecaprevir/pibrentasvir concentration via CYP3A4 induction
sofosbuvir/velpatasvir/voxilaprevir (Vosevi®)	ritonavir-boosted atazanavir	increases voxilaprevir 4-fold via OATP1B1 and P-gp inhibition	Additional monitoring for hepatic toxicity with elvitegravir/cobicistat, TAF/FTC, TDF/FTC, DRV/r, DRV/COBI Avoid TDF if CrCl < 60 mL/min If CrCl < 60 mL/min consider TAF if on ritonavir or COBI
	efavirenz	decreases concentrations of velpatasvir
	etravirine	decreases sofosbuvir/velpatasvir/voxilaprevir concentration due to CYP3A4 induction
	nevirapine	may decrease sofosbuvir/velpatasvir/voxilaprevir concentration due to CYP3A4 and CYP2C8 induction
	tipranavir	may decrease sofosbuvir/velpatasvir/voxilaprevir concentration
Low ART interaction risk
ledipasvir/sofosbuvir (Harvoni®)	tipranavir	may decrease concentration of ledipasvir/sofosbuvir	Avoid TDF if CrCl < 60 mL/min If CrCl < 60 mL/min consider TAF if on ritonavir or COBI
daclatasvir (Daklinza™)/sofosbuvir (Sovaldi®)	tipranavir	reduces therapeutic effect of sofosbuvir via induction of P-gp	Decrease daclatasvir dose to 30 mg once daily with atazanavir/r, atazanavir/COBI elvitegravir/COBI Increase daclatasvir dose to 90 mg once daily with efavirenz, etravirine or nevirapine
sofosbuvir/velpatasvir (Epclusa®)	efavirenz	decreases velpatasvir concentration	Avoid TDF if CrCl < 60 mL/min If CrCl < 60 mL/min consider TAF if on ritonavir or COBI
	etravirine	decreases sofosbuvir/velpatasvir concentration due to CYP3A4 induction
	nevirapine	decreases sofosbuvir/velpatasvir concentration due to CYP3A4 and CYP2B6 induction
	tipranavir	may reduce sofosbuvir/velpatasvir concentration

Note: DAA = direct acting antiviral; ART = antiretroviral therapy; TDF = tenofovir disoproxil fumarate; CrCl = creatinine clearance; OATP1B = organic anion transporting polypeptide 1B; CYP3A4 = cytochrome P450 3A4; CYP2B6 = cytochrome P450 2B6; P-gp = P-glycoprotein; ALT = alanine aminotransferase.

Source: American Association for the Study of Liver Diseases & Infectious Diseases Society of America, 2019.

Sofosbuvir has the fewest interactions with ART of any DAA. The prevalence of sofobusvir drug interactions in PLWH ranged from 0% to 24% in different studies (Cope et al., 2015; Patel et al., 2015; Poizot-Martin et al., 2015). Tipranavir is the only contraindicated ART medication in the presence of sofosbuvir. Co-prescribing sofosbuvir and tenofovir disoproxil fumarate introduces renal consideration, but this interaction is eliminated with the use of tenofovir alafenamide fumarate (AASLD/IDSA, 2019). For PLWH, regimens with the fewest drug interactions include sofosbuvir/ledipasvir and sofosbuvir/daclatasvir (Cope et al., 2015; Patel et al., 2015; Poizot-Martin et al., 2015). Sofosbuvir/velpatasvir also provides a relatively low-risk option (AASLD/IDSA, 2019).

According to a retrospective chart review, 40% of PLWH on boosted PI regimens may be unable to switch to a non-PI regimen to accommodate starting DAAs (Cope et al., 2015). In this case, daclatasvir/sofosbuvir is recommended. However, daclatasvir requires dose adjustment (decrease to 30 mg/d) with ritonavir- and cobicistat-boosted atazanavir, and elvitegravir/cobicistat. An increase to 90 mg/day is warranted with concomitant use of efavirenc, etravirine, or nevirapine (AASLD/IDSA, 2019; Wyles et al., 2015). Further guidance is provided in the AASLD/IDSA guidelines. HIV specialists should consider switching PLWH to an integrase inhibitor-based regimen when this is appropriate because contraindicated drug interactions between integrase inhibitors and DAAs are rare (USDHHS, 2019). However, any decisions to change ART must be made with careful consideration of an individual patient’s eligibility and ability to succeed on a new regimen.

