HIV treatment has evolved from a time where two-drug regimens (2DRs) were once considered a novel concept to current times where they are a reality. |
Over the past year, national guidelines recommend 2DRs for initial consideration in the management of HIV for patients meeting certain criteria. |
When compared with three-drug regimens, many 2DRs have demonstrated noninferiority, in terms of virologic efficacy, in both the treatment-naïve and -experienced populations. |
Introduction
Methods
Results
Initial HIV Treatment Population
NRTI Inclusive
Study | Study agents | Study design | Virologic outcomes | Protocol-defined virologic failure | Additional comments |
---|---|---|---|---|---|
NRTI-inclusive regimens | |||||
GEMINI 1/GEMINI 2 [10] | GEMINI-1 | Two parallel, phase 3 randomized, non-inferiority studies performed in 21 countries | VL < 50 copies/ml W48 (ITT): | DTG/3TC: 0/6 | Non-inferiority met |
DTG/3TC (n = 356) | |||||
DTG + TDF/FTC: 0/4 | |||||
Response rate lower in the DTG/3TC patients with CD4 < 200 cells/mm3 | |||||
DTG + TDF/FTC (n = 358) | GEMINI-1: | ||||
DTG/3TC: 90% | |||||
GEMINI-2 | DTG + TDF/FTC: 93% | ||||
GEMINI-2: | |||||
DTG/3TC (n = 360) | DTG/3TC: 93% | ||||
DTG + TDF/FTC: 94% | |||||
DTG + TDF/FTC (n = 359) | |||||
GEMINI 1/GEMI NI 2 (96 weeks) [11] | Pooled data | VL < 50 copies/ml W96 | DTG/3TC: 0/11 | ||
DTG/TDF/FTC: 0/7 | |||||
DTG/3TC: 86% | |||||
DTG/TDF/FTC: 90% | |||||
ANDES [12] | DRV/r + 3TC (n = 70) | Phase 4, open-label, randomized, non-inferiority study performed in Argentina | VL < 50 copies/ml at W48 (ITT): | 3DR group: 0/1 | Non-inferiority met |
DRV/r + TDF/FTC (n = 75) | |||||
Generic DRV/r fixed-dose combination product (Virontar™) not available in US | |||||
2DR: 93% | |||||
3DR: 94% | |||||
GARDEL [13] | LPV/r + 3TC (n = 217) | Phase 3, open-label, randomized, non-inferiority study performed in Argentina, Chile, Mexico, Peru, Spain, and the USA | VL < 50 copies/ml at W48 (ITT): | 2DR group: 2/10 | Non-inferiority met |
LPV/r + 2NRTIs (n = 209) | |||||
More treatment-related discontinuations in 3DR group, primarily due to AZT | |||||
2DR: 88% | NRTI: 2 | ||||
3DR group: 0/12 | |||||
3DR: 84% | |||||
KALEAD Study [14] | LPV/r +TDF (n = 72) | Open-label, randomized, non-inferiority study performed in Italy | VL < 50 copies/ml at W72 (ITT): | 2DR group: 1/21 | Study was underpowered |
LPV/r + two non-TDF NRTIs (n = 80) | High discontinuation rates (42% and 44%) | ||||
PI: 1 | |||||
2DR: 51% | 3DR group: 2/12 | ||||
3DR: 53% | |||||
NRTI: 2 | |||||
NRTI-sparing regimens | |||||
FLAIR [15] | 20-week induction: | Phase 3, randomized, open-label, non-inferiority study, multicenter | VL < 50 copies/ml at W48 (ITT): | LA CAB/RPV: 3/4 | Non-inferiority met |
DTG/ABC/3TC | |||||
*Required 4-week lead-in of oral CAB 30 mg + RPV for LA CAB/RPV group | |||||
