Table 3.
Integrase Inhibitor Clinical Trials and Associated Drug Resistance Data
| Trial Type | Clinical Trial* | Trial Design† | Virological Outcome and INI Resistance |
| Initial ARV Therapy | Protocol 004 [38] | Phase II randomized blinded dose-ranging trial of RAL (100, 200, 400, or 600 mg) BID + TDF/3TC vs. EFV + TDF/3TC | At 2, 4, and 8 weeks, all RAL treatment arms had a more rapid plasma HIV-1 RNA decrease than the EFV arm. At week 48, 84% of both arms had plasma HIV-1 RNA levels <50 copies/mL. |
| STARTMRK [39] | Phase III randomized blinded trial of RAL + TDF/FTC (n= 281) vs. EFV + TDF/FTC (n= 282) | Both arms had similar virological efficacy. Among 84 patients with VF defined as confirmed plasma HIV-1 RNA levels >50 copies/mL, 12 of 39 RAL recipients vs. 9 of 45 EFV recipients had plasma HIV-1 RNA levels high enough for genotypic resistance testing. Four of 12 RAL recipients and 5 of 9 EFV recipients had INI and NNRTI resistance, respectively [40]. | |
| Protocol GS-236-014 [41] | Phase II randomized blinded trial of EVG + the novel pharmacokinetic enhancer cobicistat + TDF/FTC (“QUAD” n= 48) vs. EFV + TDF/FTC (n= 23) | At week 48, 90% of EVG (“QUAD”) vs. 83% of EFV recipients had plasma HIV-1 RNA levels <50 copies/mL. | |
| SPRING-1 [42] | Phase II randomized blinded dose-ranging trial of 572 (10, 25, or 50 mg) QD (n= 155) vs. EFV (n= 50) in combination with TDF/FTC or abacavir/3TC | At 24 weeks, >90% of subjects in each of the 3 572 arms had plasma HIV-1 RNA levels <50 copies/mL. | |
| SPARTAN [43] | Pilot randomized open-label study of RAL + ATV 300 mg BID (n= 63) vs. ATV/r + TDF/FTC QD (n= 31) | Five of 6 RAL-treated subjects with VF and plasma HIV-1 RNA levels >400 copies/mL developed RAL resistance. | |
| PROGRESS [44] | Phase III randomized blinded study of RAL + LPV/r (n= 101) vs. TDF/FTC + LPV/r BID (n = 105) | One of 4 RAL-treated subjects with VF and plasma HIV-1 RNA levels >400 copies/mL developed RAL resistance. | |
| Regimen Simplification | EASIER [45] | Phase III randomized open-label trial of RAL vs. continued enfuvirtide in subjects with plasma HIV-1 RNA levels <400 copies/mL for ≥3 months | At week 24, 88% of subjects in both arms had plasma HIV-1 RNA levels <50 copies/mL. INI resistance mutations emerged in 3 of 39 subjects with low-level viremia (defined as plasma HIV-1 RNA levels <1,000 copies/mL). |
| SWITCHMRK 1 and 2 [36] | Phase III randomized blinded trial of RAL (n= 353) vs. continued LPV/r (n= 354) in subjects with plasma HIV-1 RNA levels <50 copies/mL for ≥3 months | At week 24, 84.4% of subjects receiving RAL vs. 90.6% receiving LPV/r maintained plasma HIV-1 RNA levels <50 copies/mL. Eight of 11 RAL-treated subjects with VF and plasma HIV-1 RNA levels >400 copies/mL developed RAL resistance mutations. | |
| SPIRAL [46] | Phase IV 48-week randomized open-label trial of RAL 400 vs. continued RTV-boosted PI in subjects with plasma HIV-1 RNA levels <50 copies/mL for ≥6 months | At week 48, 89.2% of subjects receiving RAL vs. 86.6% receiving continued RTV-boosted PI maintained plasma HIV-1 RNA levels <50 copies/mL. Week 48 RAL resistance data were not described. | |
