Table 2. Overview of studies in systematic review, grouped according to study-design and indication: regimens, population size, treatment duration and summary of main outcome data and conclusions.
| INI (n = ) | CTRL (n = ) | Regimen | (w) | Summary | |
| ART-naive patients: INI in combination with dual NRTI | GRADE: HIGH | ||||
| STARTMRK [15]–[19] | 281 | 282 | RAL 400 mg bd + TDF/FTC vs. EFV + TDF/FTC | 240 | Non-inferiority of raltegravir in reaching VL<50 c/ml (71% vs 61.3% EFV, mITT); Significantly more rapid decline of viral load in early phase with INI; Mean CD4 increase 374 (INI) versus 312 cells/ml (EFV). |
| Protocol 004 [20]–[22] | 160 | 38 | RAL 100, 200, 400 or 600 mg bd + TDF/3TC vs. EFV + TDF/3TC | 240 | Similar proportions of VL<50 c/ml (69% vs 63%, mITT) in all dosages (400 mg bd single arm as from w48) - non-inferiority for raltegravir; Similar mean CD4 increase (302 versus 267 cells/ml); Less frequent drug-related clinical adverse events with raltegravir (55%) than efavirenz (76%). |
| SHIELD [24] | 35 | N | RAL 400 mg bd + ABC/3TC | 96 | Proportion of VL<50 c/ml (mITT: 77%); Median CD4 increase 304 cells/ml; No drug-related serious adverse events reported |
| GS-236-014 [26] | 48 | 23 | EVG/COBI single tablet qd+ TDF/FTC vs. EFV + TDF/FTC | 48 | Non-inferiority of elvitegravir/cobicistat in suppressing VL<50 c/ml (mITT: 90% vs 83% treatment difference +8.4% (−8.8 to +25.6%). Treatment with EVG/COBI associated with more rapid achievement of undetectable VL than EFV/FTC/TDF (P<0.05 at weeks 2,4 and 8). Lower rate of drug-related central nervous system and psychiatric adverse events in EVG/COBI group |
| GS-236-0102 [25] | 348 | 352 | EVG/COBI/FTC/TDF qd vs EFV/TDF/FTC | 48 | Non-inferiority of QUAD (EVG/COBI/TDF/FTC) in suppressing VL<50 c/ml (mITT 87.6% vs 84.1%; treatment difference +3.6% CI −1.6 to +8.8%). Treatment with QUAD associated with higher CD4 increase at 48w (239 cells/µL vs 206 cells/µL p = 0.009). Similar numbers of patients discontinued treatment because of an adverse event in each group. Nausea was more common in the QUAD group, CNS and psychiatric adverse events more frequent with EFV |
| SPRING-1 [27]–[29] | 155 | 50 | DTG 10,25 or 50 mg + TDF/FTC or ABC/3TC vs. EFV + TDF/FTC or ABC/3TC | 48 | Similar response rates (VL<50 c/ml) for all doses of dolutegravir compared to efavirenz (mITT 87% versus 82%); Median CD4 increase in all dolutegravir groups were higher than efavirenz (231 cells per µL vs 174 cells per µL; p = 0·076); No serious adverse events related to dolutegravir |
| SINGLE [14] | 414 | 419 | DTG 50 mg + ABC/3TC vs. EFV/TDF/FTC | 48 | Significant better virological reponse of DTG/ABC/3TC compared to EFV/TDF/FTC (mITT 88% vs 81%); median CD4 increase significantly higher in DTG/ABC/3TC (267 vs 208 cells/µl; p<0.001) No INI or NRTI resistance observed in the DTG-treated group and no serious adverse events. |
| GS-236-0103 [31] | 353 | 355 | EVG/COBI/FTC/TDF qd vs ATV/r + TDF/FTC | 48 | Non-inferiority of QUAD (EVG/COBI/TDF/FTC) in suppressing VL<50 c/ml (mITT 89.5% vs 86.8%; treatment difference +3.0% CI −1.9 to +7.8%). Similar increase of CD4 count in both groups. Similar numbers of patients discontinued treatment because of an adverse event in each group. More Grade 3 and 4 lab abnormalities in the ATV/r group compared to QUAD. |
| SPRING -2 [30] | 413 | 414 | DTG 50 mg qd + TDF/FTC or ABC/3TC vs RAL 400 mg bd + TDF/FTC or ABC/3TC | 48 | Non-inferiority of dolutegravir versus raltegravir in reaching VL<50 c/ml (ITT 88% vs 85%). Similar median CD4 increase (230 CD4 cells/µl). Discontinuation due to serious adverse events 2% in each group. No IN or NRTI resistance upon failure in DTG group versus 1 and 4 pts in the RAL groups. |