NNRTI: 3 | |||||
LA CAB/RPV: 94% | |||||
INSTI: 3 | |||||
LA CAB/RPV every 4 weeks (n = 283)* | |||||
DTG/ABC/3TC: 0/3 | |||||
DTG/ABC/3TC: 93% | |||||
DTG/ABC/3TC (n = 283) | |||||
LATTE-2 [16] | 20-week induction: | Phase 2b, randomized, open-label, non-inferiority study performed in the USA, Canada, Spain, France, and Germany | VL < 50 copies/ml at W96 (ITT): | LA CAB/RPV 8-week group: 1/2 | Non-inferiority met |
Oral CAB 30 mg + ABC/3TC | |||||
LA CAB/RPV 4-week group: 87% | NNRTI: 1 | ||||
LA CAB 400 mg/RPV 600 mg 4-week group (n = 115) | INSTI: 1 | ||||
Oral CAB group: 0/1 | |||||
LA CAB/RPV 8-week group: 94% | |||||
LA CAB 600 mg/RPV 900 mg 8-week group (n = 115) | |||||
Oral CAB + ABC/3TC: 84% | |||||
Oral CAB 30 mg + ABC/3TC (n = 56) | |||||
LATTE-2 (160 weeks) [17] | 4-week group (n = 115) | Phase 2b, randomized, open-label extension, non-inferiority study performed in the USA, Canada, Spain, France, and Germany | VL < 50 copies/ml at W96 (ITT): | No new cases of virologic failure among any groups after original 96-week period | LATTE-2 oral group “optimized” after week 96 and switched to every 4-week or 8-week LA CAB/RPV |
8-week group (n = 115) | |||||
4-week group: 83% | |||||
8-week group: 90% | |||||
Optimized 4-week group (n = 10) | Optimized 4-week group: 100% | ||||
Original 4 and 8-week LA groups were continued | |||||
Optimized 8-week group: 97% | |||||
Optimized 8-week group (n = 34) | |||||
NEAT 001/ANRS 143 [18] | DRV/r + RAL (n = 401) | Phase 3, open-label, randomized, non-inferiority study performed in Europe | VL < 50 copies/ml at W96 (ITT): | DRV/r + RAL: 18/61 | Non-inferiority met |
NRTI: 2 | |||||
2DR group had higher failure rates when baseline CD4 < 200 cells/mm3 | |||||
DRV/r + RAL: 79% | PI: 1 | ||||
DRV/r + TDF/FTC (n = 404) | DRV/r + TDF/FTC: 82% | INSTI:15 | |||
DRV/r + TDF/FTC: 0/49 | |||||
MODERN [19] | Daily MVC (150 mg) + DRV/r (n = 396) | Phase 3, double-blind, randomized, non-inferiority study performed in Europe, the USA, Australia, and Canada | VL < 50 copies/ml at W48 (FAS): | MVC + DRV/r: 0/37 | MVC 2DR found to be inferior to 3DR |
DRV/r + TDF/FTC: 0/10 | |||||
DRV/r + TDF/FTC (n = 401) | |||||
MVC + DRV/r: 77% | Study terminated early due to virologic inferiority of the MVC arm | ||||
DRV/r + TDF/FTC: 87% | |||||
VEMAN [20] | Daily MVC (150 mg) + LPV/r twice daily (n = 26) | Prospective, open-label, randomized, proof-of concept, study performed in Italy | VL < 50 copies/ml W48 (ITT): | Not assessed | Similar virologic outcomes |
Greater immunologic benefit in MVC + LPV/r group (p = 0.033) | |||||
LPV/r + MVC: 100% | |||||
Daily TDF/FTC + LPV/r twice daily (n = 24) | LPV/r + TDF/FTC: 96% | ||||
LATTE [21] | 24-week Induction: Oral CAB 10 mg (n = 60), 30 mg (n = 60), 60 mg (n = 61) mg or EFV 600 mg (n = 62), + 2 NRTIs | Phase 2b, randomized, dose-finding study performed in the USA and Canada | VL < 50 copies/ml at W96 (ITT): | Oral CAB 10 mg: 2/2 | Dose finding study |
