Introduction
Rationale for NRTI-sparing regimens
NRTI-sparing regimens in treatment-experienced failing patients
Author, name of the trial, if any/year/published? | Design | Comparison | N | Follow-up (weeks) | Results |
---|---|---|---|---|---|
Boyd et al. [18], SECOND-LINE/2013/Yes | Phase-3/4 RCT, non-inferiority | (i) LPV/r + RAL vs. (ii) LPV/r + recycled NRTIs in those failing 1st line NNRTI-based ART | 541 (271 vs. 270) | 48 | -Arm (i) non-inferior to arm (ii) for virological outcome |
-No major differences in serious adverse events | |||||
-Greater decline in BMD in arm (ii) [25] | |||||
Paton et al. [19], EARNEST/2013/No | Phase-3/4 RCT, non-inferiority | (i) LPV/r + RAL | (i) 433; (ii) 418; (iii) 426 | 96 | -Arm (i) non-inferior to arm (iii) for a composite of virological and clinical endpoint |
(ii) LPV/r monotherapy after induction with LPV/r + RAL | |||||
(iii) LPV/r + recycled NRTIs (control) in those failing 1st line NNRTI-based ART | -Arm (ii) inferior to other arms for virological outcome and higher LPV/r resistance | ||||
-No differences in grade 3/4 events | |||||
Tashima et al. [20], OPTIONS/2013/No | Phase-3/4 RCT, non-inferiority | (i) NRTI-omitting optimised regimen | (i) 179; (ii) 181 | 48 | -Similar virlogical outcomes in both arms |
(ii) NRTI-including optimised regimen in triple-class experienced failing patients | -No differences in grade 3/4 events | ||||
-Higher mortality in arm (ii). | |||||
Ruane et al. [24], INROADS/2013/No | Single-arm exploratory phase-2b trial | DRV/r + ETV in failing patients (78%) or ART naïve patients with transmitted resistance (22%) | 54 (75% completed the study) | 48 | -100% of ART naïve and 87% of failing patients achieved virological success. |
-2 patients developed ETV mutations and none had DRV mutations. | |||||
Imaz et al. [21]/2011/Yes | Observational | Salvage regimen of at least three active agents from DRV, ETV, RAL and MVC, with or without NRTIs | 122 | 48 | -78% virologically suppressed (equal in both arms) |
-Higher baseline viral load associated with worse outcomes. | |||||
Nozza et al. [22]/2011/Yes | Observational | Salvage regimen of RAL + MVC + ETV | 28 | 96 | -96% virologically suppressed (<50 copies/ml) |
Florence et al. [23]/2010/Yes | Observational | Salvage regimen of ETV + optimised regimen, 40% without NRTIs | 941 | 24 | -70% and 90% had viral load <50 and 400 copies/mL respectively. |
NRTI-sparing regimens in patients receiving suppressive ART
Author, name of the trial, if any/year/published? | Design | Comparison | N | Follow-up (weeks) | Results |
---|---|---|---|---|---|
Monteiro et al. [36]/2013/Yes | Observational | RAL + ETV | 25 | 48 | -91% virologically suppressed in per-protocol analysis |
-Lipids improved | |||||
Ward et al. [26]/2013/No | Observational | Switching for toxicity concerns to a RAL + 1 or 2 agents, most commonly on RAL + ATV/r with or without ETV or MVC | 62 | 168 | -92% virologically suppressed; |
-3 of 15 on dual therapy had to add third agent for low-level viremia | |||||
Calin et al. [27]/2013/No | Observational | Switching to RAL + ETV regimen | 91 | 48 | -93% had viral load <50 copies/mL |
-4/5 with virological failures had past NNRTI mutations | |||||
-3 patients had RAL mutations | |||||
Katlama et al. [28], ROCnRAL/2013/No | Single-arm exploratory trial | R5-trophic suppressed patients switched to MVC + RAL | 41 | 48 | -Failure in 11.4% |
-RAL mutations in 3/5 patients who failed | |||||
-1/5 had R5 to ×4 virus switch | |||||
