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          Human Immunodeficiency Virus (HIV)
          FDA approved changes to the DOVATO (dolutegravir/lamivudine) product labelingHuman Immunodeficiency Virus (HIV) FDA approved changes to the DOVATO (dolutegravir/lamivudine) product labeling
  
  					Includes a new indication and provide longer term safety and efficacy data
	
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    PrintFDA approved changes to the DOVATO (dolutegravir/lamivudine) product labeling to include a new indication and provide longer term (96 week) safety and efficacy data from the GEMINI 1 and 2 trials. A summary of the major changes to the product labeling is as follows:

Indications and Usage

DOVATO is 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 with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO.

Adverse Reactions

This section was updated to provide the 96 week safety data from GEMINI-1 and 3 trials. Compared to the Week 48 data, the rates of adverse events leading to discontinuation increased from 2% to 3% at Week 96. The rates for the adverse reactions (all grades) reported in > 2% of subjects in any treatment group remained the same, with one exception, anxiety was added and reported in 2% and  1% of subjects randomized to dolutegravir+lamivudine vs dolutegravir/lamivudine/tenofovir disoproxil fumarate, respectively. Minor changes were made to the Selected Laboratory Abnormalities table and mean change from baseline in fasted lipids table and text and changes in serum creatinine.

Clinical Trials in Virologically Suppressed Adults subsection was added and includes:

The safety of DOVATO in virologically suppressed adults was based on Week 48 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials

Clinical Studies

This section was updated with the 96 week data from GEMINI-1 and 2 and the 48 week data from TANGO as follows.

Clinical Trial Results in HIV-1–Infected Adult Subjects with No Antiretroviral Treatment History

Week 96 outcomes (including outcomes by key baseline covariates) for the pooled GEMINI-1 and GEMINI-2 trials are shown in Table 11. The results of the pooled analysis are consistent with the results from the individual trials, for which the secondary endpoint is the difference in proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 96 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA. The proportions of subjects with plasma HIV-1 RNA <50 copies/mL in the group receiving TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA were 84% and 89%, respectively, in GEMINI‐1 and 88% and 90%, respectively, in GEMINI-2. The adjusted difference was -4.9% (95% CI: -9.8%, 0.0) for GEMINI-1 and ‐1.8% (95% CI: -6.4%, 2.7%) for GEMINI-2. At Week 96, no subjects had any treatment-emergent substitutions associated with resistance to dolutegravir or NRTIs.

Table 11. Pooled Virologic Outcomes of Randomized Treatment of HIV-1–Infected Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 Trials at Weeks 48 and 96 (Snapshot Algorithm)

Virologic Outcomes
			GEMINI-1 and GEMINI-2
			Pooled DataaWeek 48
			Week 96TIVICAY plus EPIVIR

			(n = 716)
			TIVICAY plus TRUVADA

			(n = 717)
			TIVICAY plus EPIVIR

			(n = 716)
			TIVICAY plus TRUVADA

			(n = 717)HIV-1 RNA <50 copies/mL
			91%
			93%
			86%
			90%Treatment Differenceb
			-1.7%

			(95% CI: -4.4%, 1.1%)
			-3.4%
			(95% CI: -6.7%, 0.0%)Virologic nonresponse
			3%
			2%
			3%
			2%ReasonsData in window ≥50 copies/mL
			1%
			<1%
			<1%
			<1%Discontinued for lack of efficacy
			<1%
			<1%
			1%
			<1%Discontinued for other reasons and ≥50 copies/mL
			<1%
			<1%
			<1%
			<1%Change in ART
			<1%
			<1%
			<1%
			<1%No virologic data at Week 48 or Week 96 window
			6%
			5%
			11%
			9%**Reasons**Discontinued trial due to adverse event or death
			1%
			2%
			3%
			3%Discontinued trial for other reasons
			4%
			3%
			8%
			5%Missing data during window but on trial
			<1%
			0
			0
			<1%

Proportion (%) of Subjects with HIV-1 RNA <50 copies/mL by Baseline Category% (n/N)
			% (n/N)
			% (n/N)
			% (n/N)**Plasma Viral Load (copies/mL)**≤100,000
			91% (526/576)
			94% (531/564)
			87% (499/576)
			90% (510/564)>100,000
			92% (129/140)
			90% (138/153)
			84% (117/140)
			86% (132/153)**CD4+ (cells/mm3)**≤200
			79%
			(50/63)
			93% (51/55)
			68% (43/63)
			87% (48/55)>200
			93%

