HIV/HCV therapy with ledipasvir/sofosbuvir after randomized switch to emtricitabine-tenofovir alafenamide-based single-tablet regimens

Introduction Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants. Methods Participants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12). Results Of 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93–99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens. Conclusion This study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.


LIST OF IN-TEXT FIGURES
Study Design: Randomized, multicenter, open-label, 2-part study in adult male and female subjects with HIV who are co-infected with chronic genotype (GT) 1 HCV infection. Subjects will have one of the following: 1) no cirrhosis and no prior HCV treatment (treatment-naïve); 2) no cirrhosis and have received HCV treatment only with interferon (IFN) +/-ribavirin (RBV) or IFN + RBV + an HCV protease inhibitor (PI) (treatment-experienced); or 3) compensated cirrhosis and no prior HCV therapy (treatment-naïve).
Subjects will be on stable ARV therapy for 6 months prior to screening and with HIV RNA < 50 copies/mL.

Part 1:
Approximately 240 subjects will be randomized 1:1 to switch from stable ARV therapy to one of the following treatments. Randomization will be stratified by race (black vs. non-black).
 Treatment Group 1: Switch from 2 nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) plus a third ARV agent to E/C/F/TAF fixed dose combination (FDC) (n = 120)  Treatment Group 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC (n = 120) All subjects will receive 8 weeks of treatment and will have an assessment of safety, tolerability and HIV-1 RNA values at the conclusion of 8 weeks. Plasma samples collected at Week 6 (laboratory visit only) will be included in assessing virologic suppression of HIV-1 RNA at Week 8. Subjects who tolerate the switch to E/C/F/TAF FDC or F/R/TAF FDC and maintain virologic suppression of HIV-1 RNA < 50 copies/mL will continue to Part 2. HIV treatment will be continued until their SVR12 assessment.
Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or F/R/TAF FDC treatment, subjects will continue their HIV treatment and initiate 12 weeks of LDV/SOF HCV therapy.
 LDV/SOF FDC tablet once daily for 12 weeks After LDV/SOF therapy, subjects will continue their HIV treatment and be followed for safety and efficacy for an additional 12 weeks to determine the HCV SVR12 endpoint and HIV safety and efficacy endpoints. 240 subjects (approximately 120 subjects randomized to each of E/C/F/TAF FDC or F/R/TAF FDC).
Target Population: Chronic GT 1 HCV, HIV-coinfected adults who do not have cirrhosis and are HCV treatment-naïve or treatment-experienced with IFN +/-RBV +/-PI. Compensated cirrhotic subjects must be treatment-naïve. Subjects are on a stable HIV regimen with 2 NRTI + 3 rd agent with suppressed HIV RNA.

Duration of Treatment:
Part 1: Subjects will be randomized to receive E/C/F/TAF or F/R/TAF for 8 weeks.
Part 2: Subjects will receive 12 weeks of LDV/SOF and continue their randomized F/TAF-based regimen for 12 weeks after completion of LDV/SOF (total approximately 24 weeks in Part 2).

Diagnosis and Main
Eligibility Criteria: HIV/HCV co-infected adult subjects who meet the following criteria will be given the option to participate in the study:  Chronic GT 1, HCV infected, male and nonpregnant/non-lactating female subjects, without cirrhosis, treatment-naïve or treatment-experienced with IFN +/-RBV +/-HCV PI. Compensated cirrhotic subjects must be HCV treatment-naïve. No prior treatments with NS5A and NS5B or any HCV direct acting antivirals, except boceprevir, telaprevir and simeprevir, in combination with IFN and RBV.
 Currently on an ARV regimen (2 NRTI + a third agent) without change for 6 months prior to screening. Documented plasma HIV-1 RNA levels < 50 copies/mL (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) for ≥ 6 months preceding the Screening visit. After reaching HIV-1 RNA < 50 copies/mL, single values ("blips") of HIV-1 RNA ≥ 50 copies/mL followed by resuppression is allowed. For subjects with 3 or more prior ARV regimens, a regimen history should be provided for approval by the Sponsor.
 Have no documented resistance to any of the HIV study agents at any time in the past, including but not limited to the reverse transcriptase resistance mutations K65R, K70E, K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C, M230I/L, the combination of K103N+L100I, or 3 or more thymidine analog associated mutations (TAMs) that include M41L or L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R). If a historical genotype prior to first ARV is not available or subject had 3 or more prior ARV regimens, subject will have proviral genotype analysis for archived resistance prior to Day 1.
 No history of HIV virologic failure.
 No evidence of Hepatitis B infection.
Study Procedures/ Frequency: Screening assessments will be completed within 42 days of the Day 1 visit.
After consent is obtained, screening assessments will include physical examination, medical history, historical HIV resistance test collection (if available; HIV DNA archive genotype if no historical HIV genotype available), height, weight, vital signs, 12-lead electrocardiogram (ECG), screening procedure related adverse events (AEs), concomitant medications (CM), safety laboratory tests (including hematology, chemistry, and coagulation), HCV and HIV RNA, serology (HIV, HCV, HBV), HCV genotyping, assessment of the absence of cirrhosis, serum β-hCG (females of child bearing potential only), IL28B genotyping, and urinalysis.
On treatment assessments will include AEs, CMs, study drug dosing adherence (including pill count), physical examination, weight, vital signs, safety laboratory tests, HCV and HIV RNA, urine pregnancy tests (females of child bearing potential only).

Statistical Methods:
This is a two part, randomized (for HIV therapy) multicenter study to evaluate the efficacy and safety of switching to a F/TAF-based regimen in HCV co-infected subjects on a current suppressive ARV regimen.
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks post HCV treatment) in the HCV Full Analysis Set. The primary analysis will use a two-sided exact one-sample binomial test at the 0.05 significance level and construct an associated two-sided exact 95% confidence interval (CI).
Secondary efficacy analyses will evaluate the proportion of subjects with HCV RNA < LLOQ at 4 weeks post coadministration of LDV/SOF treatment. Assessment of HIV-1 RNA ≥ 50 copies/mL (virologic failure) will be done at 24 weeks after start of the F/TAF-based regimen using modified FDA snapshot algorithm. Safety analyses will evaluate adverse events (clinical and laboratory) during switch to F/TAF-based regimen and during coadministration with LDV/SOF treatment. Additional safety analyses will evaluate the proportion of subjects who discontinued from study treatment (HIV or HCV) for an AE.
Additional endpoints to be studied will include the effect of therapy on health-related quality of life.
Assuming that at least 94% of subjects achieve HCV SVR12, the 95% CI around the SVR12 rate will be ± 3.2% using exact methods.
The assumed SVR12 rate will have at least 85% power to be greater than 6 percentage points from a performance goal of 88% by using a two-sided exact one-sample binomial test at significance level of 0.05.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) including archiving of essential documents.

General Information
Tenofovir alafenamide TAF,-yl)-1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is a second generation oral prodrug of TFV, a nucleotide analog that inhibits HIV-1 reverse transcription. TFV is metabolized intracellularly to the active metabolite, TFV-DP, a competitive inhibitor of HIV-1 reverse transcriptase (RT) that terminates the elongation of the viral DNA chain. In the development of TAF, three forms of the drug substance have been used in various studies: GS-7340, synonym for GS-7340 as the free base; GS-7340-02, synonym for TAF monofumarate (1:1) molar ratio of TAF to fumaric acid; and GS-7340-03 as the hemifumarate (2:1) molar ratio of TAF to fumaric acid. GS-7340-03, also known as TAF fumarate, is considered comparable based on physical/chemical properties to GS-7340-02 that has been used in previous studies. GS-7340-02 and GS-7340-03 exist as the free base, TAF (GS-7340), in blood and biological fluids.
For further information on the preclinical pharmacology and toxicology of TAF, refer to the current Investigator's Brochure (IB).

Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF, Genvoya ® )
Elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs) are co-formulated into a single-tablet regimen, E/C/F/TAF, or Genvoya ® . E/C/F/TAF is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of the regimen. E/C/F/TAF is not recommended in patients with estimated creatinine clearance below 30 mL per minute. The efficacy and safety of E/C/F/TAF continue to be evaluated in a broad clinical development program. Available data from key studies are described in the most current version of the E/C/F/TAF IB. The details of the key clinical studies are provided below.
 Study GS-US-292-0102 is a Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study which evaluated the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen for the initial treatment of HIV-1 infection. Antiretroviral naive adults with HIV-1 RNA ≥ 5000 copies per milliliter and a CD4 count ≥ 50 cells per microliter were randomized 2:1 to receive an STR of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 48 weeks. Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of virologic suppression (< 50 HIV copies per milliliter) at Week 24 ( Patients on E/C/F/TAF had higher increases in total cholesterol, low density lipoprotein, and high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. Treatment-naive patients given the STR that contained either TAF or TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and bone mineral density. The efficacy data from this Phase 2 study supported the Phase 3 studies and provided initial evidence of durable efficacy; 87.5% of subjects who received E/C/F/TAF achieved and maintained HIV-1 RNA < 50 copies/mL through Week 96 (M = F).
 GS-US-292-0104 and GS-US-292-0111 are two Phase 3, randomized double-blind, double-dummy, multicenter, active-controlled studies which evaluated the efficacy and safety of two single-tablet regimens, E/C/F/TAF vs E/C/F/TDF. Key inclusion criteria were estimated creatinine clearance of at least 50 mL per min and genotypic sensitivity to study drugs. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at Week 48 as defined by the US Food and Drug Administration (FDA) snapshot algorithm (pre-specified noninferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. Secondary endpoints were at Weeks 96 and 144. 1733 patients (866 E/C/F/TAF and 867 E/C/F/TDF) were enrolled (or completed the study). E/C/F/TAF was non-inferior to E/C/F/TDF, with 92% of (800/866) patients in the TAF group and 90% of (784/867) patients in the TDF group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2.0%, 95% CI -0.7 to 4.7). Patients given E/C/F/TAF had significantly smaller mean serum creatinine increases than those given E/C/F/TDF (0.08 vs 0.12 mg/dL; p < 0.001), significantly less proteinuria (median % change -3 vs 20; p < 0.001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1.30 vs -2.86; p < 0.001) and hip (-0.66 vs -2.95; p < 0.001) at 48 weeks. At 96 weeks, 86.6% in the E/C/F/TAF arm and 85.2% in the E/C/F/TDF arm had HIV-1 RNA < 50 c/mL (difference 1.5%; 95%CI [-1.8%, 4.8%]). With E/C/F/TAF, decreases in lumbar spine and hip bone mineral density and proteinuria were significantly less and creatinine increases were significantly smaller. These longer-term data support the use of E/C/F/TAF as a safe, well-tolerated and durable regimen for initial HIV-1 treatment. ). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the E/C/F/TAF group compared with those in the TDF-containing regimen group.
 GS-US-292-0112 is a Phase 3, single-arm, open-label study which evaluated the efficacy and safety of E/C/F/TAF in virologically suppressed, HIV-infected subjects with estimated creatinine clearance of 30-69 mL/min over 144 weeks. The primary endpoint was the change from baseline in glomerular filtration rate estimated using various formula. A total of 242 virologically suppressed patients enrolled and switched treatment to E/C/F/TAF. Subject baseline characteristics were mean age 58 years, 18% black, 39% hypertension, 14% diabetes. Through Week 48, no significant change in estimated CrCl was observed. Two patients (0.8%) discontinued study drug for decreased creatinine clearance, neither had evidence of renal tubulopathy and both had uncontrolled hypertension. Subjects had significant improvements in proteinuria, albuminuria, and tubular proteinuria (p < 0.001 for all). Hip and spine bone mineral density significantly increased from baseline to Week 48 (mean percent change +1.47 and +2.29, respectively, p < 0.05). 92% (222 patients) maintained HIV-1 RNA < 50 copies/mL at Week 48. The findings of this study support the use of E/C/F/TAF in patients with renal impairment down to an eGFR CG of 30 mL/min.

Clinical Trials of Emtricitabine/Rilpivirine/Tenofovir Alafenamide (F/R/TAF, Odefsey ® ) Fixed Dose Combination
The details of the key clinical studies are provided below. Please refer to the IB for additional information on the F/R/TAF FDC.  Study GS-US-337-0108 (ION-3) was a Phase 3, open-label study, which randomly assigned 647 previously untreated subjects with HCV genotype 1 infection without cirrhosis to receive LDV/SOF +/-RBV for 8 weeks or LDV/SOF for 12 weeks. The primary end point was SVR12. The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of LDV/SOF, 93% (95% CI, 89 to 96) with 8 weeks of LDV/SOF + RBV, and 95% (95% CI, 92 to 98) with 12 weeks of LDV/SOF. As compared with the SVR12 rate in the group that received 8 weeks of LDV/SOF, the rate in the 12-week group was 1 percentage point higher (97.5% CI, −4 to 6) and the rate in the group that received 8 weeks of LDV/SOF + RBV was 1 percentage point lower (95% CI, −6 to 4) demonstrating noninferiority of the 8-week LDV/SOF regimen (noninferiority margin of 12%). Adverse events were more common in the group that received ribavirin than in the other two groups.
No patient who received 8 weeks of only LDV/SOF discontinued treatment owing to adverse events. Overall, previously untreated subjects treated with 8 weeks of LDV/SOF achieved high rates of SVR. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 subjects who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No subject had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No subejct discontinued treatment because of adverse events. The study concluded that LDV/SOF for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4.

Combined Analyses of LDV/SOF Data {Bhagani et al 2015}
A combined analysis compared the safety and efficacy of the single tablet regimen of LDV/SOF in HCV genotype (GT) 1 patients co-infected with HIV-1 in the Phase 3 ION-4 study with HCV mono-infected GT1 patients in the Phase III ION 1-3 studies.
Overall, 865 patients were treated for 12 weeks. In ION 1-3, the majority of patients were male (329, 61%), non-black (449, 83%), and treatment-naïve (430, 80%) while 56 (10%) patients had cirrhosis. In ION-4, the majority of patients were male (276, 82%), non-black (220, 66%), and treatment-experienced (185, 55%). Sixty-seven (67, 20%) patients had cirrhosis. SVR12 and relapse data are reported in the table. Treatment was well tolerated in both mono-infected and co-infected patients. Most common adverse events (> 10% reported in any arm) were fatigue, headache, diarrhea, and nausea. Only two patients discontinued treatment due to an adverse event. The investigators concluded that the once daily, single tablet regimen of LDV/SOF for 12 weeks provided high rates of SVR regardless of presence of HIV infection and was a safe, well-tolerated option for patients with both HCV mono-infection and HIV/HCV co-infection. Use of anti-HCV agents such as LDV, a P-glycoprotein (P-gp) and BCRP inhibitor, with HIV ARV such as TAF, a P-gp and BCRP substrate, may be complicated by drug-drug interactions (DDIs). Two Phase 1 studies evaluated DDIs between TAF-based regimens F/R/TAF or E/C/F/TAF and the fixed-dose combination anti-HCV regimen of LDV/SOF. In two multiple-dose, randomized, crossover studies, healthy volunteers received R/F/TAF (Study 1) or E/C/F/TAF (Study 2), alone or in combination with LDV/SOF, daily with food for 11 [Study 1] or 10 [Study 2] days. Plasma concentrations of RPV, EVG, COBI, FTC, TAF, TFV (TAF metabolite), LDV, SOF, and GS-331007 (predominant circulating metabolite of SOF) were analyzed and PK parameters calculated via noncompartmental analysis. Geometric least squares mean ratio (GMR; combination vs. alone) and 90% confidence intervals (CI) for analytes' AUC tau , C max and C tau were estimated by linear mixed effect modeling and compared to lack of PK alteration bounds (70-143% except RPV: 80-125%). Safety was assessed throughout the studies.
The GMR and 90% CI for all analytes' PK parameters are: GLSM and 90% CIs for all analytes were contained within the prespecified bounds except: i) TFV when RPV/FTC/TAF was administered with LDV/SOF; ii) COBI, when E/C/F/TAF was coadministered with LDV/SOF; and iii) LDV, GS-331007 and SOF and EVG when administered with E/C/F/TAF.
Despite an increase in TFV exposure upon coadministration of R/F/TAF + LDV/SOF, the mean TFV AUC tau is ~ 5 times lower than TFV from TDF, and within the range of TFV that did not lead to renal AEs or bone loss (E/C/F/TAF Phase 3). There is no association between higher COBI exposure and incidence of AEs, renal function parameters (E/C/F/TAF Phase 2/3 data).
Higher plasma exposures of LDV, SOF and GS-331007 in the presence of E/C/F/TAF are not considered to be clinically important based on the established exposure-safety analyses for LDV/SOF. Thus, F/R/TAF or E/C/F/TAF may be coadministered with LDV/SOF without dose modification.

Rationale for This Study
Currently, LDV/SOF is approved by the US FDA for treatment of HCV genotype 1-infected HCV mono and HIV co-infected patients. This Phase 3 open-label study is designed to extend this data to examine the efficacy and safety of LDV/SOF treatment regimen for chronic genotype 1 HCV infection in HIV-infected patients who are receiving HIV therapy with E/C/F/TAF or F/R/TAF. Current guidelines for treatment of HCV in HIV co-infected patients emphasize the added need to treat co-infected patients due to higher rates of liver disease progression even if the HIV infection is treated with antiretroviral agents. The complex drug interactions that can occur between HIV ARV and HCV DAA further the need for safe, simple regimens that cure HCV in HIV-infected subjects without threatening the underlying HIV suppression. Current IDSA/AASLD guidelines recommend that "Antiretroviral drug switches may be performed to allow compatibility of DAAs, with the goal of maintaining HIV suppression without compromising future options." {HCV Guidelines 2015} Prior HIV treatment history, underlying HIV drug resistance and tolerability of regimens needs to be considered.
LDV/SOF has been used successfully to treat HIV/HCV co-infected patients and the cure rates are 96%, comparable to HCV mono-infected patients {Naggie et al 2015}, which has led to a recent update to the LDV/SOF package insert that now includes HIV/HCV co-infection in the list of indications {Gilead Sciences Inc 2015}. However, few ARV regimens were evaluated in clinical studies of HCV treatment of HIV co-infected subjects. Only RAL, EFV and RPV were used in the ION-4 study with FTC/TDF as the dual NRTI component of the regimen. In the presence of a boosting agent, such as RTV or COBI (which increase plasma TFV concentrations), further increases in plasma TFV concentrations are noted when coadministered with LDV/SOF + TDF. Guidelines recommend avoiding RTV or COBI-boosted ARV regimens with TDF when treating HCV in HIV-infected patients, mainly due to lack of data. The availability of TAF-based regimens will obviate the problem of excessive TFV concentrations due to the 91% lower plasma TFV levels when TAF is used in place of TDF. The PK drug interaction studies (GS-US-366-1689 and Study 2) further justify the ability to use LDV/SOF in HIV-infected patients who are receiving TAF-based regimens (including COBI).
Drug-drug interactions of LDV/SOF coadministered with E/C/F/TAF and F/R/TAF were evaluated in healthy volunteers; the studies found no significant interactions and concluded that LDV/SOF and TAF-regimens can be coadministered without dose modification. The duration of the healthy volunteer drug-interaction studies were 10 and 11 days. Although, the US package insert for Genvoya ® (E/C/F/TAF) suggests there should be no clinically significant drug interaction with LDV/SOF, there is no study to date that has evaluated the safety or efficacy of LDV/SOF administered with E/C/F/TAF or F/R/TAF for treatment of HCV in suppressed, HIV co-infected population. Careful assessment of safety/tolerability of LDV/SOF with TAF regimens for 12 weeks is needed to ensure that the safety data, noted in healthy volunteers PK studies, is replicated during 12 weeks of coadministration in HIV/HCV co-infected subjects. The goal of this study is to evaluate E/C/F/TAF FDC or F/R/TAF FDC with LDV/SOF by determining the efficacy of HCV therapy (SVR 12 weeks after completion of LDV/SOF) and safety and tolerability of coadministration of dual STRs.

