Approximately, 30% of people infected with HIV are estimated to be coinfected with the hepatitis C virus (HCV).1,2 In the era of highly active antiretroviral therapy, chronic HCV infection has emerged as a major cause of morbidity and mortality in HIV-infected individuals to the extent that liver-related death rates among this patient population are similar to those for AIDS-related death.3–6 Until recently, the standard of care for chronic HCV was 24–48 weeks of pegylated interferon alpha (peginterferon) plus ribavirin in all patients, with the addition of 1 protease inhibitor, boceprevir, or telaprevir, in those with genotype 1 HCV infection.3,4,7 In HIV-coinfected patients, treatment of HCV with peginterferon–ribavirin leads to disappointingly low rates of sustained virologic response (SVR) and is poorly tolerated; small studies have shown some benefit of adding a protease inhibitor to the peginterferon regimen.3,4,8,9 However, the use of boceprevir and telaprevir in HCV/HIV-coinfected patients is complicated by their interaction with many antiretrovirals, low barrier to resistance, adverse side effects, and high pill burden.3,4,8,9
Sofosbuvir is a first-in-class HCV nonstructural (NS) 5B polymerase inhibitor with potent antiviral activity against all HCV genotypes.10–12 In patients with HCV infection alone, sofosbuvir was associated with high SVR rates and barrier to resistance and had better tolerability than interferon-based regimens. Sofosbuvir is rapidly absorbed and extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. Sofosbuvir also undergoes extrahepatic metabolism to form GS-331007, the predominant circulating metabolite, which is principally eliminated in urine.13 No dose adjustment is required for hepatic impairment or for mild, or moderate renal impairment. Extensive drug–drug interaction studies in healthy volunteers indicate that sofosbuvir can be safely coadministered with a wide range of drugs, including antiretrovirals due in part to sofosbuvir's lack of effect on cytochrome P450 enzymes.14,15 Potent intestinal inducers of p-glycoprotein (such as rifamycins and St. John's wort) may significantly reduce sofosbuvir levels and should not be used with sofosbuvir. Sofosbuvir has been approved recently for use in HCV-infected patients, including those with HIV-1 coinfection.13
This report describes a 2-part study in patients coinfected with HCV/HIV: part A assessed potential drug interactions between commonly used antiretrovirals and sofosbuvir; part B was a pilot efficacy and safety assessment of short-course (12 weeks) treatment with sofosbuvir plus peginterferon–ribavirin.
Study Design and Patients
Part A followed a phase 1, 5-cohort, open-label, multiple-dose, single-sequence, single-site design; part B followed a phase 2, open-label, single-arm, single-site design. The study was conducted between February 2012 and December 2013 at 1 site in Puerto Rico.
Male and female patients aged ≥21 years with chronic HCV infection (genotype, 1–6) and HCV RNA levels ≥104 IU/mL at screening were eligible. Patients had to have no evidence of cirrhosis. For part A, patients had to have stable HIV disease with CD4 cell counts ≥200 cells per cubic millimeter and HIV-1 RNA values <200 copies per milliliter, and be receiving a stable protocol-allowed antiretroviral regimen at least 4 weeks before screening. Patients were otherwise in good health as assessed by medical history and physical examination. Patients showed no evidence of opportunistic infections within 3 months of dosing and were naive to treatment with NS5B polymerase inhibitors. For part B, patients were naive to HCV treatment (defined as no history of treatment with interferon or ribavirin) and receiving a stable antiretroviral regimen for >8 weeks before screening. Patients had to have CD4 cell counts >200 cells per cubic millimeter, and screening HIV-1 RNA levels <50 copies per milliliter. Additional inclusion criteria were creatinine clearance ≥60 mL/min, alanine aminotransferase levels ≤10 × upper limit normal, and hemoglobin concentration in female and male patients of ≥11 and ≥12 g/mL, respectively. For part B, permitted HIV antiretroviral regimens were emtricitabine/tenofovir plus either efavirenz, atazanavir/ritonavir-boosted, arunavir/ritonavir-boosted, raltegravir, or rilpivirine (further details are provided in the Appendix, available as Supplemental Digital Content, https://links.lww.com/QAI/A648).
