Long-term efficacy and safety of raltegravir in the management of HIV infection

Figures & data

Table 1 Summary of raltegravir efficacy studies with antiretroviral-naïve patients

Study	Design	Eligibility	Treatment	Efficacy results
Comparative trials
STARTMRK 1 and 2^Citation6,Citation8	Phase III R, DB, AC, MC 1:1 allocation ratio	Age ≥18 years ART-naïve HIV-1 RNA >5,000 c/mL	RAL 400 mg BID + TDF/FTC EFV 600 mg Qday + TDF/FTC	<50 c/mL in RAL arm (non-completion = failure) 16 weeks: 86%; 48 weeks: 86%; 96 weeks: 81%; 156 weeks: 75%; 240 weeks: 71% 6 patients discontinued by week 240 due to lack of efficacy
Protocol 004^Citation33,Citation34	Phase II R, DB, AC, MC 1:1:1:1:1 allocation ratio	Age ≥18 years ART-naïve HIV-1 RNA ≥5,000 c/mL CD4+ T-cell counts ≥100 cells/mm^3	RAL 100 mg BID + TDF + 3TC RAL 200 mg BID + TDF + 3TC RAL 400 mg BID + TDF + 3TC RAL 600 mg BID + TDF + 3TC EFV 600 mg Qday + TDF + 3TC At week 48, all RAL patients consolidated into RAL 400 mg BID + TDF + 3TC	<400 c/mL in RAL arm (non-completion = failure) 24 weeks: 85%; 48 weeks: 85%; 240 weeks: 80% <50 c/mL in RAL arm (non-completion = failure) 240 weeks: 69% 4 patients discontinued by week 240 due to lack of efficacy
SPRING-2^Citation35,Citation36	Phase III R, DB, AC, MC 1:1 allocation ratio	Age ≥18 years ART-naïve HIv-1 RNA >1,000 c/mL No primary resistance in reverse transcriptase or protease enzyme	RAL 400 mg BID + (TDF/FTC or ABC/3TC) DTG 50 mg Qday + (TDF/FTC or ABC/3TC)	<50 c/mL in RAL arm (intention-to-treat) 8 weeks: 79%; 48 weeks: 85%; 96 weeks: 76% 14 patients discontinued by week 96 due to lack of efficacy
PROGReSS^Citation38	Phase III R, OL, AC, 1:1 allocation ratio	Age ≥18 years ART-naïve HIV-1 RNA >1,000 c/mL	RAL 400 mg BID + LPV/r TDF/FTC + LPV/r	<40 c/mL in RAL arm (non-completion = failure) 24 weeks: 83%; 48 weeks: 83%; 96 weeks: 66% 1 patient discontinued by week 96 due to lack of efficacy
Non-comparative trials
SHIELD^Citation37	OL	Age ≥18 years ART-naïve HIV-1 RNA >1,000 c/mL HLA-B*5701-negative	RAL 400 mg BID + ABC/3TC	<400 c/mL in RAL arm (non-completion = failure) 24 weeks: 95%; 48 weeks: 88%; 96 weeks: 80% <50 c/mL in RAL arm (non-completion = failure) 24 weeks: 92%; 48 weeks: 88%; 96 weeks: 77% 7 patients discontinued by week 96 due to lack of efficacy

Abbreviations: 3TC, lamivudine; ABC/3TC, abacavir/lamivudine fixed-dose combination; AC, active controlled; ART, antiretroviral therapy; BID, twice daily; c/mL, copies/milliliter; DB, double blind; DTG, dolutegravir; EFV, efavirenz; LPV/r, lopinavir/ritonavir; MC, multicenter; OBT, optimized background therapy; OL, open label; PC, placebo controlled; Qday, daily; R, randomized; RAL, raltegravir; RNA, ribonucleic acid; TDF, tenofovir; TDF/FTC, tenofovir/emtricitabine fixed-dose combination.

Table 2 Summary of raltegravir efficacy studies with antiretroviral-experienced patients