Risk/Benefit Assessment for the Study
The risk/benefit for this study is acceptable due to the following considerations: i) treatment of HCV is indicated and important in all HIV co-infected patients due to accelerated progression of liver disease; ii) 12 weeks of LDV/SOF provides high HCV SVR rates in HIV/HCV co-infected subjects; iii) changing ARV regimens is an accepted strategy for management of patients prior to initiation of HCV therapy (AASLD/ IDSA Guidelines); iv) changing to E/C/F/TAF from other ART has been shown to be safe, effective and have superior treatment outcome than maintaining a current suppressive regimen {Mills et al 2015}; v) F/R/TAF is bioequivalent to approved HIV regimens and achieves plasma concentrations of FTC, RPV and TAF that have proven to be safe, well tolerated and effective in maintaining virologic suppression in HIV-infected patients. Thus, for individual subjects there is benefit to treating their HCV and for all co-infected patients, finding safe, tolerable, efficacious and simple regimens will be a major advance in treatment.

OBJECTIVES
The primary objective of this study is:  To evaluate efficacy of LDV/SOF as measured by the proportion of subjects achieving HCV RNA below the lower limit of quantification (LLOQ) 12 weeks after the last dose of LDV/SOF (SVR 12).
The secondary objectives of this study are:  To determine the proportion of subjects achieving HCV RNA below LLOQ 4 weeks after the last dose of LDV/SOF (SVR 4);  To evaluate maintenance of HIV-1 RNA suppression after switching to E/C/F/TAF or F/R/TAF 24 weeks from the start of the F/TAF-based regimen;  To evaluate the safety and tolerability of switching to E/C/F/TAF or F/R/TAF from the current ARV therapy in virologically-suppressed, HIV-1/HCV co-infected subjects;  To evaluate the safety and tolerability of 12 weeks of treatment for HCV with LDV/SOF in virologically-suppressed, HIV-1/HCV co-infected subjects who switched to E/C/F/TAF or F/R/TAF.

Endpoints
The primary endpoint of this study is:  The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of LDV/SOF treatment) The secondary endpoints of this study are:  SVR4 (HCV RNA < LLOQ 4 weeks after completion of LDV/SOF treatment);  The proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks after start of the F/TAF-based regimen using modified FDA snapshot algorithm;  Grades 1 through 4 adverse events after switching to E/C/F/TAF or F/R/TAF throughout the study and during coadministration with LDV/SOF treatment.

Study Design
This protocol describes a randomized, multicenter, open-label, 2-part study to evaluate the efficacy, safety, and tolerability of switching to E/C/F/TAF FDC or F/R/TAF FDC HIV treatments and adding LDV/SOF HCV treatment for 12 weeks in adult male and female subjects with HIV who are co-infected with chronic GT 1 HCV infection.

Study Treatments
Subjects will participate in 2 parts of the study. In Part 1, subjects will be randomized in a 1:1 ratio to one of the following 2 HIV treatment groups: Part 1: Approximately 240 subjects will be randomized 1:1 to switch from stable ARV therapy to one of the following treatments. Randomization will be stratified by race (black vs. non-black) at screening.
 Treatment Group 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC (n = 120)  Treatment Group 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC (n = 120) Subjects maintaining HIV-1 RNA < 50 copies/mL and tolerating E/C/F/TAF or F/R/TAF through Part 1 will continue to Part 2 where they will receive the HCV treatment. Subjects with confirmed virologic failure or who discontinue the HIV study drugs due to toxicity in Part 1 will be discontinued from the study.
CCI FTC/RPV/TAF Protocol GS-US-366-1992 Final Gilead Sciences, Inc. Amendment 1 Part 2: After 8 weeks on the randomized E/C/F/TAF FDC or F/R/TAF FDC treatment, subjects will maintain their HIV treatment and will initiate 12 weeks of LDV/SOF HCV treatment.
At the end of their LDV/SOF HCV treatment, subjects will continue to maintain their HIV treatment and be followed for safety and efficacy for an additional 12 weeks to determine the SVR12 endpoint and HIV safety and efficacy endpoints.

Duration of Treatment
The HIV treatment duration is from the Day 1 visit until the last study visit at the Post-HCV Treatment Week 12. The HCV treatment duration is 12 weeks. Screening assessments will be completed within 42 days of the Day 1 visit.
All subjects will complete the following study visits: Screening, Day 1, Weeks 4, 6 (laboratory visit only), 8 (start of HCV treatment), 12, 16, and 20 (end of HCV treatment), and post-HCV treatment visits 4 and 12 weeks after the last LDV/SOF dose.
Subjects who complete the study through the last study visit at the Post-HCV Treatment Week 12 visit will be required to return to the clinic 30 days after the completion of the study treatment for a 30-Day Follow-Up visit. Week 8 visit. c Part 2: At Week 8, once HIV-1 RNA suppression (< 50 copies/mL) is confirmed (based on the Week 6 HIV-1 RNA value), subjects will start on LDV/SOF FDC for 12 weeks (until Week 20) while maintaining their HIV treatment. At Week 20, LDV/SOF FDC will be discontinued while continuing HIV treatment. Subjects will continue in the study for another 12 weeks to determine SVR4 (4 weeks post-HCV treatment) and SVR12 (12 weeks post-HCV treatment). d Subjects who complete the study through the Post-HCV Treatment Week 12 visit will be required to return to the clinic 30 days after the completion of the study treatment for a 30-Day Follow-Up Visit. e At the Day 1 visit, subjects will switch to either E/C/F/TAF FDC or F/R/TAF FDC and continue on HIV treatment until the last study visit at the Post-HCV Treatment Week 12 visit.

Number of Subjects and Subject Selection
Approximately 240 subjects with HIV-1 who are coinfected with chronic HCV infection and who meet the eligibility criteria will be enrolled. In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, may suspend screening and/or enrollment at any site or study-wide at any time.

Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1) The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures.
3) Currently on an ARV regimen (2 NRTI + a third agent, see Table 4-1) without change for 6 months prior to screening. Documented plasma HIV-1 RNA levels < 50 copies/mL (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) for ≥ 6 months preceding the Screening visit. After reaching HIV-1 RNA < 50 copies/mL, single values ("blips") of HIV-1 RNA ≥ 50 copies/mL followed by resuppression are allowed. For subjects with 3 or more prior ARV regimens, a regimen history should be provided for approval by the Sponsor.
Note: Subjects that changed from TDF to TAF less than 6 months ago will be eligible as long as the TDF/ TAF change was the only change to the regimen  7) Have no documented resistance to any of the HIV study agents at any time in the past, including but not limited to the reverse transcriptase resistance mutations K65R, K70E, K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C, M230I/L, the combination of K103N+L100I, or 3 or more TAMs that include M41L or L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R). If a historical genotype prior to first ARV is not available or subject has 3 or more prior ARV regimens, subject will have proviral genotype analysis for archived resistance prior to Day 1 (all proviral genotype reports must be reviewed and approved by Sponsor).
8) Chronic HCV infection (≥ 6 months) documented by prior medical history. 9) HCV genotype 1 at screening as determined by the Central Laboratory. Any non-definitive genotype results will exclude the subject from study participation.
10) Classification as one of the following criteria: a) Without cirrhosis and no prior HCV treatment (treatment-naïve, defined as having never been exposed to approved or investigational HCV-specific direct-acting antiviral agents or prior treatment of HCV with IFN and RBV) b) Without cirrhosis and have received HCV treatment only with IFN +/-RBV +/-HCV PI (treatment-experienced, defined as prior treatment failure to a regimen containing IFN either with or without RBV that was completed at least 8 weeks prior to Day 1. The subject's medical records must include sufficient detail of prior treatment experience for categorization, as either: i. Non-Responder: Subject did not achieve undetectable HCV RNA levels while on treatment, or ii. Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during treatment or within 4 weeks of the end of treatment but did not achieve SVR, or iii. HCV Treatment-Intolerant: Subjects who discontinued HCV treatment of a regimen containing IFN (either with or without RBV) due to toxicity c) Compensated cirrhosis and no prior HCV treatment (treatment-naïve) 11) Cirrhosis Determination a) Presence of cirrhosis is defined as any one of the following: c) Of childbearing potential and agrees to utilize protocol-specified contraceptive methods or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following the last study drug dose (see Appendix 5 for definitions and protocol-acceptable contraceptive methods) 22) Male subjects must agree to utilize a protocol-approved method of contraception (as defined in Appendix 5) during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from first dose throughout the study period and for 30 days following the last study drug dose.
23) Male subjects must agree to refrain from sperm donation from first dose until at least 30 days after the last study drug dose.

Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) A new AIDS-defining condition diagnosed within the 30 days prior to the Screening visit (except CD4+ cell count and/or percentage criteria) (refer to Appendix 6) 2) Prior HCV treatments with NS5A and NS5B or any HCV directly acting antivirals except boceprevir, telaprevir and simeprevir in combination with IFN +/-RBV.
4) History or current decompensation of liver disease; varices at low risk of bleeding are allowed.

Randomization
Subjects will be assigned a screening number at the time of consent. Once eligibility has been confirmed, each subject will be assigned a unique subject number. Once a subject number has been assigned to a subject, it will not be reassigned to any other subject. Prior to or during the Day 1 visit, the Investigator or designee will randomize the subject using the Interactive Web Response System (IWRS). The subject number assignment and randomization may be performed up to 7 days prior to the in-clinic Day 1 visit provided that all screening procedures have been completed and subject eligibility has been confirmed.
Subjects will be randomized in a 1:1 ratio to one of the following two treatment arms: Treatment Arm 1: Switch from 2 NRTI plus a third ARV agent to E/C/F/TAF FDC (n = 120) Treatment Arm 2: Switch from 2 NRTI plus a third ARV agent to F/R/TAF FDC (n = 120) Randomization will be stratified by race (black vs. non-black).
The IWRS will assign study drug bottle numbers to be dispensed to the subject at each study visit, for all HIV and HCV study drugs. All Day 1 assessments and procedures must be completed prior to the administration of the first dose of HIV study drug. Initiation of treatment with the HIV study drug must take place within 24 hours after the Day 1 visit.

Formulation
5.2.1.1. E/C/F/TAF, Genvoya ® E/C/F/TAF tablets are capsule-shaped, film-coated green tablets debossed with "GSI" on one side of the tablet and "510" on the other side. Each E/C/F/TAF tablet contains 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (as 11.2 mg of TAF fumarate).
In addition to the active ingredients, the tablets contain silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate as inactive ingredients and are film-coated with indigo carmine aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. LDV/SOF tablets are orange, diamond-shaped, film-coated tablets debossed with "GSI" on one side and "7985" on the other side. Each LDV/SOF FDC tablet contains 90 mg of LDV and 400 mg of SOF.

Packaging and Labeling
Study drug(s) to be distributed to centers in the US and other participating countries shall be labeled to meet applicable requirements of the United States Food and Drug Administration (FDA) and/or other local regulations. To ensure the stability and proper identification, study drugs should not be stored in a container other than the container in which they were supplied. Consideration should be given to handling, preparation, and disposal through measures that minimize drug contact with the body. Appropriate precautions should be followed by avoiding direct eye contact or exposure when handling.
Commercial product of Genvoya ® , Odefsey ® , and Harvoni ® may be used for the study. Further information regarding storage and handling are available in the Prescribing Information for commercial products.

Dosage and Administration of E/C/F/TAF, F/R/TAF, and LDV/SOF
E/C/F/TAF FDC, F/R/TAF FDC, and LDV/SOF FDC tablets will be provided by Gilead Sciences.
The two HIV study treatments will be administered orally, once daily with food at approximately the same time each day: For a missed dose of E/C/F/TAF FDC, F/R/TAF FDC, and/or LDV/SOF FDC tablet, subjects should be instructed to take the missed dose of study drug as soon as possible during the same day. Subjects should be cautioned never to double the next dose with a missed dose of study drug under any circumstances.

Prior and Concomitant Medications
The use of medications for the treatment of HIV and HCV, other than the study treatments (ie, E/C/F/TAF, F/R/TAF, or LDV/SOF), is prohibited.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the Gilead Medical Monitor must be consulted prior to initiation of the new medication. In instances where an excluded medication is initiated prior to discussion with the Medical Monitor, the Investigator must notify Gilead as soon as he/she is aware of the use of the excluded medication. Concomitant medications taken within 30 days prior to the Screening visit and up to and including 30 days after the last dose of study drug need to be recorded in the source documents and electronic case report form(s) (eCRFs). Table 5-1 (E/C/F/TAF + LDV/SOF) and Table 5-2 (F/R/TAF + LDV/SOF) and use of herbal/natural supplements are excluded or should be used with caution while subjects are participating in the study due to potential drug-drug interactions.

Drug Class Agents Disallowed Use With Caution
Opiates Methadone: Methadone exposures are unaffected upon coadministration with elvitegravir and cobicistat. No dose adjustment of methadone is required upon coadministration with study drug(s).
Meperidine (Pethidine): Dosage increase and long-term use are not recommended due to increased levels of metabolite normeperidine, which has analgesic and CNS stimulant (eg, seizures) activities.
Buprenorphine: Concentrations of buprenorphine and norbuprenorphine are modestly increased and concentrations of naloxone are modestly decreased when coadministered with elvitegravir and cobicistat, with no effect on opioid pharmacodynimcs. The concentration changes are not considered clinically relevant and no dose adjustment of buprenorphine/naloxone is required upon coadministration with study drug(s).

Phosphodiesterase-5 Inhibitors Sildenafil (for PAH)
Pulmonary Arterial Hypertension: Tadalafil: Caution should be exercised, including consideration of dose reduction, when coadministered for treatment of pulmonary arterial hypertension.
Erectile Dysfunction: Sildenafil, Vardenafil, Tadalafil: It is recommended that a single dose of Sildenafil no more than 25 mg in 48 hours, Vardenafil no more than 2.5 mg in 72 hours, or Tadalafil no more than 10 mg in 72 hours be coadministered.

Accountability for Investigational Medicinal Product (IMP)
The investigator is responsible for ensuring adequate accountability of all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and unused IMP dispensed to subjects must be returned to the site.
IMP accountability records will be provided by Gilead Sciences (or equivalent documentation maintained by the study site) to:  Record the date received and quantity of IMP bottles  Record the date, subject number, subject initials, the IMP bottle number dispensed  Record the date, quantity of used and unused IMP returned, along with the initials of the person recording the information.

Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.

STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in tabular form in Appendix 2 and described in the text that follows. Additional information is provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify Gilead or contract research organization (CRO).

Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study before enrollment. Please refer to Section 5.1 for details about randomization and treatment assignment.

Screening Visit
Subjects will be screened within 42 days prior to the Day 1 visit to determine eligibility for participation in the study. The following assessments will be completed and documented at screening:  Obtain written informed consent  Determine eligibility including cirrhosis determination (see Section 4.2 for details)  If the presence of cirrhosis is determined, then appropriate diagnostic imaging (CT or Ultrasound) should be performed within 6 months of Day 1 to exclude the presence of hepatocellular carcinoma  Obtain medical history, including:  History of HIV-1 disease-related events and prior medications within 30 days of the Screening visit. For subjects with 3 or more prior ARV regimens, a regimen history should be provided for approval by the Sponsor.
 Collection of historical HIV genotype, if available. If a historical genotype prior to first ARV is not available or subject had 3 or more prior ARV regimens, subject will have proviral genotype analysis for archived resistance prior to Day 1 (all proviral genotype reports must be reviewed and approved by Sponsor).
 If HCV treatment-experienced, record the duration of the prior treatment and the type of IFN +/-RBV + HCV PI administered. Record whether the subject had a Non-Response or Relapse/Breakthrough during prior treatment or was Treatment Intolerant.
■ Non-Response: Subject did not achieve undetectable HCV RNA while on treatment. Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the clinic within 42 days after the Screening visit for the Day 1 assessments.
From the time of obtaining informed consent through the first administration of investigational medicinal product, record all serious adverse events (SAEs), as well as any adverse events (AE) related to protocol-mandated procedures on the adverse events electronic case report form (eCRF). All other untoward medical occurrences observed until dosing of study drugs, including exacerbation or changes in medical history are to be captured on the medical history eCRF. See Section 7, Adverse Events and Toxicity Management, for additional details.

Day 1 Assessments
The following assessments are to be completed at the Day 1 visit. The Investigator must have received the results from the screening assessments before proceeding with the visit. Subjects must complete all Day 1 procedures before being dispensed the study drugs. Initiation of treatment with HIV study drugs must take place within 24 hours after the Day 1 visit.