Patients provided written informed consent before screening. The protocol was approved by the Institutional Ethics Committee and the study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. This study is registered with ClinicalTrials.gov, number NCT01565889.
For part A, patients were enrolled into the cohort corresponding to the antiretroviral regimen they had been receiving to manage their HIV. Patients in cohort 1 received sofosbuvir 400 mg plus Atripla [efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg (Gilead Sciences, Foster City, CA)] in the fasted state once daily (evening) for 7 days (see Table S1 in Appendix, Supplemental Digital Content, https://links.lww.com/QAI/A648). Patients in cohort 2 were given sofosbuvir 400 mg and efavirenz 600 mg (Bristol-Myers, Princeton, NJ), both administered in the fasted state once daily (evening) for 7 days, and zidovudine 300 mg/lamivudine 150 mg (Teva Pharmaceuticals, Sellesville, PA) administered twice daily for 7 days, in the morning with no regard to food and in the evening in the fasted state. Patients in cohort 3 received sofosbuvir 400 mg, atazanavir 400 mg (Bristol-Myers) boosted with ritonavir 100 mg (Abbott Laboratories, North Chicago, IL), and emtricitabine 200 mg/TDF 300 mg (Gilead Sciences). Patients in cohort 4 were given sofosbuvir 400 mg, darunavir 800 mg (Janssen Therapeutics, Titusville, NJ) boosted with ritonavir 100 mg, and emtricitabine 200 mg/TDF 300 mg. Cohort 3 and cohort 4 regimens were administered in the fed state once daily (morning) for 7 days. Patients in cohort 5 received sofosbuvir 400 mg and emtricitabine 200 mg/TDF 300 mg, both administered in the fed state once daily (morning) for 7 days, and raltegravir 400 mg (Merck, Whitehouse Station, NJ), administered twice daily, in the fed state in the morning and with no regard to food in the evening. The treatment period was 14 days: patients received sofosbuvir in combination with their antiretroviral regimen for the first 7 days and continued with only their antiretroviral regimen for the remaining 7 days.
For part B, patients received once-daily oral sofosbuvir 400 mg, once-weekly subcutaneous injections of peginterferon alfa-2a 180 μg (Pegasys; Genentech, San Franscisco, CA), and twice-daily oral weight-based ribavirin (1000–1200 mg; Ribasphere, Kadmon Pharmaceuticals, LLC, Warrendale, PA); all were given for 12 weeks.
In part A, blood samples were collected on days 0 and 7. Plasma concentrations of sofosbuvir (parent compound) and its predominant metabolite, GS-331007 (circulating inactive nucleoside metabolite), and of efavirenz, emtricitabine, tenofovir (the measurable analyte of TDF), zidovudine, lamivudine, atazanavir, ritonavir, darunavir, and raltegravir were determined, as applicable by validated high-performance liquid chromatography-tandem mass spectroscopy methods. Noncompartmental analysis of individual plasma concentration–time data was conducted using WinNonlin (Professional version 6.3; Pharsight, Mountain View, CA). The following parameters were derived: area under the concentration versus time curve over the dosing interval (AUCtau), maximum plasma concentration (Cmax), and concentration at the end of dosing interval (Ctau).
For part A, blood samples to determine serum HCV RNA concentrations were collected throughout the study; concentrations were determined by Roche COBAS TaqMan HCV Test version 2.0 for use with the High Pure System [Roche Molecular Systems, Pleasanton, CA; lower limit of quantitation (LLOQ) 25 IU/mL].
For part B, blood samples to determine serum HCV RNA concentrations were collected throughout the study; concentrations were determined as described above.
For viral resistance analysis in both study parts, blood samples were collected before dosing (baseline) and in each subsequent visit; standard population sequencing of the HCV NS5B-encoding region was performed.
Safety assessments included monitoring of adverse events and concomitant medications, clinical laboratory tests, vital sign measurements, and physical examination. For part A, 12-lead electrocardiograms were also performed. Blood samples to determine HIV RNA concentrations were collected throughout the study; concentrations were determined by Roche COBAS Ampliprep/COBAS TaqMan HIV-1 Test version 2.0 (Roche Molecular Systems; LLOQ 48 IU/mL). An HIV-1 breakthrough was defined as HIV-1 RNA levels ≥50 copies per milliliter at 2 consecutive visits.
