Based on the data below, we generally considered a switch to ABC/3TC/DTG or TAF/FTC/BIC or TAF/FTC/EVG/c or TAF/FTC+DTG to be an acceptable option, and apply a base rank of 1.0 to these regimens when a person is virally suppressed. We considered it less desirable (SWITCHMRK below) to switch from PI regimens to RAL regimens (acknowledging that in subgroup analysis, those without background history of failure had similar rates of suppression to LPV/r).
DTG/ABC/3TC, from heterogenous pre-enrollment regimens
STRIIVING Study[bib]233[/bib]: 553 suppressed patients were randomized to switch pre-enrollment regimen to fixed dose ABC/3TC/DTG or remain on their pre-enrollment regimen. Subjects were HIV-1-positive men and women ≥18 years of age who had achieved and maintained virological suppression (HIV-1 RNA <50 copies/ml) on an ART regimen that had been stable for ≥6 months prior to screening. The inclusion criteria required that subjects have achieved plasma HIV-1 RNA level <50 copies/ml within 6 months of starting an initial ART regimen with no plasma HIV-1 RNA level >200 copies/ml following initial suppression. Patients had no history of dual therapy and no history of treatment failure. Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART. Note, that background resistance mutations was not provided.
We applied a CHANGE BASE SCORE TO 1.0 for this regimen IF NO HISTORY OF TREATMENT FAILURE.
EVG/c/TAF/FTC or EVG/c/TDF/FTC, from heterogenous
- Open label phase III GS109, unpublished data (IDweek 2015), randomized patients with virologic suppression (including a subset that were on TDF/FTC + ATV) receiving EVG/c/FTC/TDF whose eGFR was > 50 mL/min to continue, or switch to EVG/c/FTC/TAF. There was similar virologic efficacy at 48 weeks (98% in the switch arm and 97% in the continuation arm), with improvements in Cr, proteinuria, and Bone Mineral Density in the arm receiving TAF [bib]139[/bib].
- In the GS-112 study 242 patients who were virally suppressed were enrolled with CrCl 30-69 ml/min to switch to EVG/c/TAF/FTC. Through 48 weeks no significant change in CrCl was observed. 92% maintained HIV-1 RNA <50 copies/ml. Significant improvements in proteinuria, albuminuria, and tubular proteinuria were observed. Hip and bone mineral density significantly increased from baseline to week 48.
- In a study to simplify from 2 NRTI + RAL BID, to fixed dose EVG/c/TDF/FTC. 48 patients were enrolled. Ninety-six percent of participants cited regimen simplification as the reason to enroll in the switch study. At week 48, all assessed study participants remained viro-logically suppressed (HIV-1 RNA<50 copies/mL) and maintained high CD4 cell count (median, 751 cells/mL) and stable eGFR (median, 100.5 mL/min).
- Data support switching to fixed dosed INSTI regimen, from a NNRTI regimen. In the STRATEGY: NNRTI study(5), 439 participants were randomized to no switch vs switch to EVG/c/TDF/FTC. At week 48, 271 (93%) of 290 participants in the switch group and 126 (88%) of 143 participants in the no-switch group maintained plasma viral loads below 50 copies per mL (difference 5·3%, 95% CI -0·5 to 12·0; p=0·066).There was no treatment-emergent resistance in either group.
- Data support switching to fixed dosed INSTI regimen, from a PI regimen. In the STRATEGY:PI study(10) 433 participants were randomly to switch EVG/c/TDF/FTC, or remain on a boosted PI regimen. At week 48, 272 (93·8%) of 290 participants in the switch group maintained a viral load of less than 50 copies per mL, compared with 121 (87·1%) of 139 in the no-switch group (difference 6·7%, 95% CI 0·4-13·7; p=0·025). The statistical superiority of the simplified regimen was mainly caused by a higher proportion of participants in the no-switch group than in the switch group discontinuing treatment for non-virological reasons; virological failure was rare in both groups (two [1%] of 290 vs two [1%] of 139). We did not detect any treatment-emergent resistance in either group.