 Review AEs and changes in concomitant medications
 Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the Investigator)  Obtain vital signs, including weight  Obtain urine samples for the following laboratory analyses:  Urinalysis and urine chemistry  Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test is positive at Day 1, study drugs will not be dispensed. The positive result will be confirmed with a serum pregnancy test. If the serum pregnancy test is positive, the subject will not be able to participate.   Work Productivity and Activity Impairment Questionnaire: Hepatitis C, v2.0 (WPAI: Hepatitis C)

Randomization
 Obtain subject number and randomize the subject via the IWRS. The subject number assignment and randomization may be performed up to 7 days prior to the in-clinic Day 1 visit provided that all screening procedures have been completed and subject eligibility has been confirmed.
 Dispense HIV study drugs. Subjects should initiate dosing of HIV study drugs after Day 1 visit assessments. Initiation of treatment with the study drugs must take place within 24 hours after the Day 1 visit.
 Subjects should also be counseled regarding the importance of adherence and taking their study drug daily with food at approximately the same time each day.

HIV and HCV Treatment Visits (Weeks 4, 6, 8, 12, 16, and 20)
The following assessments are to be completed at the end of Weeks 4, 8, 12, 16, and 20, unless otherwise specified. The Week 6 visit is a laboratory visit only -please see Section 6.4.1.1 for details.
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be completed within ± 2 days of the protocol-specified visit date based on the Day 1 visit through Week 20.

 Review AEs and changes in concomitant medications
 Perform symptom-directed physical examination as needed  Document study drugs dispensation and accountability for all study drugs dispensed. Counsel all subjects regarding the importance of adherence and maintaining consistency to study drug administration.

 HIV study drugs are dispensed at every visit (with the exception of Week 6 laboratory visit).
 HCV treatment will commence at Week 8, after determination of HIV suppression (< 50 copies/mL) based on the Week 6 HIV-1 RNA value and tolerability of HIV study drugs. Once confirmed, dispense HCV study drug (LDV/SOF) at Weeks 8, 12, and 16 only. 6.4.1.1.
Week 6 (Laboratory Visit Only) The Week 6 visit is a laboratory visit only, to confirm HIV suppression prior to initiation of HCV treatment.
The following will be performed and documented at the Week 6 visit:

HIV Treatment and Post-HCV Treatment Assessments (Post-HCV Treatment Weeks 4 and 12)
The following evaluations are to be completed at the end of 4 and 12 weeks after completion of HCV treatment (Post-HCV Treatment Weeks 4 and 12 visits, respectively) and should be timed from the date of last administration of the HCV treatment. The Post-HCV Treatment Week 4 visit is to be completed ± 2 days, and the Post-HCV Treatment Week 12 visit is to be completed within ± 4 days; however, unless notified by Gilead Sciences, the Post-HCV Treatment Week 12 should be completed within 4 days of the protocol-specified visit date.
All subjects must complete the Post-HCV Treatment Weeks 4 and 12 visits. The end of study will occur at the Post-HCV Treatment Week 12 visit.
The following assessments are to be completed:

 Review AEs and changes in concomitant medications
 Complete physical examination (Post-HCV Treatment Week 12 only) (urogenital/anorectal exams will be performed at the discretion of the Investigator)  Perform symptom-directed physical examination as needed  Obtain vital signs, including weight  Obtain urine samples for the following laboratory analyses:  Urinalysis and urine chemistry  Urine pregnancy test (females of childbearing potential only); positive urine pregnancy tests will be confirmed with a serum test. If the serum test is positive, the subject will be discontinued.

Early Study Drug Discontinuation (ESDD) Visit
Early study drug discontinuation during Part 1 (Day 1 through Week 8): If the subject discontinues HIV study drug dosing in Part 1, the subject will be discontinued from the study and will not continue to Part 2 of the study. The subject will be asked to return to the clinic within 72 hours of stopping HIV study drugs for the ESDD visit, followed by the 30-Day Follow-Up visit.
Early study drug discontinuation during Part 2 (after initiation of HCV treatment): If the subject discontinues HCV study drug dosing only prior to completing the 12-week HCV treatment, the following will occur:  Be asked to return to the clinic within 72 hours of stopping HCV study drug for the ESDD visit.
 Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of LDV/SOF, as described in Section 6.4.2.
 Continue to receive HIV study drugs (see ESDD procedures below).
If the subject discontinues HIV study drug dosing only, the following will occur:  Be asked to return to the clinic within 72 hours of stopping HIV study drugs for the ESDD visit.
 HIV regimen may be changed, after discussion with the Medical Monitor. The new HIV regimen should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued unless an HIV regimen cannot be constructed that would allow coadministration with the new HIV regimen.
 Remain in the study to complete the 12-week HCV treatment (see Section 6.4.1) and followup visits 4 and 12 weeks after the last dose of LDV/SOF, as described in Section 6.4.2.
If the subject discontinues both HIV and HCV study drug dosing, the following will occur:  Be asked to return to the clinic within 72 hours of stopping study drugs for the ESDD visit.
 Remain in the study to return for follow-up visits 4 and 12 weeks after the last dose of LDV/SOF, as described in Section 6.4.2.  For subjects that discontinue during Part 2 of the study, perform study drug accountability for HIV and HCV study drugs.
■ If the subject discontinues HCV study drug and is staying on HIV study drug, dispense HIV study drug until the last study visit.
■ If the subject discontinues HIV study drug, HCV study drug will be dispensed at the scheduled visits as described in Section 6.4.1

30-Day Follow-Up Visit
Subjects who complete the study through the Post-HCV Treatment Week 12 visit will be required to return to the clinic 30 days after the completion of study for the 30-Day Follow-Up visit.
Subjects who permanently discontinue HIV study drug in Part 1 of the study will be asked to return to the clinic after the completion of the ESDD visit for a 30-Day Follow-Up visit.
A ± 6 days window may be used to schedule this visit. The following evaluations are to be completed at this visit:  Urinalysis and urine chemistry  Urine pregnancy test (females of childbearing potential only); positive urine pregnancy tests will be confirmed with a serum test.
 Obtain blood samples for the following laboratory analyses: At the 30-Day Follow-Up Visit, any evaluations showing abnormal results indicating that there is a reasonable possibility of a causal relationship with the study drug will be repeated weekly (or as often as deemed prudent by the Investigator) until the abnormality is resolved, returns to baseline, or is otherwise explained.

Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should be made to keep the subject in the study and continue to perform the required study-related follow-up and procedures (refer to Appendix 2). If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn from the study and asked to return for the ESDD Visit followed by the 30-Day Follow-Up Visit.

Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:  Intercurrent illness that would, in the judgment of the Investigator, affect assessments of clinical status to a significant degree.
 Unacceptable toxicity, as defined in the toxicity management section of the protocol, or toxicity that, in the judgment of the Investigator, compromises the ability to continue study-specific procedures or is considered to not be in the subject's best interest

Blood and Urine Storage
A portion of the blood drawn and urine collected at all visits (except Screening, Week 6, 30-Day Follow-Up, or Unscheduled) will be frozen and stored. From subjects who provide additional consent, a portion of the blood draw at Day 1, Weeks 4, 8, 20, Post-HCV Treatment Week 12, and ESDD visit will be frozen and stored. These stored samples may be used by Gilead or our research partners to help answer questions about the study drug, HIV-1 infection and its associated conditions, or clinical laboratory testing to provide additional safety data. No human genetic testing will be performed without express consent of the study subjects. At the conclusion of this study, these samples may be retained in storage for Gilead for a period of up to 15 years.

Bone Safety and Inflammation
For all subjects, blood will be collected for selected assessments of bone safety, including serum 25-OH Vitamin D and PTH. Assessments for inflammation may include: cystatin-C, IL 6, hs CRP, sCD14, sCD163, sTNF-R1, and Lp-PLA2. Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment Week 12.

Markers of Platelet Function and Coagulation
For all subjects, blood will be collected for selected assessments of platelet function and coagulation that may include: soluble glycoprotein VI (sGPVI), P-selectin, soluble CD40 ligand and D-dimer. Collections will be made at Day 1, Weeks 4, 8, 12, 20, and Post-HCV Treatment Week 12.

Markers of Renal Tubular Function
For all subjects, urine will be collected for selected assessments of renal tubular function that may include retinol binding protein, beta-2 microglobulin, urine albumin, and urine protein.

HIV Virologic Failure
Subjects who experience virologic rebound (VR), as defined below, will be considered to have virologic failure.
Subjects will be considered to have virologic rebound if at any visit has an HIV-1 RNA value  50 copies/mL confirmed at the next scheduled or unscheduled visit (2 to 4 weeks later).

Management of HIV Virologic Rebound
The management of virologic rebound during Part 1 and Part 2 are different; subjects that have confirmed virologic failure during Part 1 will be discontinued from the study and not begin Part 2, while subjects that have virologic failure in Part 2 will be managed as described below.  If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA value is ≥ 400 copies/mL, the blood samples from that visit will be used for HIV-1 genotype/phenotype testing.
 If virologic failure is confirmed during Part 1 (regardless of detection of HIV drug resistance), the subject should be discontinued from HIV study drug and have the ESDD and 30 Day Follow-Up visit.
 If the viral load at the Week 6 visit is ≥ 50 copies/mL (and this is not a confirmation of virologic failure value), the HIV-1 RNA will be repeated at an unscheduled visit in about 2 weeks from the Week 6 visit. This unscheduled visit for confirmation of virologic failure must be completed prior to the Week 8 visit (which subsequently means that the Week 8 visit will be delayed). The subject should not start Part 2 (nor should the subject start LDV/SOF therapy) until the repeat HIV-1 RNA value is available. If the repeat HIV-1 RNA confirms virologic rebound (≥ 50 copies/mL), then the subject will be discontinued from HIV study drugs as above. If the repeat HIV-1 RNA is < 50 copies/mL, then the subject may proceed to Part 2 and maintain the same visit schedule. Initiation of LDV/SOF therapy must occur within 2 to 4 weeks of the original visit window of the Week 8 visit. If no resistance is detected from genotype/phenotype testing, the subject may remain on HIV study drugs and an HIV-1 RNA should be repeated (2 to 4 weeks after date of test with viral load ≥ 50 copies/mL). Investigators should carefully evaluate the benefits and risks of remaining on HIV study drug for each individual subject and document this assessment in the source documents. Investigators who opt to discontinue HIV study drugs for an individual subject must discuss with the Medical Monitor prior to study drug discontinuation.
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic rebound.