Sample size for part A was based on feasibility; for part B, a sample size of 20 patients was estimated to provide 99% power to detect 40% improvement in SVR rate assuming a spontaneous rate of ≤5% using a 2-sided exact 1-sample binomial test with a significance level of 0.05.
For part A, the primary end point was to assess whether sofosbuvir significantly affected the pharmacokinetics of efavirenz, emtricitabine, tenofovir, zidovudine, lamivudine, atazanavir, ritonavir, darunavir, or raltegravir in patients coinfected with HCV/HIV by comparing log-transformed AUCtau, Cmax, and Ctau for each antiretroviral when coadministered with sofosbuvir (test, day 7) versus administration alone (reference, day 0). For each analyte, a parametric (normal theory) analysis of variance was performed using a mixed-effects model with treatment as a fixed effect and patient as a random effect. The potential effect of antiretroviral therapy on the pharmacokinetics of sofosbuvir, or GS-331007 was a secondary end point and was also assessed by analysis of variance. Natural log-transformed AUCtau, Cmax, and Ctau were used to compare data obtained in this study (test treatment) with data obtained in previous studies conducted in patients with HCV monoinfection who received only sofosbuvir therapy for 7 days (reference).16 The geometric least square mean ratio and associated 90% confidence interval were calculated for each comparison. It was concluded that there was a difference between test and reference pharmacokinetics if the 90% confidence intervals of the geometric least square mean ratios did not encompass 100%. All patients who received at least 1 dose of study treatment were included in the safety analysis. Patients who received study treatment and for whom evaluable pharmacokinetic profiles were available were included in the pharmacokinetic analysis.
For part B, the primary efficacy end point was the proportion of patients with SVR at week 12 (SVR12; defined as HCV RNA <LLOQ 12 weeks after end of treatment). Secondary efficacy end points included SVR4 and SVR24, HCV viral breakthrough (defined as on-treatment HCV RNA ≥LLOQ after previous achievement of HCV RNA <LLOQ), and relapse (defined as HCV RNA ≥LLOQ after achievement of HCV RNA <LLOQ at the last study visit). All patients who received at least 1 dose of study treatment were included in the safety and efficacy analyses.
In part A, 38 patients were enrolled and received at least 1 dose of study treatment; all patients completed the study except 1 patient in cohort 1 who withdrew consent on day 1 after receiving study treatment. Patient demographic, baseline, and disease characteristics were broadly similar across cohorts (Table 1). In part B, 23 patients were enrolled (of whom 9 were enrolled in part A) and received at least 1 dose of study treatment. Three patients did not complete study treatment and one was lost to follow-up. In both study parts, the majority of patients were male, white, Hispanic/Latino, and had HCV genotype 1a infection (Table 1).
In part A, only modest changes were observed in the pharmacokinetic parameters of the evaluated antiretrovirals after coadministration with sofosbuvir (Table 2). The greatest change observed was a 40% increase in Cmax of tenofovir. None of the observed changes was considered clinically significant. The largest increases (range, 42%–448%) in the exposure of sofosbuvir, and GS-331700 occurred after sofosbuvir coadministration with ritonavir-boosted atazanavir plus emtricitabine/TDF and ritonavir-boosted darunavir plus emtricitabine/TDF (Table 3). The modest changes observed in sofosbuvir exposure on coadministration with atripla or efavirenz plus zidovudine/lamivudine were consistent with sofosbuvir pharmacokinetics in the fed versus fasted state. The changes observed in the pharmacokinetics of sofosbuvir and GS-331007 were not considered clinically significant.
In part A, the pharmacodynamic assessment revealed a rapid decline in HCV RNA levels with a mean reduction of >4 log10 IU/mL after 7 days of treatment with sofosbuvir (see Figure S1 in Appendix, Supplemental Digital Content, https://links.lww.com/QAI/A648).