INSTI: 1 | |||||
NNRTI: 2 | |||||
CAB 10 mg: 68% | Oral CAB 30 mg: 0/1 | ||||
CAB 30 mg: 75% | |||||
CAB 60 mg: 84% | EFV + 2 NRTIs: 0/2 | ||||
EFV + 2 NRTIs: 63% | |||||
Maintenance: | |||||
Oral CAB + RPV | |||||
EFV + 2 NRTIs | |||||
LATTE (144 weeks) [22] | CAB 30 mg (n = 181) | Phase 2b, OLE performed in the USA and Canada | VL < 50 copies/ml at W144 (ITT): Stratified by original randomization | New cases after original 96-week period | |
Stratified by original randomization | |||||
CAB 10 mg: 2/2 | |||||
CAB 10 mg (n = 60) | |||||
CAB 30 mg (n = 60) | INSTI: 1 | ||||
CAB 60 mg (n = 61) | NNRTI: 2 | ||||
CAB 10 mg 58% | |||||
CAB 30 mg: 0/1 | |||||
CAB 30 mg 67% | |||||
CAB 60 mg 77% | |||||
RADAR [23] | DRV/r + RAL (n = 42) | Open-label, randomized, non-inferiority study performed in Dallas, TX, USA | VL < 48 copies/ml W48 (ITT): | DRV/r + RAL: 0/3 | NRTI-sparing regimen inferior at W48 |
DRV/r + TDF/FTC (n = 43) | |||||
DRV/r + RAL: 63% | |||||
DRV/r + TDF/FTC: 84% | |||||
PROGRESS [24] | LPV/r + RAL (n = 101) | Open-label, randomized, pilot study performed in the USA, Poland, Puerto Rico, Italy, and Spain | VL < 40 copies/ml at W96 (ITT): | LPV/r + RAL: 3/8 | Non-inferiority met |
LPV/r + TDF/FTC (n = 105) | INSTI: 3 | ||||
PI: 1 | |||||
LPV/r + TDF/FTC: 1/5 | |||||
LPV/r + RAL: 71% | |||||
LPV/r + TDF/FTC: 71% | |||||
SPARTAN [25] | ATV + RAL (n = 63) | Phase 2b, open-label, randomized, non-inferiority, pilot study performed in New Haven, CT, USA | VL < 50 copies/ml at W24 (mITT): | ATV + RAL: 4/6 | Study terminated early due to hyperbilirubinemia and RAL resistance emergence in ATV + RAL |
ATV/r +TDF/FTC (n = 31) | INSTI: 4 | ||||
ATV/r +TDF/FTC: 0/1 | |||||
ATV + RAL: 75% | |||||
ATV/r +TDF/FTC: 63% |
NRTI Sparing
Maintenance/Switch Treatment Population
NRTI Inclusive
Title | Study agents | Study design | Outcomes | Emergent resistance | Additional comments |
---|---|---|---|---|---|
NRTI-inclusive regimens | |||||
TANGO [27] | DTG + 3TC (n = 369) | Phase 3, open-label, randomized non-inferior, switch study performed in the USA, Spain, UK, The Netherlands, Germany, Japan, France, Canada, Belgium, Australia | VL < 50 copies/ml at W48 (ITT): | TAF-based regimen: 0/1 | Non-inferiority met |
TAF-containing 3 or 4DR (n = 372) | |||||
2DR: 93% | |||||
3 or 4DR: 93% | |||||
ASPIRE [28] | DTG + 3TC (n = 45) | Open-label, randomized, non-inferiority study performed in the USA | VL < 50 copies/ml at W48 (ITT): | 2DR group: 0/1 | Non-inferiority met |
Continue 3DR (n = 45) | |||||
2DR: 91% | |||||
3DR: 89% | |||||
ATLAS-M [29] | ATV/r + 3TC (n = 133) | Open-label, randomized, non-inferiority study performed in Italy | VL < 50 copies/ml at W48 (ITT): | 2DR group: 0/2 | Non-inferiority met |