| QDMRK [23] | 382 | 388 | RAL 800 mg bd + TDF/FTC vs. RAL 400 mg bd + TDF/FTC | 48 | mITT: 83% in the once-daily group had virological response compared with 89% in the twice-daily group (difference −5·7%, 95% CI −10·7 to −0·83; p = 0·044); Mean CD4+ increase comparable in both groups; serious adverse events reported in 7% and 10% of resp. once-daily recipients and twice-daily recipients. |
| ART-naive patients: INI in combination with PI | GRADE: MODERATE | ||||
| SPARTAN [13] | 63 | 31 | RAL 400 mg bd + ATV vs. ATV/r + TDF/FTC | 24 | Through week 24, both arms achieved comparable efficacy rates (ITT 74,6% versus 63,3% VL<50 c/ml) |
| PROGRESS [32] | 101 | 105 | RAL 400 mg bd + LPV/r vs. LPV/r + TDF/FTC | 48 | Non-inferiority of the study regimen at reaching VL<40 c/ml at week 48 (ITT 81.2% versus 85.7% ; difference −4.5%; 95% CI, −15.1% to 5.9%); Mean CD4 increase was similar between groups. |
| ACTG A5262 [34] | 112 | N | RAL 400 mg bd + DRV/r | 48 | DRV/r plus RAL was effective (mITT 73% VL<50 c/ml at week 48) and well tolerated in treatment-naive patients, but those with base-line viral load >100,000 copies/mL had more VF and INI resistance. |
| RADAR [33] | 40 | 40 | RAL 400 mg bd + DRV/r vs. DRV/r + TDF/FTC | 24 | mITT VL<50 c/ml at week 24 achieved in 75.0% (RAL treated) versus 82.5%; mean CD4 increase +143 versus 109 cells/ml |
| Fallon et al [83] | 15 | 15 | RAL 400 mg bd (naive) + LPV/r vs RAL 400 mg bd (exp) + LPV/r | 48 | mITT: 80.0% (12/15 treatment-naive) versus 73.3% (11/15 treatment-experienced) had VL<50 c/ml at 48 weeks; mean CD4 change 102 versus 66 cells/ml |
| ART-experienced patients: virological failure | GRADE: MODERATE | ||||
| BENCHMRK 1 and 2 [2], [35] | 462 | 237 | RAL 400 mg bd + NNRTI + NRTI vs. Placebo + NNRTI + NRTI | 96 | Sustained VL<50 c/ml in the combined studies of 57% (raltegravir) versus 26% (placebo) (mITT 96w); mean CD4 increase 109 versus 45 cells/ml (P<0.001 for each study individually and the combined studies); Frequencies and exposure-adjusted rates of clinical adverse events and laboratory abnormalities similar in both groups |
| Protocol 005 [36], [37] | 133 | 45 | RAL 200, 400 or 600 mg bd + optimized BR vs. Placebo + optimzed BR | 96 | Raltegravir in all doses superior than placebo in reaching undetectable VL at double-blind phase (till 24 weeks); No dose-dependent differentiation in the safety or antiviral activity of raltegravir; After 96weeks (RAL 400 mg bd >24w all groups) 55% and 48% reached VL<400 c/mL and VL<50 c/ml (mITT); There were few discontinuations of raltegravir (4%) due to adverse events. |
| ANRS 139 TRIO [3] | 103 | N | RAL 400 mg bd + ETV + DRV/r | 96 | mITT: 86% VL<50 c/ml at 48w; median CD4 increase 108 cells/ml. Grade 3 or 4 clinical adverse events reported 14,6%, though only 1 patient discontinued the regimen because of an adverse event |
| Canestri et al [39] | 20 | N | RAL 400 mg bd + ETV + optimized BR | 24 | mITT: 65% of patients reached VL<40 c/ml and 100% VL<400 c/ml; median CD4 increase +80cells/ml |
| Nozza et al [41] | 28 | N | RAL 400 mg bd + MVC + ETV | 48 | mITT/OT: At week 48, 26/28 patients achieved VL<50 c/ml. The median CD4 increase was 267 cells/µL. No patient discontinued treatment. |
| Caby et al [42] | 67 | N | RAL 400 mg bd + BR | 48 | At 48 weeks, 43/67 patients had complete (VL<50 c/ml) and 16/67 incomplete (VL<400 c/ml) suppression, while 8 patients failed (mITT). Upon failure, 6/8 patients harbored RAL resistance |
| GS-183-105 [38] | 205 | 73 | EVG/RIT 20, 50 or 125 mg bd + optimized BR vs. PI/r + optimized BR | 24 | mITT: Elvitegravir 50 mg was noninferior and elvitegravir 125 mg superior compared with the PI/r (based on DAVG24 scores). Efficacy was impacted by activity of background agents. Similar mean CD4 increase across all treatment arms; no relationship between elvitegravir dosage and adverse events. |
