Viread (Tenofovir Disoproxil Fumarate) - Indications and Dosage

Description of Clinical Studies

Treatment-Naïve Patients

Study 903: VIREAD + Lamivudine +Efavirenz Compared to Stavudine + Lamivudine + Efavirenz

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing VIREAD (300 mg QD) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve patients. Patients had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4 cell count was 279 cells/mm³ (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads >100,000 copies/mL and 39% had CD4 cell counts <200 cells/mm³. Treatment outcomes through 144 weeks are presented in Table 6.

Table 6 Outcomes of Randomized Treatment (Study 903)

	At Week 48		At Week 144
Outcomes	VIREAD + 3TC + EFV (N=299)	d4T + 3TC + EFV (N=301)	VIREAD + 3TC + EFV (N=299)	d4T + 3TC + EFV (N=301)
	%	%	%	%
ResponderPatients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144.	79%	82%	68%	62%
Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144.	6%	4%	10%	8%
Rebound	5%	3%	8%	7%
Never suppressed	0%	1%	0%	0%
Added an antiretroviral agent	1%	1%	2%	1%
Death	<1%	1%	<1%	2%
Discontinued due to adverse event	6%	6%	8%	13%
Discontinued for other reasons Includes lost to follow-up, patient's withdrawal, noncompliance, protocol violation and other reasons.	8%	7%	14%	15%

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4 cell count (< or ≥200 cells/mm³). Through 144 weeks of therapy, 62% and 58% of patients in the VIREAD and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 263 cells/mm³ for the VIREAD arm and 283 cells/mm³ for the stavudine arm.

Through 144 weeks, eleven patients in the VIREAD group and nine patients in the stavudine group experienced a new CDC Class C event.

Study 934: VIREAD + EMTRIVA + Efavirenz Compared with Zidovudine/Lamivudine + Efavirenz

Data through 48 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing VIREAD + EMTRIVA administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve patients. Patients had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4 cell count was 245 cells/mm³ (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log₁₀ copies/mL (range 3.56–6.54). Patients were stratified by baseline CD4 count (< or ≥200 cells/mm³); 41% had CD4 cell counts <200 cells/mm³ and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 7.

Table 7 Outcomes of Randomized Treatment at Week 48 (Study 934)

Outcome at Week 48	VIREAD + FTC + EFV (N=244)	AZT/3TC + EFV (N=243)
	%	%
ResponderPatients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48.	84%	73%
Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.	2%	4%
Rebound	1%	3%
Never suppressed	0%	0%
Change in antiretroviral regimen	1%	1%
Death	<1%	1%
Discontinued due to adverse event	4%	9%
Discontinued for other reasonsIncludes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.	10%	14%

The difference in the proportion of patients who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of patients in the VIREAD + EMTRIVA group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 190 cells/mm³ in the VIREAD + EMTRIVA group and 158 cells/mm³ in the zidovudine/lamivudine group.

Through 48 weeks, 7 patients in the VIREAD + EMTRIVA group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event.

Treatment-Experienced Patients

Study 907: VIREAD + Standard Background Therapy (SBT) Compared to Placebo + SBT

Study 907 was a 24-week, double-blind placebo-controlled multicenter study of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label VIREAD for an additional 24 weeks. Patients had a mean baseline CD4 cell count of 427 cells/mm³ (range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

Changes from baseline in log₁₀ copies/mL plasma HIV-1 RNA levels over time up to Week 48 are presented below in Figure 1.

The percent of patients with HIV-1 RNA <400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 8.

Table 8 Outcomes of Randomized Treatment (Study 907)

Outcomes	0–24 weeks		0–48 weeks	24–48 weeks
	VIREAD (N=368) %	Placebo (N=182) %	VIREAD (N=368) %	Placebo Crossover to VIREAD (N=170) %
	HIV-1 RNA <400 copies/mLPatients with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively.	40%	11%	28%	30%
Virologic failurePatients with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively.	53%	84%	61%	64%
Discontinued due to adverse event	3%	3%	5%	5%
Discontinued for other reasonsIncludes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.	3%	3%	5%	1%

At 24 weeks of therapy, there was a higher proportion of patients in the VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4 counts by Week 24 was +11 cells/mm³ for the VIREAD group and -5 cells/mm³ for the placebo group. Mean change in absolute CD4 counts by Week 48 was +4 cells/mm³ for the VIREAD group.

Through Week 24, one patient in the VIREAD group and no patients in the placebo arm experienced a new CDC Class C event.