Table 3.
Clinical trials of ART modification in virologically suppressed patients
| Classes | Study | Study design | Key inclusion criteria | Findings |
|---|---|---|---|---|
| Within NRTI | BICOMBO [52] | • 2 NRTIs → ABC/3TC (n = 190) vs. TDF/FTC (n = 290) • 48 W |
• VL <200 × 24 W • Cr <2 mg/ml |
• Trend towards increased TFa by ITT with ABC (19 %) vs. TDF (13 %; p = 0.06) • 4 patients on ABC vs. 0 on TDF developed VF (p = 0.04) • Median CD4 increase was greater with ABC (44 cells/mm3) vs. TDF (−3 cells/mm3) |
| STEAL [53] | • ≥2 NRTIs → ABC/3TC (n = 180) vs. TDF/FTC (n = 180) • 96 W |
• VL <50 × 12 W • eGFR ≥70 |
• Similar rates of VF (confirmed VL >400) for ABC/3TC (5.6 %) vs. TDF/FTC (3.9 %) • ↑ Cardiac events with ABC/3TC (2.2/100 patient years) vs. TDF/FTC (0.3/100 patient years; p = 0.05) • ↓ Bone mineral density (hip T-score) with TDF/FTC |
|
| SWIFT [54] | • ABC/3TC + PI/r → TDF/FTC + PI/r (n = 155) vs. no change (n = 156) • 96 W |
• VL <200 × 12 W • No resistance to TDF/FTC or PI/r • eGFR ≥50 |
• ↑ VF (confirmed VL >200) with ABC/3TC (11/156; 7.1 %) than TDF/FTC (3/155; 1.9 %, p = 0.03) • ↓ Cholesterol, triglycerides and Framingham risk with TDF/FTC • ↓ Bone mineral density (hip T-score) with TDF/FTC • ↓ eGFR (8.3 vs. 4.5 ml/min) with TDF/FTC |
|
| Behrens et al. [55] | • ABC/3TC + LPV/r → TDF/FTC + LPV/r (n = 43) vs. no change (n = 42) • 12 W |
• VL <50 × 12 W • Total cholesterol ≥200 mg/dl |
• ↓ Total cholesterol (26 mg/dl, p < 0.001) and LDL cholesterol (15 mg/dl, p = 0.005) with TDF/FTC. ↓ HDL cholesterol with TDF/FTC (4 mg/dl) compared to control (1 mg/dl, p = 0.026) | |
| ASSURE [56] | • TDF/FTC + ATV/r → ABC/3TC + ATV (n = 199) vs. no change (n = 97) • 24 W |
• VL <75 × 2 tests • No prior VF |
• 87 % of patients in both arms had VL <50 at week 24 • Adverse reactions were low in both arms |
|
| ROCKET [57] | • ABC/3TC + EFV → TDF/FTC + EFV (n = 78) vs. no change (n = 79) • 12 W |
• VL <50 × 12 W • Hyperlipidemia • eGFR ≥60 |
• ↓ LDL cholesterol with TDF/FTC (22 mg/dl). ↓ HDL cholesterol with TDF/FTC (5 mg/dlL) | |
| SWAP [58, 59] | AZT/3TC → ABC/3TC (n = 20) vs. TDF/FTC (n = 20) | VL <40 × 12 W | • ↓ Bone mineral density by 2 % at 24 and 48 W with TDF/FTC | |
| Within PI | SWAN [60] | • PI or PI/r-regimen → ATV (n = 278) (ATV/r if on TDF, n = 26) vs. no change (n = 141) • 48 W |
• Stable PI ≥12 W • VL <50 × ≥12 W • No prior VF on a PI-containing regimen |
• ↓ VF for those on ATV or ATV/r (19/278; 7 %) vs. control (22/141; 16 %, p = 0.004) • ↓ Total cholesterol, non-HDL cholesterol, and fasting TG for those on ATV or ATV/r |
| ATAZIP [61] | • LPV/r + NRTIs → ATV/r + NRTIs (n = 121) vs. no change (n = 127) • 48 W |
• VL <200 × 24 W • ≤2 episodes of VF on a PI-regimen • ≤5 PI-DRMs |
• Similar rates of TF with ATV/r (21/121; 17 %) vs. LPV/r (25/127; 20 %) • Similar rates of VF (confirmed VL >200) with ATV/r (6/121; 5 %) vs. LPV/r (9/127; 7 %) |
|
| ARIES [62] | • ATV/r + ABC/3TC induction × 36 W → ATV + ABC/3TC (n = 210) vs. no change (n = 209) • 48 W |
• ART-naïve • VL <50 × 36 W • HLA-B*5701− |
• Similar rates of overall TF (14 vs. 19 % by TLOVRb) and VF (1/210; 0.5 % vs. 7/209; 3.5 %) with ATV vs. ATV/r, respectively | |
| InduMa [63] | • ATV/r + 2 NRTIs induction × 24 W → ATV + 2 NRTIs not including TDF (n = 87) vs. no change (n = 85) • 48 W |
• ART-naïve • VL <50 × 24 W |