			(605/653)
			93%

			(618/662)
			88% (573/653)
			90% (594/662)

GenderMale
			92% (555/603)
			94% (580/619)
			87% (523/603)
			90% (557/619)Female
			88% (100/113)
			91%

			(89/98)
			82% (93/113)
			87% (85/98)

RaceWhite
			93% (447/480)
			95% (471/497)
			89% (429/484)
			91% (453/499)African-American/African Heritage
			84%

			(83/99)
			84%

			(64/76)
			73% (66/90)
			83% (59/71)Asian
			94%

			(67/71)
			94%

			(68/72)
			83% (59/71)
			90% (65/72)Other
			88%

			(58/66)
			92%

			(66/72)
			87% (62/71)
			87% (65/75)

EthnicityHispanic or Latino
			90% (193/215)
			93% (216/232)
			86% (185/215)
			90% (208/232)Not Hispanic or Latino
			92% (462/501)
			93% (453/485)
			86% (431/501)
			89% (434/485)

Age (years)<50
			92% (597/651)
			94% (597/637)
			86% (561/651)
			90% (572/637)>e;50
			89%

			(58/65)
			90%

			(72/80)
			85% (55/65)
			88%

			(70/80)

a The results of the pooled analysis are similar to the individual trials, for which the primary endpoint (proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA) was met. The adjusted difference was -2.6% (95% CI: -6.7%, 1.5%) for GEMINI-1 and -0.7% (95% CI: -4.3%, 2.9%) for GEMINI-2.

bBased on Cochran–Mantel–Haenszel-stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA (≤100,000 copies/mL versus >100,000 copies/mL) and CD4+ cell count (≤200 cells/mm3 versus >200 cells/mm3). Pooled analysis also stratified by trial.

The primary endpoint was assessed at Week 48 and the virologic success rate was 91% in the group receiving TIVICAY plus EPIVIR and 93% in the group receiving TIVICAY plus TRUVADA, with a treatment difference of -1.7% (95% CI: -4.4%, 1.1%) in the pooled data. The results of the pooled analysis are similar to the individual trials, for which the primary endpoint (proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA) was met. The adjusted difference was -2.6% (95% CI: ‐6.7%, 1.5%) for GEMINI-1 and -0.7% (95% CI: ‐4.3%, 2.9%) for GEMINI-2.

Virologic outcomes by baseline CD4+ (cells/mm3) in GEMINI-1 and GEMINI-2 at Week 96 are shown in Table 12. In both trials, lower response rates (HIV-1 RNA <50 copies/mL) were observed in subjects with baseline CD4+ ≤200 cells/mm3. These findings were seen irrespective of baseline plasma HIV-1 RNA.

Table 12. Virologic Outcomes by Baseline CD4+ in GEMINI-1 and GEMINI-2 Trials at Week 96 in Subjects with No Antiretroviral Treatment History

GEMINI-1
			GEMINI-2TIVICAY plus EPIVIR

			(n = 356)
			TIVICAY plus TRUVADA

			(n = 358)
			TIVICAY plus EPIVIR

			(n = 360)
			TIVICAY plus TRUVADA

			(n = 359)**Proportion (%) of Subjects with HIV-1 RNA <50 copies/mLa**Baseline CD4+ (cells/mm3)

			≤200

			>200
			65% (20/31)

			91% (29586% (280/325)
			90% (26/29)

			89% (294/329)
			72% (23/32)

			89% (293/328)
			85% (22/26)

			90% (300/333)

a Four subjects treated with TIVICAY plus EPIVIR were withdrawn for treatment-related reasons (3 due to confirmed loss of virologic response and 1 due to drug-related adverse reactions). Two subjects also had HIV-1 RNA ≥50 copies/mL at Week 96 but remained in the study. The other 14 subjects treated with TIVICAY plus EPIVIR who did not have HIV-1 RNA <50 copies/mL at Week 96 (based on Snapshot Algorithm) were discontinued for non–treatment-related reasons by Week 96. One subject in GEMINI-1 whose last HIV-1 RNA was 64,366 copies/mL was lost to follow-up. Three subjects receiving TIVICAY plus EPIVIR with HIV-1 RNA ≥50 copies/mL at Week 48 remained in the study, all with <50 copies/mL at Week 96, 1 of which had a Week 96 HIV-1 RNA of 46 copies/mL.