In part B, the efficacy analysis showed a rapid decline in HCV RNA levels with 11/23 (47.8%) patients exhibiting HCV RNA levels <LLOQ at week 1 and 22/23 (95.7%) patients at week 2; by week 4 and at each subsequent assessment, 23/23 (100%) patients had HCV RNA levels <LLOQ. Overall, 21 (91.3%) patients achieved the primary efficacy end point of SVR12. The same 21 (91.3%) patients achieved the secondary efficacy end points of SVR4 and SVR24. No patient experienced on-treatment HCV virologic failure (defined as breakthrough, rebound, or nonresponse). Of the 2 patients who did not achieve SVR12, 1 discontinued study treatment after 6 weeks and the other completed study treatment but subsequently relapsed. Both patients had an HCV genotype 1a infection and a non-CC IL28 genotype. One of the patients was receiving tenofovir/emtricitabine/efavirenz and had a baseline CD4 count of 546 cells per cubic millimeter; the other patient was receiving atazanavir ritonavir-boosted plus tenofovir/emtricitabine and had a baseline CD4 count of 172 cells per cubic millimeter.
No S282T or other nucleoside inhibitor resistance-associated variants (namely, S96T, N142T, L159F, M289L, L320F, and V321A) were found in any patient at baseline or after 7 days (part A) or 12 weeks (part B) of study treatment.
In part A, 5 of 38 (13.2%) patients reported adverse events. No deaths, serious adverse events, or treatment discontinuations due to an adverse event were reported. No adverse event was reported by more than 1 patient. All adverse events were grade 1 or 2. The only adverse event judged related to study treatment was a grade 2 episode of hemorrhoids. Five (13.2%) patients experienced grade 3 laboratory abnormalities; none was reported as an adverse event. All 8 patients in cohort 3 reported grade 1 or 2 increases in total bilirubin at screening and baseline. Addition of sofosbuvir did not lead to any further increases in total bilirubin.
In part B, 16 of 23 (69.6%) patients reported adverse events; no deaths or serious adverse events were recorded (Table 4). Two patients discontinued study treatment due to an adverse event: grade 2 altered mood and grade 3 anemia; both were judged related to study treatment. The altered mood event occurred on day 42 of treatment, at which time the patient discontinued all study treatment. The event resolved 15 days after cessation of study treatment; the patient remained in the study and had HCV RNA levels <LLOQ 12 weeks after discontinuing treatment. The patient with anemia discontinued peginterferon and ribavirin when the event occurred on day 42 of treatment; the patient subsequently discontinued from all study treatment and withdrew consent. Grade 3 adverse events were reported by 7 (30.4%) patients: hyperbilirubinemia (3 patients, 13.0%), and anemia, leukopenia, and neutropenia (each in 2 patients, 8.2%); all judged related to study treatment. The cases of hyperbilirubinemia occurred in patients receiving atazanavir as part of their antiretroviral regimen. No grade 4 adverse events were reported. Three (13.0%) patients reported grade 3 laboratory abnormalities and 4 (17.4%) patients grade 4; none required intervention. No renal adverse events or graded elevations in creatinine were observed during part B of this study.
In both part A and part B, the CD4 cell count decreased during the treatment period, which was coincident with a decrease in total lymphocytes. However, there was no change in CD4% (Table 5). No patient required intervention or prophylactic medication as a consequence of the decrease in CD4 cell counts. Additionally, HIV-1 RNA levels remained stable during the study, and there was no evidence of HIV viral breakthrough; no patient had to change antiretroviral regimen. No clinically significant changes in vital signs and electrocardiogram (part A only) results were reported.
In the present study conducted in HCV/HIV-coinfected patients, sofosbuvir had no clinically significant effect on the pharmacokinetics of the antiretrovirals evaluated with only modest changes observed. These changes do not preclude sofosbuvir coadministration with the antiretrovirals evaluated. Also, no clinically significant changes were observed in the pharmacokinetics of sofosbuvir and GS-331007, although there were increased exposures of these compounds after coadministration of sofosbuvir with ritonavir-boosted atazanavir plus emtricitabine/TDF or ritonavir-boosted darunavir plus emtricitabine/TDF. These changes were smaller or of equal magnitude to those observed in a study that assessed potential drug interactions between sofosbuvir and cyclosporine and which did not require any dose modification.13 In addition, studies performed in healthy volunteers demonstrated no clinically significant drug interactions between sofosbuvir (or its metabolites) and efavirenz, emtricitabine, tenofovir, darunavir, ritonavir, rilpivirine, or raltegravir.14 The results from part A of this study together with those previously reported indicate that sofosbuvir may be coadministered with all antiretrovirals evaluated. Future studies will be required to identify any potential interactions with other and newer anti-HIV agents such as abacavir.