Cotte et al. [29], No Nuc No Boost/2013/No | Single-arm exploratory trial | MVC + RAL | 10 | 48 | -No virological failures (>50 copies/mL) |
-No serious adverse event | |||||
Burgos et al. [30]/2012/No | Observational | Switching for toxicity concerns to a PI/r + 2nd agent, many with no NRTI | 131 | 56 | - > 90% virologically suppressed. |
Ofotokun et al. [31], KITE/2012/No | Exploratory pilot trial | (i) LPV/r + RAL; (ii) standard ART | 60 | 48 | -92% in arm (i) and 88% in arm (ii) with viral load <50 copies/mL; |
-Higher triglycerides in arm (i) | |||||
-No difference in BMD or body composition. | |||||
Carey et al. [32], SPARTA/2012/Yes | Pilot cross-over RCT | Patients receiving ATV/r randomized to: (i) ATV/r (300/100 mg respectively once daily) + RAL (800 mg once daily) | 25 | 76% in follow-up for 48 weeks | -Both agents pharmacologically compatible. |
(ii) ATV (300 mg twice daily) + RAL (400 mg twice daily) | -All patients remained virologically suppressed | ||||
Cordery et al. [35]/2010/Yes | Observational | RAL + ATV (unboosted) | 20 | 72 | -Only 1 (5%) failure |
Allavena et al. [33]/2009/Yes | Observational | Switching for toxicity concerns to a PI/r + RAL. | 29 | 48 | -100% virologically suppressed |
Fischl et al. [34]/2007/Yes | RCT, not fully powered | (i) LPV/r + EFV; | 236 | 96 | -Arm (i): shorter time to failure or discontinuation; |
(ii) EFV + NRTIs | |||||
-Arm (i): greater increase in triglycerides |
Boosted-PI monotherapy
NRTI-sparing regimens in ART naïve patients
Author, name of the trial, if any/year/published? | Design | Comparison | N | Follow-up (weeks) | Results |
---|---|---|---|---|---|
Mills et al. [41], A4001078/2013/Yes | RCT, phase-2b pilot | (i) MVC + ATV/r | 121 | 48 | -75% in arm (i) and 84% in arm (ii) had viral load <50 copies/mL. |
(ii) TDF + FTC + ATV/r | |||||
-More hyperbilirubenmia in arm (i) | |||||
-Nine in arm (i) and 3 in arm (ii) had low-level viremia after virological suppression | |||||
Reynes et al. [42], PROGRESS/2013/Yes | RCT pilot study | (i) LPV/r + RAL | (i) 101; (ii) 105 | 96 | -66.3% in arm (i) and 68.6% in arm (ii) responded by FDA-TLOVR |
(ii) LPV/r + TDF + FTC | |||||
-Better body comp in arm (i) | |||||
-Greater decline in eGFR in arm (ii) | |||||
Kozal et al. [47], SPARTAN/2012/Yes | RCT pilot study | (i) ATV + RAL | (i) 63; (ii) 31 | 24 | -74.6% in arm (i) and 63.3% in arm (ii) had viral load <50 copies/mL |
(ii) ATV/r + TDF + FTC | |||||
-4/6 failures in arm (i) had RAL mutations. | |||||
-20% incidence of grade-4 hyperbilirubenimia in arm (i). | |||||
Single-arm pilot | MVC + DRV/r | 25 | 96 | -Viral load < 50 copies/mL: 8.3% and 10% at week 48 and 96, respectively. | |
-Virological failures mainly explained be high baseline viral load >100000 copies/mL | |||||
Bedimo R et al. [44], RADAR/2011/No | RCT pilot | (i) RAL + DRV/r | 80 | 24 | -86% in arm (i) and 87% in arm (ii) had viral load <50 copies/mL |
(ii) DRV/r + TDF + FTC | |||||
Taiwo et al. [45], ACTG5262/2011/Yes | Single-arm pilot | DRV/r + RAL | 112 | 48 | -26% with viral load > 50 copies/mL, majority with low-level viremia (<200 copies/mL) |
-Baseline viral load >100000 copies/mL strongly associated with failure | |||||
Riddler et al. [46], ACTG5142/2008/Yes | RCT | (i) EFV + NRTIs | (i) 250 | 96 | -89%, 77% and 83% had viral load <50 copies/mL in arms (i), (ii) and (iii) respectively |
(ii) LPV/r + NRTIs | (ii) 253 | ||||
(iii) LPV/r + EFV | (iii) 250 | ||||
-No difference in time to toxic effects | |||||
-At failure, resistance mutations more common in arm (iii) |