The adjusted mean change from baseline in CD4+ cell count based on the pooled analysis at Week 96 was 269 cells/mm3 for the group receiving TIVICAY plus EPIVIR and 259 cells/mm3 for the group receiving TIVICAY plus TRUVADA.

14.3     Clinical Trial Results in HIV-1–Infected Virologically Suppressed Adult Subjects Who Switched to DOVATO

The efficacy of DOVATO in HIV-1–infected, antiretroviral treatment-experienced, virologically suppressed subjects is supported by data from a 200-week, Phase 3, randomized, open-label, multicenter, parallel-group, non-inferiority controlled trial (TANGO). A total of 741 adult HIV-1–infected subjects who were on a stable suppressive TBR received treatment in the trial. Subjects were randomized in a 1:1 ratio to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Randomization was stratified by baseline third-agent class (protease inhibitor [PI], INSTI, or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL (virologic non-response) at Week 48 (Snapshot algorithm adjusting for randomization stratification factor).

At baseline, the median age of subjects was 39 years, 8% were female, 21% non-white, 5% were CDC Class C (AIDS), and 98% of subjects had baseline CD4+ cell count ≥200 cells/mm3; these characteristics were similar between treatment arms. Subjects receiving DOVATO and a TBR had been on an antiretroviral regimen for a median of 2.8 and 2.9 years, respectively, prior to Day 1. Most subjects were on an integrase inhibitor-based TBR (78% and 80% of subjects who received DOVATO and a TBR, respectively).

In the primary analysis, <1% of subjects in both arms experiencing virologic failure (HIV-1 RNA ≥50 copies/mL) at Week 48 based on the Snapshot algorithm (Table 13).

Table 13.  Virologic Outcomes of Randomized Treatment in TANGO Trial at Week 48 in Virologically Suppressed Subjects Who Switched to DOVATO

Virologic Outcomes
			DOVATO

			(n = 369)
			TBR

			(n = 372)Virologic nonresponse (≥50 copies/mL)a
			<1%
			<1%Treatment Difference (95% CI)b
			-0.3% (-1.2%, 0.7%)HIV-1 RNA <50 copies/mLc
			93%
			93%Reasons for virologic nonresponseData in window ≥50 copies/mL
			0
			0Discontinued for lack of efficacy
			0
			<1%Discontinued for other reasons and ≥50 copies/mL
			<1%
			0Change in ART
			0
			0Reasons for no virologic data at Week 48 window
			7%
			6%Discontinued trial due to adverse event or death
			3%
			<1%Discontinued trial for other reasons
			3%
			6%Missing data during window but on trial
			0
			<1%

a  Based on a 4% non-inferiority margin, DOVATO was non-inferior to TBR at Week 48 in the primary analysis (proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL); the upper bound of the 95% CI for the adjusted treatment difference was <4%.

b  Based on Cochran–Mantel–Haenszel-stratified analysis adjusting for baseline third-agent class (PI, INSTI, or NNRTI).

c At Week 48 in the secondary analysis (proportion of subjects achieving plasma HIV-1 RNA <50 copies/mL), the adjusted treatment difference was 0.2% (95% CI: -3.4%, 3.9%).

In TANGO, treatment outcomes between treatment arms were similar across the stratification factor, baseline third-agent class (PI, INSTI, or NNRTI), and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells/mm3 in subjects who switched to DOVATO and 11.0 cells/mm3 in subjects who stayed on the TBR.

                                                                                  Content current as of:
      08/07/2020
              
              
Regulated Product(s)
		 Drugs
			  			     			  						              
			
			
			
			
						  HIV/AIDS DrugsHealth Topic(s)
			  HIV/AIDSHuman Immunodeficiency Virus (HIV)

          
                        About HIV and the Center for Drug Evaluation and Research's role
          What's New at CDER in HIV/AIDS


                        HIV Treatment
 
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