Figure 6-1. HIV Virologic Rebound Schema
a. If virologic rebound is not confirmed, the subject will remain on their current HIV regimen. b. If virologic rebound is confirmed, and the HIV-1 RNA is ≥ 400 copies/mL, the HIV-1 genotype and phenotype (reverse transcriptase, integrase, and protease) will be analyzed. c. Based on the results of the genotype/phenotype assays, the subject will remain on HIV study drugs or study drugs will be discontinued. If genotyping/phenotyping fails, a new ARV regimen may be configured at the discretion of the Investigator. d. If no resistance detected, HIV-1 RNA will be repeated (2 to 4 weeks later). Investigator reviews HIV study drug continuation/discontinuation options and discuss with Medical Monitor prior to study drug discontinuation. e. A new ARV regimen will be configured, after discussion with the Medical Monitor. The new HIV regimen should be designed to allow continued dosing of LDV/SOF. LDV/SOF should be continued unless an HIV regimen cannot be constructed that would allow coadministration with the new HIV regimen.

Subjects with ≥ 400 copies/mL of HIV-1 at the Last Study Visit
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed rebound happens at the Post-HCV Treatment Week 12 visit, or last visit while receiving HIV study drugs (or within 72 hours of discontinuation of study treatment).

HCV Virologic Response-Based Treatment Stopping Criteria
The following on treatment HCV virologic response-based treatment stopping criteria will be utilized:  Confirmed > 1 log 10 increase from on treatment nadir  HCV RNA ≥ LLOQ through 8 weeks of treatment Confirmation should be performed as soon as possible and must occur no later than 2 weeks after an initial observation indicating virologic failure during the HCV on treatment phase.
All subjects who terminate LDV/SOF treatment early will complete the ESDD visit (see Section 6.5.1) and post-HCV treatment follow-up visits at 4 and 12 weeks after the last dose of LDV/SOF (see Section 6.4.2).

End of Study
End of study is defined as completion of the Post-HCV Treatment Week 12 visit and the 30-Day Follow-Up visit.

Post Study Care
After a subject has completed/terminated their participation in the study, long-term care for the subject will remain the responsibility of their primary treating physician.

Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs may also include pre-or post-treatment complications that occur as a result of protocol specified procedures, overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that increase in severity or change in nature during or as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:  Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. The condition that led to the procedure may be an adverse event and must be reported.
 Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the screening visit that do not worsen  Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for elective surgery, social and/or convenience admissions)  Overdose without clinical sequelae (see Section 7.7.1)  Any medical condition or clinically significant laboratory abnormality with an onset date before the consent form is signed and not related to a protocol-associated procedure is not an AE. It is considered to be pre-existing and should be documented on the medical history CRF.

Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:  Death  Life-threatening (Note: The term "life-threatening" in the definition of "serious" refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.)  In-patient hospitalization or prolongation of existing hospitalization  Persistent or significant disability/incapacity  A congenital anomaly/birth defect  A medically important event or reaction: such events may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific judgment must be exercised to determine whether such an event is a reportable under expedited reporting rules. Examples of medically important events include intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; and development of drug dependency or drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal product will be considered a medically important event and subject to expedited reporting requirements.

Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical intervention or lead to IMP interruption, modification, or discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please refer to Section 7.5.

Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for causality and severity, and for final review and confirmation of accuracy of event information and assessments.

Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP therapy using clinical judgment and the following considerations:  No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an alternative causality must be provided (eg, pre-existing condition, underlying disease, intercurrent illness, or concomitant medication).
 Yes: There is reasonable possibility that the event may have been caused by the investigational medicinal product. It should be emphasized that ineffective treatment should not be considered as causally related in the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) should be assessed using the following considerations:  No: Evidence exists that the adverse event has an etiology other than the study procedure.
 Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)

Assessment of Severity
Severity should be recorded and graded according to the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities (Appendix 4). For adverse events associated with laboratory abnormalities, the event should be graded on the basis of the clinical severity in the context of the underlying conditions; this may or may not be in agreement with the grading of the laboratory abnormality.

Investigator Requirements and Instructions for Reporting Adverse Events and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation: After informed consent, but prior to initiation of study medication, the following types of events should be reported on the eCRF: all SAEs and adverse events related to protocol-mandated procedures.

Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, until 30 days or 4 weeks after last administration of study IMP and report to the eCRF database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up period.

Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to participate in the study (ie, signing the informed consent) and throughout the duration of the study, including the protocol-required post treatment follow-up period, must be reported to the eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also includes any SAEs resulting from protocol-associated procedures performed after informed consent is signed. Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; however, if the investigator learns of any SAEs that occur after study participation has concluded and the event is deemed relevant to the use of IMP, he/she should promptly document and report the event to Gilead DSPH.
 All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the eCRF completion guideline.

Electronic Serious Adverse Event (eSAE) Reporting Process
 Site personnel record all SAE data in the eCRF database and from there transmit the SAE information to Gilead DSPH within 24 hours of the investigator's knowledge of the event.
Detailed instructions can be found in the eCRF completion guidelines.
 If for any reason it is not possible to record the SAE information electronically, ie, the eCRF database is unable to be accessed, record the SAE on the paper serious adverse event reporting form and submit within 24 hours as described above.
GSI Drug Safety and Public Health (DSPH): Fax: +1 (650) 522-5477 E-mail: safety_fc@gilead.com  As soon as it is possible to do so, any SAE reported via paper must be transcribed into the eCRF Database according to instructions in the eCRF completion guidelines.
 If an SAE has been reported via a paper form because the eCRF database has been locked, no further action is necessary.
 For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other documents are also to be submitted by e-mail or fax when requested and applicable. Transmission of such documents should occur without personal subject identification, maintaining the traceability of a document to the subject identifiers.
 Additional information may be requested to ensure the timely completion of accurate safety reports.
 Any medications necessary for treatment of the SAE must be recorded onto the concomitant medication section of the subject's eCRF and the event description section of the SAE form.
 All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the eCRF completion guideline.

Gilead Reporting Requirements
Depending worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety information specified in the IB or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is required by local regulatory agencies, and in accordance with the local institutional policy.

Toxicity Management
 All clinical and clinically significant laboratory toxicities relating to HIV ARV agents will be managed according to uniform guidelines detailed in Appendix 3.
 Management for toxicity should be differentiated between ARV and HCV medications.
 Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat testing within 3 calendar days of receipt of results and before investigational medicinal product discontinuation, unless such a delay is not consistent with good medical practice.
 Clinical events and clinically significant laboratory abnormalities will be graded according to the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities (Appendix 4).
 When restarting investigational medicinal product following resolution of the adverse event, the investigational medicinal product should be restarted at full dose after discussion with the Medical Monitor.
 Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or clinically significant laboratory adverse event following dose interruption mandates permanent discontinuation of investigational medicinal product.
 Any questions regarding toxicity management should be directed to the Medical Monitor 7.5.1.

Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the Investigator.

Grade 3 Laboratory Abnormality or Clinical Event
 For Grade 3 clinically significant laboratory abnormality or clinical event, investigational medicinal product may be continued if the event is considered to be unrelated to investigational medicinal product.
 For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by repeat testing, that is considered to be related to investigational medicinal product, investigational medicinal product should be withheld until the toxicity returns to  Grade 2.
 If a laboratory abnormality recurs to  Grade 3 following rechallenge with investigational medicinal product and is considered related to investigational medicinal product, then investigational medicinal product should be permanently discontinued and the subject managed according to local practice. Recurrence of laboratory abnormalities considered unrelated to investigational medicinal product may not require permanent discontinuation.

Grade 4 Laboratory Abnormality or Clinical Event
 For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality confirmed by repeat testing that is considered related to investigational medicinal product, investigational medicinal product should be permanently discontinued and the subject managed according to local practice. The subject should be followed as clinically indicated until the laboratory abnormality returns to baseline or is otherwise explained, whichever occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by repeat testing should be managed according to the algorithm for the new toxicity grade.
 Investigational medicinal product may be continued without dose interruption for a clinically non-significant Grade 4 laboratory abnormality (eg, Grade 4 creatinine kinase (CK) after strenuous exercise or triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event considered unrelated to investigational medicinal product 7.5.4.