- Additional support for simplification from PI to INSTI comes from the WAVES study, evaluating switching to EVG/c/TAF/FTC in women [bib]126[/bib] [bib]190[/bib]. This study evaluated TDF/FTC+ATV/r with TDF/FTC/EVG/c in 575 treatment naive patients, with primary endpoint at 48 weeks. 212 women that met viral suppression then either continued ATV/r or switched to TAF/FTC/EVG/c. An additional 48 weeks later, 94% were suppressed in the TAF/FTC/EVG/c arm compared to those that stayed on the PI. Switching led to improvements in spinal and hip bone mineral density, but did also have greater lipid increased compared to the TDF/FTC+ATV/r regimen.
2 NRTI + RAL, from 2 NRTI + LPV/r
- 2 NRTI + RAL The SWITCHMARK 032 and 033 studies are good examples of the challenges of switching from regimens with high barriers to resistance, to lower barriers to resistance in the setting of archived mutations. Both studies randomized patients w 2 NRTI + LPV/r to remaining or switching to 2NRTI + RAL, and were stopped early because the RAL arm failed to show non-inferiority. A post hoc analysis suggested that the subgroup without history of virologic failure had similar efficacy as the LPV/r arm. [bib]93[/bib].
- 2NRTI +RAL: SPIRAL [bib]292[/bib] study randomized 273 patients with suppressed viral load for 6 months on a stable boosted-PI regimen to continue PI or switch to RAL. Few were taking boosted DRV (most were LPV/r or ATV/r). After 48 weeks, 124 (89%) of 149 patients in the raltegravir arm had an HIV RNA level less than 50 copies/mL compared with 116 (87%) of 134 in the ritonavir-boosted PI group (meeting criteria for non-inferiority). SPIRAL did not identify prior virologic failure or NRTI resistance mutations as risk factors for virologic failure. SPIRAL patients also had improvements in lipid parameters, cardiovascular biomarkers and bone mineral density compared to boosted PI
- ABC/3TC/DTG, to TAF/FTC/BIC Study 380-1844: Randomized phase III trial of patients suppressed on ABC/3TC/DTG with eFGFR>50, no active HBV, and no known resistance to study drugs randomized to stay or switch to BIC/FTC/TAF. At 48 weeks there was no treatment emergent resistance, and 94% vs 95% were virologically suppressed, respectively. (Molina JM CROI 2018, Abstract O22)
Suppresseive INSTI or PI based regimen, to TAF/FTC/BIC
- Randomized trial in Uganda, Russia, Thailand, US, DR among Women randomized to stay on baseline regimen of EVG/c/FTC/(TAF or TDF)(95%) or ATV/r+FTC/TDF(5%). At 48 weeks 85% suppressed on baseline ART vs 96% on BIC/FTC/TAF. (Kityo et al. CROI 2018 Abstract 500)
Early data suggests this may be an effective strategy; Consequently when there is multi-class resistance, we prioritized regimens that included EVG/c, DTG, or BIC (extrapolated data) with 2NRTI's and a boosted DRV.
In Virally suppressed patients with baseline ≥2 ARV class mutations, but no INSTI mutations and no DRV mutations, were randomized to continue current regimen vs EVG/c/FTC/TAF plus DRV. At 48 weeks, 94% of patients on EVG/c/FTC/TAF + DRV maintained Vl <50 copies/mL vs 76% on their baseline regimen.[bib]219[/bib][bib]484[/bib]
There isevidence from treatment naïve patients that DTG + 3TC is effective. We considered the data to be sufficient to Apply a Base-Rank of 1.0 to regimens that included DTG plus 3TC. based on DHHS (2019) guidelines. While data is more limited, we also applied a base rank of 1.5 to scenarios of DTG+ an additional unspecified ARV.
In the ANRS 167 LAMIDOL study, an open Label single arm study of switching from suppressive Triple ART to DTG+3TC. Patients had to have viral suppression for greater than or equal to 2 years on first line ART with less than 2 ART modifications and have CD4>200. 101/104 maintained suppression at 48 weeks. There were 3 virologic failures, none with INSTI resistance.[bib]192[/bib]
The GEMINI studies (see education sheet for DTG+3TC) have suggested that DTG_3TC may be an acceptable regimen in patients that are newly initiating ARV's. We extrapolate this data to infer that this regimen may therefore be acceptable when already virally suppressed.
