Table 4: Drug-drug interactions between antiretroviral agents and directly acting antivirals for hepatitis C.

Usual doses90 mg/400 mg daily150/100/25 mg daily + 250 mg BID with food150 mg daily and 400 mg daily with food60 mg daily plus 400 mg daily

Nucleoside/nucleotide reverse transcriptase inhibitors
Abacavir/lamivudine18% ↑ AUC, 10%, ↑ and 26% ↑ of ledipasvir. 21% ↑ AUC of sofosbuvir, not considered clinically significant. No dose adjustment required (Harvoni PM),Coadministration has not been studied but no clinically significant drug interaction expected.Coadministration has not been studied but no clinically significant drug interaction is expected.Coadministration has not been studied but no clinically significant drug interaction is expected.
Tenofovir disoproxil fumarate (TDF)/emtricitabineTDF exposures are increased (AUC 40–98%, 32–79% and 47–163%) when ledipasvir/sofosbuvir is coadministered with TDF-containing antiretroviral regimens, including NNRTIs, boosted PIs, and integrase inhibitors. Appropriate monitoring for TDF-associated toxicity is recommended (Harvoni PM).No clinically significant changes. No dose adjustment required (Holkira Pak PM)No clinically significant changes in pharmacokinetics of TDF, simeprevir, or sofosbuvir noted. No dose adjustment is required (Galexos PM, Harvoni PM).No clinically significant changes in pharmacokinetics of TDF, daclatasvir, or sofosbuvir noted. No dose adjustment is required (Galexos PM, Harvoni PM).

Integrase strand transfer inhibitors
DolutegravirTDF exposures were 65–115% higher when ledipasvir/sofosbuvir was coadministered with dolutegravir plus TDF DF/emtricitabine. Ledipasvir/sofosbuvir may be coadministered with dolutegravir. If TDF DF/emtricitabine is included as an NRTI backbone, appropriate monitoring for TDF-associated toxicities is recommended [227].Dolutegravir exposures increased 22–38% while paritaprevir ↓ 34%. These changes are not considered clinically significant and dolutegravir may be administered with the 3D regimen without dose adjustment [228].Coadministration has not been studied but no clinically significant drug interaction is expected.No clinically significant changes in pharmacokinetics of dolutegravir or daclatasvir noted. No dose adjustment is required [229].
Elvitegravir/cobicistatIncreased TDF exposures anticipated with coadministration; appropriate monitoring for TDF-associated toxicities is recommended [227] (Harvoni PM).
Increased cobicistat exposure. Clinical significance unknown but likely not clinically relevant [227].
Coadministration has not been studied but cobicistat is expected to increase paritaprevir and ritonavir concentrations (Holkira Pak PM). Coadministration cannot be recommended.Not recommended with cobicistat-boosted regimens due to risk of significantly increased simeprevir concentrations [230, 231].Potential for increased daclatasvir exposures due to CYP3A4 inhibition by cobicistat. Reduce daclatasvir dose to 30 mg once daily when coadministering with cobicistat-based regimens (Daklinza PM).
RaltegravirNo clinically significant changes noted with coadministration. No dose adjustment required (Harvoni PM).No clinically significant changes noted with coadministration. No dose adjustment required (Holkira Pak PM).No clinically significant changes noted with coadministration. No dose adjustment is required [230, 232, 233].Coadministration has not been studied but no clinically significant drug interaction is expected (Daklinza PM).

Nonnucleoside reverse transcriptase inhibitors
EfavirenzIn combination with TDF/FTC, no clinically significant changes in sofosbuvir or efavirenz pharmacokinetics were noted, while tenofovir AUC ↑ 98% and ↑ 163%. Appropriate monitoring for tenofovir-associated toxicities is recommended [227] when the combination of efavirenz, tenofovir DF, and FTC is coadministered with ledipasvir/sofosbuvir (Harvoni PM).Coadministration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir is contraindicated due to poor tolerance and liver enzyme elevations (Holkira Pak PM).91% ↓ , 71% ↓ AUC of simeprevir. Avoid combination  [230, 231].Daclatasvir exposures are decreased with coadministration. Increase daclatasvir to 90 mg once daily with efavirenz (Daklinza PM).
EtravirineCoadministration has not been studied.Contraindicated with etravirine due to risk of decreased paritaprevir, ombitasvir, and dasabuvir concentrations (Holkira Pak PM).Not recommended with etravirine due to risk of decreased simeprevir concentrations  [230].Coadministration has not been studied. Potential for decreased daclatasvir concentrations; avoid coadministration until further data available.
RilpivirineIn combination with TDF/FTC, no clinically significant changes in sofosbuvir or rilpivirine pharmacokinetics were noted, while tenofovir AUC ↑ 40% and ↑ 91%. Appropriate monitoring for tenofovir-associated toxicities is recommended [227] when the combination of rilpivirine, tenofovir, and FTC is coadministered with ledipasvir/sofosbuvir (Harvoni PM).3.25-fold ↑ AUC, 2.55-fold ↑ , and 3.62-fold ↑ of rilpivirine, not mitigated by staggered administration. Coadministration is not recommended due to increased risk for prolonged QTc (Holkira Pak PM).No clinically significant changes noted with coadministration. No dose adjustment required [233].Coadministration has not been studied but no clinically significant drug interaction expected (Daklinza PM).

