Associate Professor of Medicine
Division of Infectious Diseases
Department of Internal Medicine
Duke University Medical Center
Durham, North Carolina
Susanna Naggie, MD, MHS, has disclosed that she has received funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Tacere.
Patients diagnosed with HIV infection in the contemporary era are commonly prescribed unboosted integrase inhibitor–based regimens, per DHHS and IAS-USA guidance. Among the benefits of these treatment options is their relative lack of interactions with the direct-acting antivirals (DAAs) recommended by the AASLD/IDSA. However, patients stably suppressed on HIV therapy for many years or demonstrating characteristics that disallow use of these “go-to” regimens may present for HCV treatment while receiving a boosted protease or integrase inhibitor–based HIV regimen or a nonnucleoside reverse transcriptase inhibitor. In the forthcoming commentary, I review 2 case scenarios to foster discussion of how best to avoid drug–drug interactions between ART and HCV DAA regimens during treatment of HCV/HIV coinfection.
Case 1: ATV + RTV + FTC/TDF
The first patient is a 32-year-old man with HIV infection stably suppressed on atazanavir (ATV) plus ritonavir (RTV) plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). In terms of lab values, he has an APRI of 0.3, liver elastography of 6.5 kPa, platelet count of 250,000 cells/µL, and eGFR of 110 mL/min. Hepatic function is normal. He recently acquired genotype (GT) 1a HCV and wants to proceed with HCV treatment. What factors should shape how we think about carefully selecting an HCV regimen in the context of HIV coinfection?
Among the main pretreatment characteristics to appraise are his HCV GT, cirrhosis status, treatment experience, and renal function. Based on these parameters, AASLD/IDSA guidelines recommend one of 4 first-line regimens for a treatment-naive patient with GT1a HCV, normal renal function, and without cirrhosis (Table).
Table. AASLD/IDSA Recommendations for First-line HCV Treatment
Next, we must consider which of the recommended HCV regimens may interact with his current HIV regimen, ATV + RTV + FTC/TDF. According to DHHS and AASLD/IDSA guidelines, coadministration of ATV + RTV with GLE/pibrentasvir (PIB) or GZR/EBR is not recommended owing to an increased risk of hepatotoxicity in the setting of higher exposure to GLE or GZR. This limits the choices for DAAs to either SOF/LDV or SOF/VEL. Both are valid options, with the caveat that because TDF is being used, monitoring for tenofovir-associated renal toxicity is advised with either in light of the interaction between VEL or LDV and TDF, which increases tenofovir exposure. Data from 56 patients receiving either RTV or cobicistat (COBI)-boosted regimens in the phase III ASTRAL-5 study suggest that TDF can be administered safely with SOF/VEL without significant changes in creatinine clearance, but study enrollees were required to have, at minimum, an eGFR of 60 mL/min. Thus, if the case patient exhibited reduced renal function (ie, eGFR < 60 mL/min), it may be preferable to switch the TDF component to tenofovir alafenamide (TAF). The results from the ASTRAL-5 study likely translate to SOF/LDV.
My approach would likely favor SOF/LDV over SOF/VEL in this case, as a pangenotypic regimen is not needed. In fact, most HIV drugs can be readily used with SOF/LDV; one exception noted in DHHS guidance is the boosted integrase inhibitor regimen, elvitegravir (EVG)/COBI/FTC/TDF.
Case 2: EVG/COBI/FTC/TAF
The second patient is a 56-year-old woman with stable virologic suppression on EVG/COBI/FTC/TAF. Despite a long-standing GT3 HCV infection, she has never received DAA therapy and is ready to explore her options. Lab results include an APRI of 2.0, liver elastography of 13.5 kPa, platelet count of 110,000 cells/µL, AST of 90 IU/L, ALT of 80 IU/L, eGFR of 95 mL/min, bilirubin of 0.8 mg/dL, and INR of 1.1.
Employing an algorithm as above to this case, we can narrow in on which HCV regimens are AASLD/IDSA recommended for this treatment-naive patient with GT3 HCV, Child-Pugh A cirrhosis, and elevated liver enzymes but normal renal function (Table). Here, the options are fewer: GLE/PIB or SOF/VEL.
Very few safety data are available for coadministration of EVG/COBI/FTC/TAF with GLE/PIB, as the phase III EXPEDITION-2 study enrolled just 1 HCV/HIV-coinfected patient receiving an EVG/COBI-based regimen. Consequently, close monitoring for hepatotoxicity would be advised if GLE/PIB is chosen due to concern for increased exposure of GLE (driven by the patient’s cirrhosis and the pharmacologically boosted antiretroviral regimen) and where there are no data to inform the safety of these combinations.
My approach would be to treat this patient with SOF/VEL for 12 weeks. Before doing so, NS5A resistance associated substitution testing should be performed to assess for Y93H, which, if present, a different regimen should be considered. In this case, that regimen would be SOF/VEL/voxilaprevir (VOX), but this has the same challenge as GLE/PIB, which is increased exposure to an NS3/4A protease inhibitor (eg, VOX or GLE).
Boosted ATV should not be given with GLE/PIB, GZR/EBR, or SOF/VEL/VOX; appropriate options are, then, limited to SOF/LDV and SOF/VEL, with further decision making about which regimen to select based on patient and viral factors. For EVG/COBI-based regimens, GZR/EBR should be avoided. For EVG/COBI/FTC/TDF specifically, SOF/LDV is also not recommended in DHHS guidelines. Be aware that monitoring for tenofovir toxicity is commonly advised, especially when TDF is coadministered with SOF/LDV, SOF/VEL, or alongside boosted antiretrovirals. What key ART/DAA interactions do you find yourself avoiding in practice? Please join this conversation on the optimal treatment of HCV/HIV coinfection by answering the polling question or leaving a note in the comments box.