Sofosbuvir and Velpatasvir (Page 9 of 11)

14.3 Clinical Trial in Subjects Coinfected with HCV and HIV-1

ASTRAL-5 was an open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection who were coinfected with HIV-1. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, raltegravir or elvitegravir/cobicistat.

Of the 106 treated subjects, the median age was 57 years (range: 25 to 72); 86% of the subjects were male; 51% were White; 45% were Black; 22% had a baseline body mass index at least 30 kg/m2 ; the proportions of patients with genotype 1, 2, 3, or 4 HCV infection were 74%, 10%, 11%, and 5%, respectively; no subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir; 77% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 18% had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/µL (range: 183−1513 cells/µL) and 57% of subjects had CD4+ counts > 500 cells/μL.

Table 17 presents the SVR12 for the ASTRAL-5 trial by HCV genotype.

Table 17 Study ASTRAL-5: Virologic Outcomes by HCV Genotype in Subjects Coinfected with HIV-1 without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment)
Sofosbuvir and Velpatasvir 12 Weeks(N=106)
Total(all GTs) (N=106) GT-1 GT-2(N=11) GT-3(N=12) GT-4(N=5)
GT-1a(N=66) GT-1b(N=12) Total(N=78)
*
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.
Other includes subjects who did not achieve SVR and did not meet virologic failure criteria.
SVR12 95%(101/106) 95%(63/66) 92%(11/12) 95%(74/78) 100%(11/11) 92%(11/12) 100%(5/5)
Outcome for Subjects without SVR
On-Treatment Virologic Failure 0/106 0/66 0/12 0/78 0/11 0/12 0/5
Relapse * 2%(2/103) 3%(2/65) 0/11 3%(2/76) 0/11 0/11 0/5
Other 3%(3/106) 2%(1/66) 8%(1/12) 3%(2/78) 0/11 8%(1/12) (0/5)

No subject had HIV-1 rebound during treatment and CD4+ counts were stable during treatment.

14.4 Clinical Trials in Subjects with Decompensated Cirrhosis

ASTRAL-4 was a randomized, open-label trial in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection and Child-Pugh B cirrhosis at screening. Subjects were randomized in a 1:1:1 ratio to treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks (N=90), sofosbuvir and velpatasvir tablets (400 mg/100 mg) with ribavirin for 12 weeks (N=87), or sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 24 weeks (N=90). Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).

Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated subjects, the median age was 59 years (range: 40 to 73); 70% of the subjects were male; 90% were White; 6% were Black; 42% had a baseline body mass index at least 30 kg/m2. The proportions of subjects with genotype 1, 2, 3, 4, or 6 HCV were 78%, 4%, 15%, 3%, and less than 1% (1 subject), respectively. No subjects with genotype 5 HCV infection were enrolled. 76% had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels at least 800,000 IU/mL; 55% were treatment-experienced; and 95% of subjects had Model for End Stage Liver Disease (MELD) score less than or equal to 15 at baseline. Although all subjects had Child-Pugh B cirrhosis at screening, 6% and 4% of subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively, on the first day of treatment.

Treatment with sofosbuvir and velpatasvir with ribavirin for 12 weeks resulted in numerically higher SVR12 rates than treatment with sofosbuvir and velpatasvir for 12 weeks or 24 weeks. Because sofosbuvir and velpatasvir with ribavirin for 12 weeks is the recommended dosage regimen, the results of the 12- and 24-week sofosbuvir and velpatasvir treatment groups are not presented.

Table 18 presents the SVR12 for subjects treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks in the ASTRAL-4 trial by HCV genotype. No subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks.

Table 18 Study ASTRAL-4: Virologic Outcomes in Subjects with Decompensated Cirrhosis After 12 Weeks of Treatment by HCV Genotype
Sofosbuvir and Velpatasvir + RBV 12 Weeks(N=87)
SVR12 Virologic Failure(relapse and on-treatment failure)
RBV = ribavirin.
*
Includes subjects with baseline CPT C cirrhosis: all 4 subjects achieved SVR12.
This subject with genotype 1a experienced relapse.
One subject had on-treatment virologic failure; pharmacokinetic data from this subject was consistent with non- adherence.
Overall SVR12* 94% (82/87) 3% (3/87)
Genotype 1 96% (65/68) 1% (1/68)
Genotype 1a 94% (51/54) 2% (1/54)
Genotype 1b 100% (14/14) 0% (0/14)
Genotype 3 85% (11/13) 15% (2/13)

All subjects with genotype 2 (N=4) and genotype 4 (N=2) HCV infection treated with sofosbuvir and velpatasvir and ribavirin achieved SVR12.

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