• Similar rates of TF with ATV/r (21/85; 25 %) vs. ATV (19/87; 22 %) • ↓ TG with ATV but no differences in LDL or HDL levels • ↓ hyperbilirubinemia (26 % vs. 15 %) with ATV |
|
| ASSURE [56] | • TDF/FTC + ATV/r → ABC/3TC + ATV (n = 199) vs. no change (n = 97) • 24 W |
• VL <75 × 2 tests • No prior VF |
• 87 % of patients in both arms had VL <50 at week 24 • Adverse reactions were low in both arms |
|
| SLOAT [64] | • LPV/r-containing regimen → ATV (n = 102) (ATV/r if TDF used n = 53) vs. no change (n = 87) • 48 W |
• VL <50 × 24 W | • Similar rates of VF with ATV (5/49; 10 %), ATV/r (7/53; 13 %), and LPV/r (9/87; 10 %). Of patients with VF, 5/12 on ATV or ATV/r vs 1/9 on LPV/r failed with PI resistance • ↓ TG (−80mg/dl) and total cholesterol (−19mg/dl; p < 0.001) in the ATV group |
|
| PIs to INSTI | SWITCHMRK [65] | • LPV/r + ARVs → RAL + ARVs (n = 350) vs. no change (n = 352) • 24 W |
• VL <50–75 × ≥12 W • No CAD, DM, lipid-lowering drugs |
• ↑ TF with RAL (16 %) vs. control (9 %; p < 0.05) • ↓ 13 % reduction in total cholesterol and 42 % reduction in TG with RAL |
| SPIRAL [66] |
• PI/r + ARVs → RAL + ARVs (n = 134) vs. no change (n = 139) • 48 W |
• VL <50 × 24 W | • Similar proportion with TF for RAL (15/139; 11 %) vs. control (18/134; 13 %). 4 patients in RAL arm vs 6 in control arm with VF | |
| STRATEGY-PI [67] |
• PI/r + TDF/FTC → EVG/c + TDF/FTC (n = 293) vs. no change (n = 140) • 48 W |
• No prior VF • No pre-ART TDF or FTC resistance |
• ↓ TF with TDF/FTC/EVG/c (6 %) vs. control (13 %; p = 0.025) driven by non-VF discontinuations in control arm | |
| PI to NNRTI | NEFA [68] | • PI or PI/r-regimen to 2NRTIs + NVP (n = 155), EFV (n = 156), or ABC (n = 149) • 48 W |
• NNRTI and ABC-naïve • VL <200 × 24 W |
• Kaplan–Meier estimates of death, AIDS progression, or VL >200 were 6, 10, and 13 % for EFV, NVP, and ABC, respectively. Both EFV and NVP were superior to ABC. No significant difference between EFV and NVP • 23 of 29 with VF had prior suboptimal ART regimen |
| AI266073 [69] | • PI, PI/r, NNRTI-regimen to TDF/FTC/EFV (n = 203) vs. no change (n = 97) • 48 W |
• VL <200 × 12 W • No prior VF |
• Similar proportion with TF (confirmed VL >200) for TDF/FTC/EFV (11 %) vs. unchanged therapy (12 %) • Similar results when stratified by baseline PI, PI/r, or NNRTI-regimen |
|
| SPIRIT [49] |
• PI/r + 2NRTIs → TDF/FTC/RPV (n = 317) vs. no change (n = 159) • 24 W |
• VL <50 × 24 W • No prior VF • No NRTI or RPV-resistance |
• Similar proportion with TF for TDF/FTC/RPV (6 %) vs. PI/r therapy (10 %; p = 0.15) • VF in 3/317 (0.9 %) on TDF/FTC/RPV and 8/159 (5 %) in the PI/r arm • None of 18 with a pre-ART K103N developed VF on TDF/FTC/RPV |
|
| Within NNRTI | Waters et al [70] | • 2 NRTIs + EFV → 2NRTIs + ETR 400 mg OD (intermediate vs. delayed switch) • n = 38 • 12 W |
• VL <50 • Ongoing CNS symptoms after 12 W |
• ↓ CNS symptoms with ETR vs. continued EFV by 12 W (90 % vs. 60 %; p = 0.04) |
| SWITCH-EE [71] | • EFV + 2 NRTIs → EFV vs. ETR + 2 NRTIs × 12 W (double-blind crossover) • ETR administered 400 mg OD • n = 58 |
• VL <50 × 12 W | • Median time on EFV was 3.9 years, few reported adverse CNS effects at baseline • No significant differences in CNS symptoms on EFV vs. ETR |
|
| Mills et al [72] | • TDF/FTC/EFV → TDF/FTC/RPV • n = 49 • 48 W |
• VL <50 × 12 W • EFV intolerance • No prior ART or RPV resistance |