Protease inhibitors
Atazanavir/ritonavir75% ↑ , 33% ↑ AUC of atazanavir. 2.13-fold ↑ AUC, 1.98-fold ↑ , and 2.36-fold ↑ of ledipasvir. No dose adjustment required (Harvoni PM). Monitor for atazanavir toxicity (e.g., hyperbilirubinemia).Atazanavir should be taken without additional ritonavir with the 3D regimen (Holkira Pak PM).Not recommended with ritonavir, boosted or unboosted HIV protease inhibitors due to risk of significantly increased simeprevir concentrations [230].Reduce dose of daclatasvir to 30 mg once daily when coadministering with atazanavir/ritonavir (Daklinza PM).
Atazanavir/cobicistatCombination is not studied. In combination with elvitegravir/cobicistat, cobicistat exposure is increased. Clinical significance is unknown but likely not clinically relevant [227]. Monitor for atazanavir toxicity (e.g., hyperbilirubinemia).Atazanavir plus cobicistat is not recommended with HOLKIRA PAK (Holkira Pak PM).Not recommended with cobicistat due to risk of significantly increased simeprevir concentrations [230].Reduce dose of daclatasvir to 30 mg once daily when coadministering with cobicistat (Daklinza PM).
Darunavir/ritonavirNo changes in darunavir pharmacokinetic parameters; 39% ↑ AUC, 45% ↑ , and ↑ 39%   of ledipasvir. Changes not considered clinically significant. No dose adjustment is required (Harvoni PM).24% ↓ AUC, 8% ↓ , and 48% ↓ of darunavir 800 mg daily. Darunavir should be taken without additional ritonavir with the 3D regimen since ritonavir is already included.
Monitor for HIV viral breakthrough (Holkira PM).
2.59-fold ↑ AUC, 1.79-fold ↑ , and 4.58-fold ↑ of simeprevir and 18% ↑ AUC, 31% ↑ of darunavir. Coadministration not recommended  [230].Daclatasvir AUC increased 41%, decreased 23% with coadministration. Changes not considered clinically significant. No dose adjustment is required [234].
Darunavir/cobicistatCoadministration has not been studied but no clinically significant drug interaction expected. In combination with elvitegravir/cobicistat, cobicistat exposure is increased. Clinical significance is unknown but likely not clinically relevant [227].Darunavir plus cobicistat is not recommended with the 3D regimen, which already includes ritonavir (Holkira PM).Not recommended with cobicistat due to risk of significantly increased simeprevir concentrations [230].Coadministration has not been studied but no clinically significant drug interaction is expected.
Lopinavir/ritonavirCoadministration has not been studied. Significant drug interaction not anticipated.Should not be coadministered with HOLKIRA PAK due to the potential for an increase in paritaprevir exposures (Holkira Pak PM).Not recommended with ritonavir, boosted or unboosted HIV protease inhibitors due to risk of significantly increased simeprevir concentrations [230].No clinically significant changes noted with coadministration. No dose adjustment required [234].

CCR5 antagonist
MaravirocCoadministration has not been studied but no clinically significant drug interaction expected.Coadministration has not been studied but maraviroc exposure is expected to be increased by ritonavir. Reduce maraviroc to 150 mg BID or 300 mg daily.Coadministration has not been studied but no clinically significant drug interaction is expected (Galexos PM).Coadministration has not been studied but no clinically significant drug interaction is expected (Daklinza PM).

Key: avoid combination; caution/dose adjustment; acceptable combination OK.
AUC: area under the curve; : concentration minimum; : peak concentration; : trough concentration; BID: twice a day; NNRTI: nonnucleoside reverse transcriptase inhibitor; PI: protease inhibitor; PM: product monogram.