--Unresolved question: whether this regimen would be effective in patients with baseline 3TC resistance.
- In a retrospective analysis of the Antiertroviral Resistance Cohort Analysis Database (N=436), outcomes were assessed among those with HIV Vl<=50, who were switching to 3TC +PI/r (36% DRV, 24%ATV, 10% LPV+3TC) or 3TC+INSTI (29% DTG+3TC), and had M184V in hisotoric genotypes. At 3 years of follow up, there was no difference in risk of VF comparing those with and without M184V (p=.323), though higher amount of viral blips with M184V compared to without M184V(90% free of VB without M184V vs 79.8% free with M184V). (Gagliardini CROI 2018 Abstract 498)
- There are two phase III RCTS (SWORD1 and SWORD 2) that evaluated the strategy of switching from stable ARV regimens (2NRTIs + etiher PI, INSTI or NNRTI) to DTG plus RPV. 516 participants were randomized to dolutegravir-rilpivirine and 512 to continue with current regimen. At week 48, in the pooled analysis 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the current regimen group) and showed non-inferiorityThe most common adverse events were nasopharyngitis (49 [10%] for dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]).[bib]191[/bib][bib]293[/bib]
- In an observational cohort at eight centers in Italy, 132 subjects were followed for median of 24 months on DTG + RPV. Most were switched to this regimen for simplification (53%) or toxicity (35%), and nearly half had RT mutations and nearly half had PI mutations, and majority were virally suppressed at time of starting on to DTG +RPV. At 24 weeks, all but one individual appeared virally suppressed [bib]140[/bib].
- In an open label cohort study switching virologically suppressed patients with multiple previous treatment failures to once daily RPV/DTG was found to be safe and effective through week 48. CD4 cell count remained stable after the switch, and the regimen was associated with improved liver function tests, improved lipid profile, and stable kidney function at 48 weeks [bib]128[/bib].
- Cabotegravir plus RPV: Latte I and II. [bib]294[/bib][bib]295[/bib] These studies of long acting injectable cabotegravir have suggested that this regimen may be acceptable for maintance or simplification in patients that are virally suppressed.
We have applied a base-score change to 1.0 for DTG/RPV, if there is no history of treatment failure. Otherwise, DTG+one other active drug is modified to a 1.5.
New DHHS guidelines suggest that DTG/RPV may be an acceptable regimen in patients with virologic suppression without history of treatment failure. As such, we assign a 'base-score' of 1.2 (preferred regimen) for DTG/RPV in suppressed patients without prior treatment experience or failure. Given lack of data (but emerging data) on this regimen in patients with history of treatment failure, we prioritize it but not to the same degree in such cases (base score of 2.0).
Pending more data, avoid DTG monotherapy, particularly if there is a history of INSTI exposures.
- Unpublished, presented EACS 2015: Spanish study of 33 patients with suppression for at least 12 months on PI (67%) regimen, or NNRTI regimen (27%), or INSTI (6%) regimen, being simplified due to either comorbidities, drug interactions, side effects, or other resistance. 32/33 maintained virologic suppression at 24 weeks.
- Unpublished, presented EACS 2015: Cohort study of 28 patients in Paris with long term virological suppression, and naïve or without history of failure to INSTI, were switched to DTG monotherapy. 3/28 experienced viral failure (all of whom had prior exposures to INSTI).
- Dolumono study[bib]301[/bib]: In this rerospective single center cohort study, 31 patients on suppressive ART were switched to DTG monotherapy (with no known piror INSTI resistance or failure). Prior ART included NNRTI, PI, or INSTI regimens (32%, 6%, and 61% respectively). At 24 weeks, 94% had HIV RNA <50 copies/ml (all suppressed except 2). One of those two developed a new INSTI mutation (Q148H//G140S).
- DOMONO study was a multicenter Dutch randomized trial of 104 patients of DTG QD compared to continued ART in patients virally suppressed for at least 6 months (51 immediate switch, 53 delayed switch). At week 24, dolutegravir monotherapy was non-inferior to combination ART, with VL> 200 copies per mL in 2% (1/50) in the immediate switch group and in no patients in the delayed switch group . Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation..[bib]302[/bib]