| GS-183-0145 [43] | 361 | 363 | EVG 150 mg qd + PI/r + NRTI vs. RAL 400 mg bd + PI/r + NRTI | 48 | Elvitegravir non-inferior (59%) compared to raltegravir (58%) in achieving complete virological response (mITT treatment diff erence +1·1%, 95% CI −6·0 to 8·2); Median CD4 increases and proportion of adverse events attributed to study drugs similar in the two treatment arms |
| VIKING I [45], [46] | 27 | N | DTG 50 mg qd + optimized BR | 24 | mITT: 52% and 41% of patients treated till 24weeks achieved VL<400 c/ml and VL< 50 c/ml; Drug related AEs (any grade) were observed in 6 (22%) subjects |
| VIKING II [47] | 24 | N | DTG 50 mg bd + BR | 11d | After 11days of functional monotherapy (triple resistant virus including INI), 54% of patients reached VL<400 c/ml (mITT). No discontinuation due to AE/lab toxicities. 17% treatment emergent grade 3 lab abnormalities. |
| ART-experienced patients: switch strategy | GRADE: LOW | ||||
| SWITCHMRK 1 and 2 [48] | 353 | 354 | RAL 400 mg bd + BR − LPV/r vs. BR | 24 | 84·4% in the raltegravir group versus 90·6% in the lopinavir-ritonavir group (mITT treatment diff erence −6·2%, −11·2 to −1·3) had VL<50 c/ml, leading to study stop. Majority of RAL-failures had RAL resistance. Mean CD4 increase was small and did not diff er between treatment groups. |
| SPIRAL [49] | 139 | 134 | RAL 400 mg bd + BR − PI/r vs. BR | 48 | Non-inferiority of raltegravir (mITT 89.2% versus 86.6% of patients remained free of treatment failure [difference +2.6%; 95% CI −5.2 to +10.6]; No differences between treatment groups in CD4 increase |
| EASIER ANRS 138 [50] | 85 | 85 | RAL 400 mg bd + BR − T20 vs. BR +− T20 or RAL (>24w) | 48 | At week 48, 90% of patients in both the immediate and deferred groups had plasma VL<50 c/ml (mITT); Median CD4 cell counts remained stable during follow-up. |
| ODIS [55] | 149 | 73 | RAL 800 mg qd + BR − PI/r vs. RAL 400 mg bd + BR − PI/r | 24 | 6.4% in the oncedaily arm and 2.9% in the twice-daily arm (mITT) experienced virological failure, with significant higher rates in patients with prior nucleoside reverse transcriptase inhibitor resistance (16,2% versus 0,7% P<0,001); significant increase in CD4 (+32 cells/µL) after switch to RAL. |
| RASTA [56] | 21 | 19 | RAL 400 mg bd + TDF/FTV vs. RAL 400 mg bd + ABC/3TC | 24 | One virological failure in TDF/FTC arm at 24 weeks; At 24w, a higher increase in CD4 count was observed in arm B versus arm A (mean +62 vs −9 cells/mm3 respectively, p = 0.04). |
| Talbot et al [53] | 28 | N | RAL 400 mg bd + BR − T20 | 24 | 26/27 patients with data at 24 weeks remained with a VL <50 c/ml; No significant changes, statistically or clinically, were observed in the CD4 counts |
| CHEER [54] | 52 | N | RAL 400 mg bd + BR − T20 | 24 | 49/52 (94.2%, confidence interval: 1.2% to 15.9%) remained with a VL<50 c/ml 24 weeks (mITT); mean CD4 increase of 32 cells/ml was seen after 24 weeks |
| Harris et al [51] | 35 | N | RAL 400 mg bd + BR − T20 | 16 | 34/35 patients have HIV RNA <50 c/ml at 16 weeks of follow-up (mITT) |
| Santos et al [52] | 36 | N | RAL 400 mg bd + BR − T20 | 48 | All but 1 patient (discontinuation) maintained VL<50 copies/mL at Weeks 24 and 48 |
| Reliquet et al [57] | 20 | N | RAL 400 mg bd + NVP | 48 | At week 48, 19/20 patients (100% undetectable VL at start) achieved VL<50 c/ml (mITT) |
| ART-experienced patients: treatment intensification | GRADE: INSUFFICIENT | ||||