Superiority identified in post hoc analysis for 2DR group | |||||
Continue ATV/r + 2 NRTIs (n = 133) | 3DR group: 0/6 | ||||
2DR: 90% | |||||
3DR: 80% | |||||
DUAL GESIDA [30] | DRV/r + 3TC (n = 129) | Phase 4, open-label, randomized, non-inferiority study performed in Spain | VL < 50 copies/ml W48 (ITT): | 2DR group: 0/4 | Non-inferiority met |
DRV/r + 2NRTIs (n = 128) | 3DR group: 0/2 | ||||
2DR: 89% | |||||
3DR: 93% | |||||
OLE [31] | LPV/r + 3TC (n = 123) | Open-label, randomized, non-inferiority trial performed in Spain and France | VL < 50 copies/ml at W48 (ITT): | 2DR group: 0/3* | Non-inferiority met |
*One case of NRTI resistance in 2DR group found to be a previously archived mutation | |||||
LPV/r + 2NRTIs (n = 127) | 3DR group: 0/3 | ||||
2DR: 88% | |||||
3DR: 87% | |||||
SALT [32] | ATV/r + 3TC (n = 143) | Open-label, randomized, non-inferiority study performed in Spain | VL < 50 copies/ml at W48 (ITT): | 2DR group: 0/6 | Non-inferiority met |
ATV/r + 2NRTIs (n = 143) | 3DR group: 1/4 | ||||
2DR: 77% | |||||
3DR: 76% | |||||
NRTI: 1 | |||||
SALT (96 weeks) [33] | VL < 50 copies/ml at W96 (ITT): | 2DR group: 0/9 | Non-inferiority met | ||
3DR group: 1/5 | |||||
2DR: 74% | |||||
3DR: 74% | NRTI: 1 | ||||
COOL [34] | EFV + TDF (n = 74) | Open-label, randomized, non-inferiority study performed in France | VL < 50 copies/ml at W48 (ITT): | 2DR group: 3/3 | 2DR failed to meet non-inferiority |
EFV + TDF + 3TC (n = 74) | NNRTI: 3 | ||||
2DR: 82% | |||||
3DR: 97% | |||||
NRTI-sparing regimens | |||||
DUALIS [35] | DTG + DRV/r (n = 131) | Phase 3b, open-label, randomized, non-inferiority, switch study performed in Germany | VL < 50 copies/ml at W48 (ITT): | Not reported but no treatment emergent resistance | Non-inferiority met |
Continue 3DR (n = 132) | Premature termination of recruitment due to slow recruitment | ||||
DTG + DRV/r: 86% | |||||
Continued 3DR: 88% | |||||
SWORD 1/SWORD 2 [36] | SWORD-1 | Phase 3, open-label, parallel-group, randomized, non-inferiority switch study performed in 12 countries | VL < 50 copies/ml at W48 (ITT): | 2DR group: 1/3 | Non-inferiority met |
DTG/RPV (n = 252) | |||||
NNRTI: 1 | |||||
Current 3DR (n = 256) | SWORD-1 | 3DR group: 0/6 | |||
2DR: 95% | |||||
SWORD-2 | 3DR: 96% | ||||
DTG/RPV (n = 261) | SWORD-2 | ||||
2DR: 94% | |||||
Current 3DR (n = 255) | 3DR: 94% | ||||
SWORD 1/SWORD 2 148-Week Open-Label Extension Data [37] | Early switch-original SWORD 1/SWORD 2 DTG/RPV cohort | Phase 3, OLE performed in 12 countries | VL < 50 copies/ml at W148 (ITT): | Early switch: 4/14 | Non-inferiority met |
NNRTI: 4 | |||||
Early switch: 84% | Late switch: 2/11 | ||||
Late switch-3DR patients virologically suppressed at W48 switched to DTG/RPV at W52 | |||||
Late switch: 90% | NNRTI: 2 | ||||
DTG/RPV early switch (n = 513) | |||||