In part B, it was demonstrated that a 12-week regimen of sofosbuvir plus peginterferon–ribavirin led to a rapid decline in HCV RNA levels and that 91.3% of patients achieved SVR12. These results are supported by those previously reported by large phase 3 studies conducted in patients with HCV monoinfection receiving the same regimen and in which similar viral kinetics and SVR12 rates of 90% were observed.11 Although our study was limited by the small sample size, the SVR12 rates reported were higher than those previously described for boceprevir or telaprevir plus peginterferon–ribavirin in the HCV/HIV-coinfected population (63% and 61%–74%, respectively).8,9,17 In addition, both boceprevir and telaprevir are known to have a low genetic barrier to the development of resistance with many resistance-associated variants reported.18 In fact, resistance-associated variants have been associated with HCV breakthrough in patients coinfected with HCV/HIV treated with boceprevir8 or telaprevir.9 In our study, no resistance-associated variants were observed at baseline or after sofosbuvir treatment and accordingly, no patient experienced an HCV virologic breakthrough while on treatment. Altogether, the efficacy results obtained with our 12-week regimen suggest that the addition of a potent direct-acting antiviral with a high barrier to resistance, such as sofosbuvir, may overcome the underlying differences in immune status that have been thought responsible for the low response rates to HCV treatment in patients coinfected with HCV/HIV.4,19–21
The profile of adverse events reported in this study is consistent with that associated with administration of peginterferon–ribavirin to HCV/HIV-coinfected patients.19–21 The frequency of adverse events was also lower than that seen with a similar regimen in HCV-monoinfected patients.11 However, given the single-arm design of this study, the contribution of sofosbuvir to the overall adverse event profile cannot be determined definitively.
The event of altered mood that led to a patient discontinuing study treatment was deemed associated with interferon. Also, the decrease in CD4 count but not of CD4% was coincident with a decrease in total lymphocytes and similar findings have been reported for peginterferon–ribavirin therapy in patients with HCV/HIV coinfection.19–21 Importantly, the observed increase in sofosbuvir and GS-331007 exposure was not reflected in an increase in the frequency or intensity of adverse events in part A. Episodes of elevated bilirubin were noted exclusively in patients taking atazanavir, a finding that has been seen in studies with concurrent use of atazanavir and peginterferon-ribavirin.22 Of note, none of these episodes required a change in antiretroviral or study drugs. No renal adverse events were observed in part B of this study suggesting no significant changes in TDF levels with this treatment. This finding is consistent with a recently published phase 3 study evaluating sofosbuvir and ribavirin in HIV/HCV-coinfected patients.23 No HIV breakthrough was seen in our study underscoring the safe and potent HIV suppression on coadministration of sofosbuvir with antiretrovirals commonly used for HIV treatment. Taken together, the safety and efficacy data suggest that our 12-week regimen has the potential to offer a novel therapy with an improved profile for patients with HCV/HIV.
In conclusion, no clinically significant drug interactions were observed in patients coinfected with HCV/HIV after coadministration of sofosbuvir with several antiretrovirals. In this population, sofosbuvir was safe when administered in combination with several antiretrovirals or peginterferon–ribavirin. The pilot assessment revealed that sofosbuvir plus peginterferon–ribavirin was highly effective in HCV/HIV-coinfected patients. Phase 3 studies exploring all-oral, interferon-free sofosbuvir regimens in patients coinfected with HCV/HIV are currently ongoing.
The authors thank the staff and patients who participated in the study. Severina Moreira, PhD, from Niche Science and Technology (Richmond-Upon-Thames, London, United Kingdom) provided writing and editorial support during development of this article; these services were paid for by Gilead Sciences.
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