| Hatano et al [63] | 15 | 15 | RAL 400 mg bd + BR vs. Placebo + BR | 48 | The proportion of subjects with undetectable VL did not differ between the 2 groups (mITT p = 0.42); Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue. |
| CORAL [59] | 19 | 54 | RAL 400 mg bd + BR vs. HIBC/placebo + BR | 24 | Compared with placebo, the addition of neither raltegravir nor HIBC to cART for 24 weeks resulted in a significant change in CD4 count (mITT mean difference, 95% confidence interval [CI]: 3.09 cells/lL, 214.27; 20.45, p = .724 and 9.43 cells/lL, 27.81; 26.68, p = .279, respectively) |
| ACTG A5244 [62] | 25 | 24 | RAL 400 mg bd + BR vs. placebo + BR | 12 | 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. |
| Buzon et al [58] | 45 | 24 | RAL 400 mg bd + BR vs. BR | 48 | Raltegravir intensification of a three-drug suppressive ART regimen resulted in a specific and transient increase in episomal DNAs in a 29% of ART-suppressed subjects; With these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. |
| McMahon et al [65] | 10 | N | RAL 400 mg bd + BR | 4 | There was no evidence in any subject of a decline in HIV-1 RNA level (ultra-sensitive assay) during the period of raltegravir intensification or of rebound after discontinuation |
| Cesar et al [60] | 10 | 10 | RAL 400 mg bd + BR vs. Placebo + BR | 48 | After 48 weeks all patients remained with VL<5 c/mL. No differences in CD4 gain were observed between placebo and raltegravir arms (mITT 11 vs. −4 respectively, t18 = 0.586, p = 0.565); Increased immune activation did not change after 48 weeks |
| Lichtenstein et al [64] | 30 | N | RAL 400 mg bd+ BR | 12 | Addition of raltegravir to a suppressive ART regimen improves some immunologic, cytokine/chemokine, and effector memory cell parameters (IFNγ, MIP-1α; IL-2 and RANTES) in immunologic non-responders. |
| Dahl et al [66] | 14 | 9 | RAL 400 mg bd + BR vs BR | 12 | Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression |
| ART-experienced patients: INI in combination with PI | GRADE: INSUFFICIENT | ||||
| Ripamonti et al [69] | 27 | N | RAL 400 mg bd + ATV | 24 | After a median follow up of 7 (IQR 5–7) months, VL was <50 c/ml in all but one of the 27 patients (63% undetectable VL at start); The median CD4 count increment was 168 cells/µl. |
| Tsukada et al [70] | 19 | N | RAL 400 mg bd + DRV/r | 48 | After a median follow up of 47 (24–102) weeks, VL<100 c/mL detected in 16/19 patients (68% undetectable VL at start) |
| Allavena et al [67] | 29 | N | RAL 400 mg bd + PI/r | 22 | After a median follow-up of 22 weeks, VL<50 c/ml in 24/29 patients (79% undetectable VL at start) |
| Cordery et al [68] | 20 | N | RAL 400 mg bd + ATV | 72 | At week 72, 13/20 patients (100% undetectable VL at start) achieved VL<50 c/ml (mITT) Median CD4 cell counts remained stable during follow-up. |
| Gardner et al [71] | 39 | N | RAL 400 mg bd + PI | 48 | After median follow-up of 47 weeks, 74% and 44% of patients reached HIV RNA<200 c/ml and <50 c/ml – mITT (46% HIV RNA<200 c/ml at start) in heavily pre-treated patients. Adherence and pre-existing PI resistance are associated with virological failure. |
GRADE level of evidence per category is added. INI-containing treatment arms are underlined.
(c)ART = (combination) antiretroviral treatment; INI = integrase inhibitor; CTR = control arm; (w) = weeks; VL<50 = viral load or HIV RNA <50 copies/ml; N = not applicable; RAL = raltegravir; EFV = efavirenz; EVG = elvitegravir; COBI = cobicistat; DTG = dolutegravir; ATV = atazanavir; DRV = darunavir; TDF/FTC = tenofovir/emtricitabine; ABC/3TC = abacavir/lamivudine; LPV = lopinavir; r = ritonavir; (N)NRTI = (non-)nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; BR = background regimen; T20 = enfurvirtide; NVP = nevirapin; HIBC = hyperimmune bovine colostrum.