• EFV remained therapeutic for 2–4 W post switch. RPV was therapeutic by 1–2 W post switch, because of EFV CYP450 3A4 induction • VF without drug resistance in 2/49 patients by 48 W |
|
| NNRTIs to INSTIs | SWITCH-ER [73] | • EFV + 2NRTIs → RAL + 2NRTIs vs. no change × 4 W (double-blind crossover) • n = 57 |
• VL <50 × 12 W | • Patient preference for RAL in 41 %, EFV in 23 %, and neither in 36 % based on CNS symptomatology |
| STRATEGY-NNRTI [74] | • NVP or EFV + TDF/FTC → EVG/c + TDF/FTC (n = 292) vs. no change (n = 147) • 48 W |
• VL <50 × 24 W • No prior VF • No TDF or FTC resistance • eGFR ≥70 |
• Approximately 75 % were on TDF/FTC/EFV at entry • Similar proportion with TF, TDF/FTC/EVG/c (7 %) vs. no change (12 %; p = 0.07). VF in 1 % in each arm, none failed with drug resistance |
|
| Multiple regimens to INSTIs | STRIIVING [75] | • PI, PI/r, NNRTI, or INSTI (RAL or EVG)-regimen → ABC/3TC/DTG (n = 274) vs. no change (n = 277) • 24 W |
• VL <50 × 2 tests • Stable ART × 24 W • No prior VF |
• Virologic non-inferior, 85 vs. 88 % had VL <50 • More discontinuations due to adverse events in switch arm 10/275 (4 %) vs. 0/277 in the continuation arm |
| GS Study 109[76] | • EFV, EVG/c, ATV/r or ATV/c + TDF/FTC → TAF/FTC/EVG/c (n = 959) vs. no change (n = 477) • 48 W |
• VL <50 × 24 W • eGFR ≥50 • Successful completion of prior clinical study for ARV initiation |
• Switch superior, 97 vs. 93 % had VL < 50 at 48 W (p < 0.001). • VF 1 % in both arms • Small improvement in bone density and markers of renal tubular dysfunction (measured as % change) in the switch arm |
3TC lamivudine, ABC abacavir, ART antiretroviral therapy, ARV antiretroviral, ATV atazanavir, AZT zidovudine, c cobicistat, CNS central nervous system, Cr serum creatinine, d4T stavudine, ddI didanosine, EFV efavirenz, eGFR estimated glomerular filtration rate in ml/min, ETR etravirine, EVG elvitegravir, FDA US Food and Drug Administration, FTC emtricitabine, HDL high-density lipoprotein, INSTI integrase strand transfer inhibitor, ITT intention-to-treat, LDL low-density lipoprotein cholesterol, LPV lopinavir, N number in overall study, n number in study subgroup, NNRTI non-nucleoside reverse transcriptse inhibitor, NRTI nucleos(t)ide reverse transcriptase inhibitor, NFV nelfinavir, NVP nevirapine, PI protease inhibitor, PI/r ritonavir-boosted protease inhibitor, r low-dose ritonavir, RAL raltegravir, TDF tenofovir disoproxil fumarate, TF treatment failure, TG triglycerides, TLOVR time to loss of virologic response, VF virologic failure, VL plasma viral load, vs. versus, W week
aTreatment failure (TF) definitions differ slightly between studies. TF typically encompasses virologic breakthrough, confirmed virologic failure, and medication switches due to intolerance. In ITT analyses participants lost to follow-up are considered TFs. Individual study differences are noted in the table
bTLOVR analysis is a time-dependent method of assessing antiviral treatment efficacy in study subjects with virologic suppression. Subjects with two consecutive viral load measurements over the threshold (typically 50 copies/ml) are considered failures. The FDA Snapshot algorithm has now become the preferred method of assessment because it gives similar results but is easier to calculate and interpret. Details can be found at the FDA’s website [77]