Nurses should be prepared to initiate ART switches in patients at least 1 month prior to a planned DAA start date (Stambough, Roman, Blair, Sidman, & Miller, 2016). When an ART modification has been made to accommodate DAAs, a patient should not start DAAs for at least 2 weeks after changing the ART regimen. An HIV viral load should be checked within 2 to 8 weeks after making the switch to ensure viral suppression. It is recommended to wait 2 weeks after completing DAA until resuming original ART regimen if switching back (USDHHS, 2019).

Discussion

We have the opportunity to cure all patients with chronic HCV, but drug interactions between ART and DAAs pose a clinical challenge in people living with HIV/HCV infection. Although ART/DAA drug interactions are common, it is important to note that ART switches should be avoided if possible, as modifying ART is associated with lower SVR rates (Falade-Nwulia et al., 2017). In 2019 there are multiple options for effective HCV treatment. Newer DAAs are emerging that have limited drug interactions with ART. In addition, the U.S. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV (USDHHS, 2019) have replaced PIs with integrase inhibitor-based regimens as the recommended initial therapy for HIV. The currently recommended DAAs do not have major interactions with HIV integrase inhibitors; thus, as patients are newly initiating ART and some treatment-experienced patients choose to transition to Integrase Strand Transfer Inhibitor-based regimens for reasons other than HCV treatment, the prevalence of ART/DAA drug interactions may naturally decrease. Similarly, the addition of tenofovir alafenamide to replace tenofovir disoproxil fumarate will render the renal considerations in patients prescribed tenofovir-containing regimens potentially obsolete. In the meantime, providers may consider temporary ART modifications for patients who are opposed to a permanent switch; in this case, it is recommended that a patient remain on the temporary ART regimen for at least 2 weeks after completion of HCV treatment before switching back to the original regimen (USDHHS, 2019).

Clearly, there is strong clinical evidence in favor of treating HCV, even when ART regimen modification and simplification in accordance with guidelines is required. It is important to note that the benefits of ART modification and simplification are just as important for patients who do not have HCV co-infection. Many patients remain on outdated ART regimens that need modification to prevent other toxicities. As the HIV treatment guidelines favor minimizing toxic drug interactions, HIV care providers should continue to move toward Integrase Strand Transfer Inhibitor-based HIV therapy in all patients, regardless of HCV infection (USDHHS, 2019). In co-infected patients, initiation of HCV DAAs may serve as a motivation to change a suboptimal ART regimen that has persisted due to the “don’t fix what isn’t broken” mindset of both clinicians and patients.

While ART/DAA drug interactions are well documented, there is a paucity of evidence-based interventions to minimize the impact of ART/DAA drug interactions on PLWH who are starting treatment for HCV. Nurses are in a position to lead the way in addressing the new need for ART switches in PLWH where switching ART cannot be avoided. Although we are not aware of any studies to date that specifically examine an intervention to mitigate the impact of ART modifications for DAA initiation, systems in place to help nurses recognize the potential for drug interactions, coordinate an ART switch, and use nurse-driven pathways for HCV treatment initiation and adherence, may support the role of nurses in this process (Redulla, Reddy, Faust, & Dudley-Brown, 2015; Stambough et al., 2016).

Limitations

This article must be referenced within the context of its limitations. Primarily, development and approval of DAAs are happening rapidly. Guidelines for the treatment of HIV and HCV change often, and so the most up-to-date clinical resources should always be referenced. Figure 1 lists several resources for the management of the patient with HIV/HCV co-infection, many of which are continuously updated, living documents.

Figure 1.

Resources for the management of hepatitis C in the co-infected patient living with HIV.

Note: HCV = hepatitis C virus; FDA = U.S. Food and Drug Administration.

Conclusion

Drug interactions pose a clinical challenge for patients living with HIV and HCV co-infection. Nurses are in a position to identify, mitigate and manage ART/DAA drug interactions and should be knowledgeable in this area. Multiple first-line options for DAAs are available that have few ART drug interactions. While ART modifications should be avoided when possible, Integrase Strand Transfer Inhibitor-based HIV regimens have few contraindicated drug interactions with DAAs and therefore offer a useful option when appropriate for the patient. Current clinical and prescribing guidelines, as well as individual patient characteristics, should always be consulted when making treatment decisions.