Management of Potential Nephrotoxicity
Estimated glomerular filtration rate, according to the Cockcroft-Gault (eGFR CG ) formula for creatinine clearance, will be followed post-baseline during the study. All subjects with estimated eGFR CG < 30 mL/min must have serum creatinine measured again within 3 calendar days of receipt of results. At the time of this repeat serum creatinine assessment, Cystatin C will also be measured and the eGFR by CKD-EPI (cystatin C) will be calculated and compared with the baseline measurement. Any subjects who have an estimated eGFR CG < 30 mL/min that also experience > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline or who have other clinical and/or laboratory evidence of acute renal failure will be discussed with the Medical Monitor and may discontinue from study drugs.
For subjects with eGFR CG < 30 mL/min who are not discontinued based on toxicity management procedures above and considered to have stable renal function per Principal Investigator and Medical Monitor, it is not mandatory to repeat eGFR assessments within 3 days. where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of Scys/κ or 1, and max (Scys/0.8,1) indicates the maximum of Scys/κ or 1.
All subjects with a change from baseline serum creatinine of ≥ 0.4 mg/dL must have serum creatinine repeated, with a concurrent urinalysis and urine chemistry, within two weeks of receipt of results. If a subject has a confirmed change from baseline serum creatinine of ≥ 0.4 mg/dL, the Medical Monitor should be notified and a consultation with a nephrologist should be obtained.

Stopping Rules for HCV Treatment
The Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF unless the investigator believes that immediate action is warranted to ensure the continued safety of the subject.
Administration of study drug may be discontinued in the event of a clinical or laboratory event.
There is no option for dose reduction of LDV/SOF. If LDV/SOF FDC is stopped due to toxicity, it must not be restarted. The ESDD visit should be completed after discontinuation of LDV/SOF. The Post-HCV Treatment Week 4 and Week 12 visits must also be completed.
Subjects who meet any of the following laboratory criteria must stop HCV study treatment:  Elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate repeat testing  Abnormal elevation of ALT > 3x Day 1 and total bilirubin > 2 x ULN, confirmed by immediate repeat testing  Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing  Any Grade 3 or greater rash associated with constitutional symptoms  Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate repeat testing) as related to LDV/SOF 7.7. Special Situations Reports 7.7.1.

Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports of adverse events associated with product complaints, occupational exposure with an AE, and pregnancy reports regardless of an associated AE. Medication error is any unintentional error in the prescribing, dispensing, or administration of a medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal product given per administration or cumulatively which is above the maximum recommended dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in question). In cases of a discrepancy in drug accountability, overdose will be established only when it is clear that the subject has taken the excess dose(s). Overdose cannot be established when the subject cannot account for the discrepancy except in cases in which the investigator has reason to suspect that the subject has taken the additional dose(s).
Product complaint associated with an adverse event is defined as complaints arising from potential deviations in the manufacture, packaging, or distribution of the medicinal product associated with an adverse event, which is any untoward medical occurrence in a study subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the study drug.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of one's professional or non-professional occupation.

Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after initiation of study medication and throughout the study, including the post study drug follow-up period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of the pregnancy. The same reporting obligations shall apply to female partners of male study subject (ie, partner pregnancies).
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic abortion due to complications or other medical reasons) must be reported within 24 hours as an SAE. The underlying medical reason for this procedure should be recorded as the AE term.

Other Endpoints of Interest
No other endpoints of interest will be considered. HIV Full Analysis Set: The primary analysis set for HIV efficacy analysis will be the HIV full analysis set (HIV FAS) and is defined as all subjects randomized and who received at least one dose of F/TAF-based regimen.
HCV Full Analysis Set: The primary analysis set for HCV efficacy analysis will be the HCV full analysis set (HCV FAS) and is defined as all subjects who received at least one dose of LDV/SOF.
Subjects will be grouped according to the treatment they were randomized to.

Safety
HIV Safety Analysis Set: The primary analysis set for HIV safety analyses will be the HIV safety analysis set and is defined as all subjects randomized to the study and who received at least one dose of F/TAF-based regimen.
HCV Safety Analysis Set: The primary analysis set for HCV safety analyses with coadministration with the F/TAF-based regimen in Part 2 will be the HCV safety analysis set and is defined as all subjects who received at least one dose of LDV/SOF.
All data collected during treatment will be included in the safety summaries. Subjects will be grouped according to the treatment they actually received.

Pharmacokinetics
The PK analysis set will include all subjects who were randomized and have received at least one dose of either the F/TAF-based regimen (at Week 4) or coadministration of the F/TAF-based regimen and LDV/SOF, and for whom concentration data of any analyte of interest are available. The PK analysis set will be used for listing PK concentration data and summaries.

Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized by standard descriptive methods using the safety analysis set. Demographic and baseline measurements will be summarized by treatment group (E/C/F/TAF; F/R/TAF) and overall.
Summaries will include sex, race/ethnicity, age, height, weight and body-mass index. Baseline data will include a summary of risk factors for HIV-1 infection and HCV infection, and enrollment distribution.
For categorical demographic and baseline characteristics, a Cochran-Mantel-Haenszel (CMH) test will be used to compare treatment groups. For continuous demographic and baseline characteristics, a Wilcoxon rank sum test will be used to compare the treatment groups.

Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation of therapy). The primary analysis will be performed after all enrolled subjects have been followed through post-HCV treatment Week 12 or discontinued from study.
In the primary efficacy analysis, the SVR12 rate will be compared to the performance goal of 88% by using two-sided exact one-sample binomial test at the 0.05 significance level. The basis for this benchmark includes the overall trend toward increasing SVR rates in recent years; and the general appeal of using a fixed clinically relevant threshold as a measure of treatment benefit of LDV/SOF.
The null (H 0 ) and alternative (H 1 ) hypotheses used to assess superiority of LDV/SOF relative to the performance goal of 88% are: The primary efficacy analysis will also include the construction of an associated two-sided exact 95% CI.
Furthermore, SVR12 will also be summarized by the HIV treatment arms (F/TAF-based regimen).

Secondary Analyses
The methods to assess proportion of HIV-1 RNA ≥ 50 copies/mL (virologic failure) 24 weeks after start of the F/TAF-based regimen using a modified FDA snapshot algorithm will be provided in detail in the Statistical Analysis Plan.
The changes from baseline in CD4+ count at Week 8 and Post-HCV Treatment Week 12 will be summarized using descriptive statistics.
The analysis of SVR4 will be summarized using similar methods as for the primary endpoint.

Safety Analysis
All safety data collected on or after the date F/TAF-based ARV regimen was first dispensed up to the date of last dose of study drug(s) (either F/TAF-based regimen alone or in combination with LDV/SOF) plus 30 days will be summarized overall, according to the study drug(s) received.
Additionally, safety data collection on or after the first dose of LDV/SOF until the last dose of LDV/SOF plus 30 days (ie, during coadministration of HIV/HCV study drugs), will also be summarized.
Data for pretreatment and post-last-dose-plus-30-days will be included in data listings.

Extent of Exposure
A subject's extent of exposure to each study drug will be generated from the corresponding study drug administration data. Duration of exposure to each study drug will be expressed as the number of weeks between the first and last dose for each study drug, inclusive, regardless of temporary interruptions in study drug administration.
Dosing information for individual subjects will be listed.

Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to the clinical database.
HIV treatment-emergent AEs are events that meet one of the following criteria up to 30 days after the permanent discontinuation of HIV study drug(s):  AEs with onset dates on or after the first dose date of HIV study drug(s) and no later than 30 days after permanent discontinuation of HIV study drug(s), or,  AEs that result in permanent study drug discontinuation of HIV study drug(s).
The number and percentage of subjects with treatment-emergent AEs (by SOC and PT) will be summarized as described in Section 8.5. A similar definition will be used to define HCV treatment-emergent AEs during coadministration of HIV/HCV study drugs. Additional summaries will include summaries for AEs by grade, Investigator's assessment of relationship to study drug, and effect on study drug dosing.
All treatment-emergent and non-treatment emergent AEs will be included in a data listing.

Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for severity of Adverse Events and Laboratory Abnormalities (Appendix 4).
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post baseline up to the date of last dose of HIV study drug(s) plus 30 days, will be summarized as described in Section 8.5. Similarly, treatment-emergent abnormalities during coadministration of HIV/HCV study drugs will also be summarized. If baseline data are missing, then any graded abnormality (ie, at least a Grade 1) will be considered treatment emergent. The maximum toxicity grade will be summarized by laboratory parameter.
Laboratory abnormalities that occur before the first dose of HIV study drug(s) or after the subject has been discontinued from HIV study drug(s) plus 30 days will be included in a data listing.

Other Safety Evaluations
Weight will be summarized by visit.
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number and percent of subjects with abnormal safety ECG will be summarized by visit.

Pharmacokinetic Analysis
Population PK assessments may be conducted for some of the relevant analytes: TAF, TFV, RPV, FTC, EVG, COBI, LDV, SOF, or GS-331007. Population PK assessments will be summarized in a separate report.

Biomarker Analysis
The renal, vascular and inflammatory markers (see Sections 6.8.2 -6.8.4 for details) will be summarized by treatment group and visit using descriptive statistics. The difference in change from baseline in these biomarkers between the treatment groups (E/C/F/TAF and F/R/TAF) will be tested using Wilcoxon rank sum test.

Sample Size
A sample size of 240 subjects will provide at least 85% power to detect an improvement of at least 6 percentage points in SVR12 rate from the performance goal of 88% by using a two-sided exact one-sample binomial test at significance level of 0.05. The investigator and all applicable sub-investigators will comply with 21 CFR 54, "Financial Disclosure by Clinical Investigators", providing documentation of their financial interest or arrangements with Gilead, or proprietary interests in the investigational drug under study. This documentation must be provided prior to the investigator's (and any sub-investigator's) participation in the study. The investigator and sub-investigator agree to notify Gilead of any change in reportable interests during the study and for 1 year following completion of the study. Study completion is defined as the date when the last subject completes the protocol-defined activities.