| ODIS [47] | Pilot open-label randomized trial of RAL 800 mg QD (n= 177) vs. RAL 400 mg BID (n= 35) as a substitute for continued RTV-boosted PI in subjects with plasma HIV-1 RNA levels <50 copies/mL for ≥6 months | At week 24, 6.4% of those receiving RAL QD vs. 2.9% of those receiving RAL BID (P = .2) had virological failure. All but one virological failure occurred in patients with a history of prior NRTI resistance. | |
| Late-Stage Therapy: INI Naive | Protocol 005 [48] | Phase II blinded dose-ranging trial of RAL 200, 400, or 600 mg BID + OBR (n= 133) vs. placebo + OBR (n= 45) | At 24 weeks, the mean plasma HIV-1 RNA decrease was >1.8 log copies/mL in each of the RAL recipients vs. .35 log copies/mL in the placebo recipients. Among 38 RAL recipients with VF, 35 had RAL resistance [35]. |
| BENCHMRK 1 and 2 [12] | Phase III randomized blinded trials of RAL (n= 462) vs. placebo (n= 267) + OBR in subjects with 3-class resistant virus | At week 16, 62% of RAL recipients vs. 35% of placebo recipients had plasma HIV-1 RNA levels <50 copies/mL. Sixty-four of 94 subjects with VF had RAL resistance to IN mutations at positions 143, 148, or 155 usually in combination with one or more accessory INI resistance mutations. | |
| ANRS 139 TRIO [49] | Phase II open-label trial of RAL + DRV/r + etravirine + OBR in subjects with 3-class resistant virus (n= 103) | At week 48, 86% had plasma HIV-1 RNA levels <50 copies/mL. The 14 subjects with VF generally had low-level viremia (median plasma HIV-1 RNA levels of 90 copies/mL); none had INI resistance mutations [30]. | |
| Protocol GS-183-105 [20] | Phase IIb randomized dose-ranging trial of RTV (100 mg)-boosted EVG (20, 50, or 125 mg) QD + OBR (n= 205) vs. RTV-boosted PI + OBR (n= 73). Adding DRV or TPV to EVG/r was permitted later in the trial and used after week 16. | The EVG 20 mg arm was discontinued at week 8. The 125 mg EVG dosage regimen produced a significantly greater decrease in plasma HIV-1 RNA levels than the comparator RTV-boosted PI arm. However, plasma HIV-1 RNA levels <50 copies/mL occurred mainly in those EVG recipients who also received enfuvirtide or subsequently added TPV or DRV. EVG resistance occurred commonly among EVG recipients with VF. | |
| Late-Stage Therapy: INI Experienced | VIKING [33] | Phase II single-arm study of 572 50 mg QD as RAL replacement × 10 days followed by 572 50 mg + OBR × 23 weeks (n= 27). The initial primary end point was a plasma HIV-1 RNA decrease ≥.7 logs by day 11. | In the 18 subjects with viruses having mutations belonging to the N155H or Y143 pathways, the mean plasma HIV-1 RNA decrease by day 11 was 1.8 log copies/mL. Three of 5 subjects with Q148H + G140S had an RNA decrease ≥.7 logs by day 11. None of 4 subjects with a Q148 mutation plus ≥2 additional mutations at positions 74, 138, and 140 had an RNA decrease ≥.7 logs. |
NOTE. RAL, raltegravir; EVG, elvitegravir; 572, S/GSK1349572; TDF, tenofovir; 3TC, lamivudine; FTC, emtricitabine; EFV, efavirenz; RTV, ritonavir; ATV, atazanavir; TPV, tipranavir; DRV, darunavir; LPV/r, lopinavir/ritonavir; ARV, antiretroviral; BID, twice daily; INI, integrase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; OBR, optimized background regimen; PI, protease inhibitor; QD, once daily; VF, virological ≥failure.
*Clinical trials are ordered according to their year of publication. †Raltegravir dosage was 400 mg twice daily unless otherwise specified. Other regimens and antiretrovirals were used at standard dosages unless otherwise specified.