Study	Design	Eligibility	Treatment	Efficacy results
Comparative trials
BENCHMRK 1 and 2^Citation7,Citation9	Phase III R, PC, MC 2:1 allocation ratio DB week 156 OL week 240	Age ≥16 years ART-experienced HIV-1 RNA >1,000 c/mL (on ART) 3 ART class resistance	RAL 400 mg BID + OBT Placebo BID + OBT	<400 c/mL in RAL arm (non-completion = failure) 16 weeks: 77%; 48 weeks: 72%; 96 weeks: 62%; 156 weeks: 54%; 240 weeks: 45% 77% of patients continuing from week 156 to week 240 maintained viral loads,50 c/mL with only 8 withdrawals due to virologic failure
Protocol 005^Citation39,Citation40	Phase II R, PC, MC 1:1:1:1 allocation ratio DB week 24 OL week 96	Age ≥18 years ART-experienced INSTI-naïve HIV-1 RNA >5,000 c/mL 3 ART class resistance	RAL 200 mg BID + OBT RAL 400 mg BID + OBT RAL 600 mg BID + OBT Placebo BID + OBT	<400 c/mL in RAL arm (non-completion = failure) 24 weeks: 70%; 48 weeks: 68%; 96 weeks: 55% Of the 94 RAL patients who entered the OL, only 3 discontinued prior to 96 weeks due to lack of efficacy
Study 145^Citation41	Phase III R, DB, AC, MC 1:1 allocation ratio	Age ≥18 years ART-experienced INSTI-naïve HIV-1 RNA >1,000 c/mL (on ART) 2 ART class resistance or 6 months’ experience with at least 2 classes of ART	RAL 400 mg BID + EVG placebo Qday + boosted PI + 3rd agent EVG 150 mg Qday + RAL placebo BID + boosted PI + 3rd agent	<50 c/mL in RAL arm (ITT) 48 weeks: 58%; 96 weeks: 45% Between weeks 48 and 96, virologic failure occurred in 6.3% of RAL patients
Non-comparative trials
SALIR^Citation42	OL, MC	ART-experienced	RAL 400 mg BID + OBT	292/320 patients remained on their initial regimen at 96 weeks 273/300 patients still receiving RAL at week 96 achieved viral load <50 c/mL
TRIO^Citation43	Phase II OL, MC	HIV-1 RNA >1,000 c/mL (on ART) Naïve to RAL, DRV, ETR ≥3 PI resistance mutations, DRV susceptible ≥3 NRTI resistance mutations ETR susceptible	RAL 400 mg BID + ETR 200 mg BID + DRV/r 600/100 mg BID ± OBT (T20 or NRTI)	<50 c/mL (missing = failure) 24 weeks: 90%; 48 weeks: 86%; 96 weeks: 88% 19/103 patients with virologic failure in 96 weeks, 12 before 48 weeks, 7 between weeks 48 and 96 Virologic success did not differ regardless of presence of OBT

Abbreviations: AC, active controlled; ART, antiretroviral therapy; BID, twice daily; c/mL, copies/milliliter; DB, double blind; DRV, darunavir; DRV/r, darunavir/ritonavir; ETR, etravirine; EVG, elvitegravir; INSTI, integrase strand-transfer inhibitor; ITT, intention-to-treat analysis; MC, multicenter; NRTI, nucleoside reverse-transcriptase inhibitor; OBT, optimized background therapy; OL, open label; PC, placebo controlled; PI, protease inhibitor; Qday, daily; R, randomized; RAL, raltegravir; RNA, ribonucleic acid; T20, enfuvirtide.

Table 3 Summary of raltegravir switch studies

Study	Design	Eligibility	Treatment	Efficacy results
SWITCHMRK 1 and 2^Citation47	Phase III R, DB, AC, MC 1:1 allocation ratio	Age ≥18 years HIV-1 RNA <50 c/mL for ≥3 months on LPV/r regimen	LPV/r 400/100 mg BID + BBR RAL 400 mg BID + BBR	<50 c/mL at week 24 (non-completion = failure) RAL: 84.4% (293/347) LPV/r: 90.6% (319/352) Did not establish noninferiority of RAL to LPV/r, leading to early termination
EASIER ARNS 138^Citation45,Citation48	R, OL, MC 1:1 allocation ratio	Age ≥18 years ART-experienced INSTI-naïve HIV-1 RNA <400 c/mL for >3 months on ENF regimen	ENF 90 mg SQ BID + BBR RAL 400 mg BID + BBR At week 24, ENF arm was offered to switch to RAL; all of them switched	<50 c/mL at week 24 (ITT) RAL: 88% ENF: 89% <50 c/mL at week 48 RAL: 90%
SPIRAL^Citation46	R, OL, MC 1:1 allocation ratio	Age ≥18 years PI-based ART HIV-1 RNA <50 c/mL for 6 months INSTI-naïve	RTV-boosted PI + BBR RAL 400 mg BID + BBR	% free of treatment failure at week 48 (non-completion = failure) RAL: 89.2% RTV-boosted PI: 86.6%
CHEER^Citation49	OL, MC, HC	Age ≥18 years ENF-based ART HIV-1 RNA <50 c/mL for 6 months INSTI-naïve	ENF 90 mg SQ BID + BBR RAL 400 mg BID + BBR	<50 c/mL at week 24 (ITT) RAL: 94.2% (one virologic failure prior to week 24)
SWITCH-ER^Citation44	R, DB, CO	Age ≥18 years EFV-based ART HIV-1 RNA <50 c/mL for 3 months	Week 1 and 2 Group 1 RAL 400 mg BID + EFV placebo + BBR Group 2 EFV 600 mg Qday + RAL placebo + BBR Week 3 and 4 Group 1 EFV 600 mg Qday + RAL placebo + BBR Group 2 RAL 400 mg BID + EFV placebo + BBR	Patient preference at week 4 64% expressed a preference: 35% favored EFV, 65% favored RAL 36% reported two treatments as equal

Abbreviations: AC, active controlled; ART, antiretroviral therapy; BBR, baseline background regimen; BID, twice daily; c/mL, copies/milliliter; CO, cross-over; DB, double blind; EFV, efavirenz; ENF, enfuvirtide; HC, historic control; INSTI, integrase strand-transfer inhibitor; ITT, intention-to-treat analysis; LPV/r, lopinavir/ritonavir; MC, multicenter; OL, open label; PI, protease inhibitor; Qday, daily; R, randomized; RAL, raltegravir; RNA, ribonucleic acid; RTV, ritonavir; SQ, subcutaneous.

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