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this protocol, informed consent form, and any accompanying material to be provided to the subject (such as advertisements, subject information sheets, or descriptions of the study used to obtain informed consent) to an IRB/IEC. The investigator will not begin any study subject activities until approval from the IRB/IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from the IRB/IEC any modifications made to the protocol or any accompanying material to be provided to the subject after initial IRB/IEC approval, with the exception of those necessary to reduce immediate risk to study subjects.

Informed Consent
The investigator is responsible for obtaining written informed consent from each individual participating in this study after adequate explanation of the aims, methods, objectives, and potential hazards of the study and before undertaking any study-related procedures. The investigator must use the most current IRB-or IEC-approved consent form for documenting written informed consent. Each informed consent (or assent as applicable) will be appropriately signed and dated by the subject or the subject's legally authorized representative and the person conducting the consent discussion, and also by an impartial witness if required by IRB/IEC or local requirements.

Confidentiality
The Investigator must assure that subjects' anonymity will be strictly maintained and that their identities are protected from unauthorized parties. Only subject initials, date of birth, another unique identifier (as allowed by local law) and an identification code will be recorded on any form or biological sample submitted to the Sponsor, or laboratory. Laboratory specimens must be labeled in such a way as to protect subject identity while allowing the results to be recorded to the proper subject. Refer to specific laboratory instructions NOTE: The Investigator must keep a screening log showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the trial. Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the investigator brochure, this protocol, eCRF, the IMP, and any other study information, remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. This information is not to be disclosed to any third party (except employees or agents directly involved in the conduct of the study or as required by law) without prior written consent from Gilead. The investigator further agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of the study site to any third party or otherwise into the public domain.

Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. These documents should be classified into at least the following two categories: (1) investigator's study file, and (2) subject clinical source documents.
The investigator's study file will contain the protocol/amendments, eCRF and query forms, IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following information for each subject:  Subject identification (name, date of birth, gender);  Documentation that subject meets eligibility criteria, ie, history, physical examination, and confirmation of diagnosis (to support inclusion and exclusion criteria);  Documentation of the reason(s) a consented subject is not enrolled  Participation in study (including study number); All clinical study documents must be retained by the investigator until at least 2 years or according to local laws, whichever is longer, after the last approval of a marketing application in an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned marketing applications in an ICH region; or, if no application is filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and regulatory authorities have been notified. Investigators may be required to retain documents longer if specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of the documents, special arrangements must be made between the investigator and Gilead to store these records securely away from the site so that they can be returned sealed to the investigator in case of an inspection. When source documents are required for the continued care of the subject, appropriate copies should be made for storage away from the site.

Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member whose training for this function is documented according to study procedures. eCRF should be completed on the day of the subject visit to enable the sponsor to perform central monitoring of safety data. The Eligibility Criteria eCRF should be completed only after all data related to eligibility have been received. Subsequent to data entry, a study monitor will perform source data verification within the electronic data capture (EDC) system. Original entries as well as any changes to data fields will be stored in the audit trail of the system. Prior to database lock (or any interim time points as described in the clinical data management plan), the investigator will use his/her log in credentials to confirm that the forms have been reviewed, and that the entries accurately reflect the information in the source documents. The eCRF capture the data required per the protocol schedule of events and procedures. System-generated or manual queries will be issued to the investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the data for completeness, correctness, and consistency. The site coordinator is responsible for responding to the queries in a timely manner, within the system, either by confirming the data as correct or updating the original entry, and providing the reason for the update (eg, data entry error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of the data entered by that site. This archive must be stored in accordance with the records retention requirements outlined in Section 9.1.5.

Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from which it came for eventual destruction. The study monitor will provide instructions for return. If return is not possible, the study monitor will evaluate each study center's IMP disposal procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site has an appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead Quality Assurance (QA), the site may destroy used (empty or partially empty) and unused IMP supplies in accordance with that site's approved SOP. A copy of the site's approved SOP will be obtained for central files.
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP destroyed. Records must show the identification and quantity of each unit destroyed, the method of destruction, and the person who disposed of the IMP. Upon study completion, copies of the IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.

Inspections
The investigator will make available all source documents and other records for this trial to Gilead's appointed study monitors, to IRB/IEC, or to regulatory authority or health authority inspectors.

Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the procedures and evaluations described in this protocol.

Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in accordance with local requirements and receive documented IRB/IEC approval before modifications can be implemented.

Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or other scholarly media only after the following conditions have been met: the results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form or the study has been completed at all study sites for at least 2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the respective scientific journal or presentation forum at least 30 days before submission of the publication or presentation.
No such communication, presentation, or publication will include Gilead's confidential information (see Section 9.1.4).
The investigator will comply with Gilead's request to delete references to its confidential information (other than the study results) in any paper or presentation and agrees to withhold publication or presentation for an additional 60 days in order to obtain patent protection if deemed necessary.

Payment Reporting
Investigators and their study staff may be asked to provide services performed under this protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel expenses or reimbursements, consulting fees, and any other transfer of value.

Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the investigator's source documentation in order to verify the accuracy of the data recorded in the CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout the study to verify adherence to the protocol and the completeness, consistency, and accuracy of the data being entered on them. The monitor should have access to any subject records needed to verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to ensure that any problems detected through any type of monitoring (central, on site) are resolved.

Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the clinical study. If the investigator is notified of an inspection by a regulatory authority the investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to provide to representatives of a regulatory agency or Gilead access to records, facilities, and personnel for the effective conduct of any inspection or audit.

Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should this be necessary, both parties will arrange discontinuation procedures and notify the appropriate regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator will assure that adequate consideration is given to the protection of the subjects' interests.

a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with cessation of previously occurring menses for > 12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age.
Women who are not post-menopausal or permanently sterile in accordance with these definitions will be considered of childbearing potential.

b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of puberty unless permanently sterile by bilateral orchidectomy or medical documentation.

2) Contraception Requirements for Female Subjects a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of E/C/F/TAF have demonstrated that E/C/F/TAF reduces the exposure of ethinyl estradiol in hormonal contraceptives. No clinically significant interactions between the components of F/R/TAF and LDV/SOF and hormonal contraception are known. Female subjects who choose hormonal contraception will be required to select a second backup method as defined below.
Non-clinical toxicity studies of LDF/SOF, F/R/TAF, and E/C/F/TAF have demonstrated no adverse effect on fertility or embryo-fetal development. However, there is insufficient clinical data available on use of these products in pregnant women. Please refer to the latest version of the IB (F/R/TAF) and package inserts (E/C/F/TAF and LDV/SOF) for additional information.

b. Contraceptive Methods allowed for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable effective contraceptive measure. Women must also not rely solely on hormone-containing contraceptives (except for intrauterine devices [IUDs] that may release hormones) as a form of birth control during the study. Women may continue oral, injectable, transdermal, or other hormonally based contraceptives that are designed to inhibit ovulation, if desired, but these will not be acceptable as a sole form of contraception; an additional form of acceptable effective contraception (methods below) must be chosen even if hormonal ovulation-inhibiting contraception is continued.
Women of childbearing potential must have a negative serum pregnancy test at Screening and a negative pregnancy test on the Day 1 visit prior to randomization. At minimum, a pregnancy test will be performed at the end of relevant systemic exposure. In the event of a delayed menstrual period (over one month between menstruations), a pregnancy test must be performed to rule out pregnancy. This is even true for women of childbearing potential with infrequent or irregular periods.
Women of child bearing potential in this study must agree to use the following forms of contraception from Screening until 30 days after the last dose of study drug.
 Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable method of contraception only when it is in line with the subject's preferred and usual lifestyle.
Or  Consistent and correct use of 1 of the following methods of birth control listed below.
 Intrauterine device (IUD) with a failure rate of < 1% per year. Hormonal IUDs meeting this criterion are acceptable as a sole method.
 Tubal sterilization  Essure micro-insert system (provided confirmation of success 3 months after procedure)  Vasectomy in the male partner (provided that the partner is the sole sexual partner and had confirmation of surgical success 3 months after procedure)  Combined barrier methods: ■ Diaphragm with spermicide and a male condom without spermicide Or ■ Cervical cap with spermicide and male condom without spermicide  Women who choose to continue on their hormonal contraceptive method (eg, combined oral contraceptives, injectable, transdermal, and intravaginal contraceptives) are asked to also choose one of the above methods to supplement the hormonally based method given the effect of E/C/F/TAF on ethinyl estradiol. These women may, however, use their hormonal contraceptive method and choose a single barrier method to supplement their hormonal contraceptive method (preferably the male condom).
Female subjects must also refrain from egg donation and in vitro fertilization during treatment and until at least 30 days after the last dose of study drug.

3) Contraception Requirements for Male Subjects
During the study and for 30 days after the last dose of study drug, male subjects with female partners of childbearing potential should use condoms without spermicide when engaging in intercourse of reproductive potential.

4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM). Female condom and male condom should not be used together.

5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during the study, or if they become pregnant within 30 days of last study drug dose. Subjects who become pregnant or who suspect that they are pregnant during the study must report the information to the investigator and discontinue study drug immediately. Male subjects should also notify the investigator if their female partner becomes pregnant during the study or within 30 days of last dose of study drugs. Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.7.2.1.