DTG/RPV late switch (n = 477) | |||||
ATLAS [38] | 4-week induction for IM CAB/RPV group: oral CAB 25 mg + RPV 25 mg | Open-label, randomized, non-inferiority, switch study performed in the USA, Italy, Germany, Spain, South Africa, Russia, Canada, and Belgium | VL < 50 copies/ml at W48 (ITT): | 2DR group: 3/3 | Non-inferiority met |
Patient satisfaction survey reported 97% of patients were more satisfied with IM regimen over oral regimen during lead-in phase | |||||
NNRTI: 3 | |||||
INSTI: 1 | |||||
IM CAB/RPV: 93% | 3DR group: 3/4 | ||||
3DR: 96% | |||||
LA CAB/RPV (400/600 mg) every 4 weeks (n = 308) | NRTI: 2 | ||||
NNRTI: 2 | |||||
NNRTI/PI/INSTI + 2 NRTIs (n = 308) | |||||
PROBE [39] | DRV/r + RPV (n = 30) | Open-label, randomized, non-inferiority, switch study performed in Italy | VL < 50 copies/ml at W48 (ITT): | None in either group | Non-inferiority met |
Continue 3DR (n = 30) | 3DR limited to ATV or DRV/r + 2NRTIs (most common NRTI-backbone TDF/FTC) | ||||
2DR: 97% | |||||
3DR: 93% | |||||
MARCH [40] | MVC + PI/r (n = 158) | Open-label, randomized, non-inferiority, switch study performed in various countries | VL < 50 copies/ml at W48 (ITT): | MVC + PI/r: 4/18 | Switch to NRTI-sparing 2DR found to be inferior and was discontinued from the complete 96-week study period |
NNRTI: 1 | |||||
MCV + PI/r: 78% | |||||
PI: 1 | |||||
MVC + 2NRTIs: 92% | |||||
MVC + 2NRTIs (n = 157) | CXCR4 tropic: 3 | ||||
Continued 3DR: 95% | |||||
MVC + 2NRTIs: 5/6 | |||||
Continue 3DR (n = 82) | |||||
NNRTI: 2 | |||||
NRTI: 5 | |||||
PI: 1 | |||||
Continued 3DR: 1/1 | |||||
NNRTI: 1 | |||||
HARNESS [41] | ATV/r + RAL (n = 72) | Open-label randomized, pilot switch study performed in the USA, UK, Germany, Spain, Italy, France, and Poland | VL < 50 copies/ml at W48 (ITT): | 2DR group: 2/9 | Study terminated due to increased virologic rebound and emergent resistance in 2DR |
ATV/r + TDF/3TC (n = 37) | |||||
2DR: 69% | |||||
3DR: 87% | PI: 1 | ||||
INSTI: 2 | |||||
3DR group: 0/1 | |||||
SECOND-LINE [42] | LPV/r + RAL (n = 270) | Phase 3b/4, randomized, open-label, non-inferiority study performed in Africa, Asia, Europe, and Latin America | VL < 50 copies/ml at W96 (ITT): | 2DR group: 23/83 | Non-inferiority met |
LPV/r + 2 NRTIs (n = 271) | NRTI: 2 | Limited to treatment-experienced patients with evidence of virologic failure on NNRTI + dual NRTI regimen | |||
2DR: 70% | PI: 1 | ||||
3DR: 68% | INSTI: 20 | ||||
3DR group: 11/82 | |||||
NRTI: 8 | |||||
PI: 2 | |||||
INSTI: 1 | |||||
KITE [43] | LPV/r + RAL (n = 40) | Open-label, randomized, pilot switch study performed in Atlanta, GA, USA | VL < 50 copies/ml at W48 (ITT): | 2DR group: */1 | *Treatment-emergent resistance among cases of virologic failure not assessed |
Current 3DR (n = 20) | 3DR group: */2 | ||||
2DR: 92% | |||||
3DR: 88% |