Associate Professor of Medicine
Division of HIV, ID, & Global Medicine
San Francisco General Hospital
University of California, San Francisco
San Francisco, California
Annie Luetkemeyer, MD, has disclosed that she has received funds for research support (paid to her institution) from AbbVie, Gilead Sciences, Merck, and Proteus.
I recently saw 2 persons living with HIV for whom I was prescribing first-line HCV treatment. For different reasons, each patient provided a challenge. I’d like to invite you to review these cases with me to see if you’d do anything differently.
The first patient is a 64-year-old man with hypercholesterolemia and hypertension (controlled with ezetimibe/simvastatin 10 mg/40 mg, benazepril 20 mg, and aspirin) and living with HIV (suppressed with dolutegravir/abacavir/lamivudine once daily). He became infected with genotype 1b HCV and wants to proceed with HCV treatment. What considerations about these medications should one take into account before prescribing HCV treatment?
Individuals living with HIV can present challenges when selecting an HCV regimen, due to antiretroviral and other medications that they may be taking, the number of which can increase as patients age. Drug–drug interactions must be considered carefully when adding new medications to their regimens.
The first step is to select appropriate HCV treatment options; the AASLD/IDSA guidelines are an excellent resource. HCV medications should then be evaluated for potential drug–drug interactions using an appropriate, current resource. University of Liverpool and Toronto General are 2 excellent resources.
Given that it is not possible to study all drug–drug interactions, databases do not always entirely agree but can provide valuable guidance based on both anticipated drug interactions as well as clinical pharmacokinetic data when they are available.
This patient’s ART is compatible with all first-line HCV regimens; his statin is the drug that should cause concern. He is receiving one of the statins—simvastatin—whose drug levels are affected by the currently available direct-acting antiviral (DAA) drugs. The question we must consider is whether to change the statin or reduce its dose, or whether we can choose an HCV regimen that is compatible.
Selecting Statin-Compatible DAAs
Among the first-line HCV choices, glecaprevir/pibrentasvir is contraindicated with atorvastatin, lovastatin, or simvastatin owing to concern for increased statin concentrations. This increase in statin levels results from inhibition of P-gp, BCRP, and OATP1BI by glecaprevir/pibrentasvir and may lead to toxicity.
Fluvastatin, pitavastatin, pravastatin, and rosuvastatin levels may also be increased by glecaprevir/pibrentasvir; reduction to the lowest possible statin dose is recommended with monitoring for statin toxicity, including possible rhabdomyolysis.
Ezetimibe concentrations may also be increased by coadministration with glecaprevir/pibrentasvir.
In terms of the other first-line HCV regimens—elbasvir/grazoprevir, sofosbuvir/ledipasvir, or sofosbuvir/velpatasvir—I would prefer a statin that will be least affected by DAA coadministration (typically pitavastatin or pravastatin), use the lowest dose, and monitor for possible toxicity. The only combinations that do not have anticipated increases in statin concentrations are elbasvir/grazoprevir coadministered with pravastatin or pitavastatin and sofosbuvir/velpatasvir coadministered with pravastatin (Table 1).
Table 1. Administration of HCV DAA Regimens With Statins: My Approach
My strategy—when feasible—is to change to a statin that is less affected by DAA coadministration for the few months required for HCV treatment. Glecaprevir/pibrentasvir can raise ezetimibe levels, so the lowest dose of this medication should be used, if it is required during HCV treatment. Ezetimibe can be coadministered with sofosbuvir/ledipasvir and sofosbuvir/velpatasvir without dose adjustment.
For this patient, I recommended that he change his statin to pravastatin 40 mg and administer ezetimibe 10 mg separately during treatment with sofosbuvir/velpatasvir or elbasvir/grazoprevir for 12 weeks. If his insurance had required starting HCV therapy with glecaprevir/pibrentasvir or sofosbuvir/ledipasvir, I would still change to pravastatin, but I would consider reducing the pravastatin dose to < 20 mg/day during the period of coadministration and potentially stopping the ezetimibe during glecaprevir/pibrentasvir coadministration.
With all these choices, this patient’s ART regimen should be unaffected by the other drugs in the regimen.
My second patient was a younger man (40 years of age) with a long history of gastritis who required ongoing treatment with omeprazole 40 mg/day. He was recently found to be coinfected with HIV and genotype 1a HCV. His most recent HIV-1 RNA was 76,000 copies/mL and his CD4+ cell count was 375 cells/mm³. His HCV RNA was 125,000 IU/mL and he had no cirrhosis.
How would his current drug regimen affect your treatment choices for HCV?
In this situation, 2 choices for HCV treatment should be avoided: sofosbuvir/velpatasvir and sofosbuvir/ledipasvir, which require acid for optimal gastric absorption. When prescribing these regimens, coadministration of proton pump inhibitors, H2 blockers, and even over-the-counter antacids should be avoided if possible. If it is necessary to continue acid blockers and if other HCV treatment choices are not available, the acid blockers must not exceed omeprazole dose equivalent of 20 mg and administration should be separated temporally from the DAA (Table 2).
Table 2. Administration of HCV DAA Regimens With Acid-Reducing Agents
Proton pump inhibitors also decrease glecaprevir concentrations by approximately 25%, but studies suggest that no dose adjustment of glecaprevir/pibrentasvir is required. In an analysis of registrational studies evaluating HCV treatment outcomes with individuals on H2 blockers, low-dose proton pump inhibitors (omeprazole dose equivalent of ≤ 20 mg/day), and high-dose proton pump inhibitors (omeprazole dose equivalent of > 20 mg/day) coadministered with glecaprevir/pibrentasvir, there was no difference in SVR12 outcomes among the 3 groups.
Nonetheless, it is prudent to reduce proton pump inhibitor dose to the lowest amount clinically indicated during HCV treatment and overall to consider the clinical indication for ongoing higher-dose proton pump inhibitors.
I have found that the University of Liverpool Web site and the Toronto General Hospital database have been invaluable resources when approaching ART and DAA selection in a patient with polypharmacy.
What resources do you use to help you make informed decisions about patients with polypharmacy? Please leave your comments below.