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Switch Strategies in Virally Suppressed Patients

ART regimens in patients that are virologically suppressed confers risks including emergence of resistance (i.e. risk of virologic failure), or new toxicities. A central goal of switching ART regimens is to maintain viral suppression, without jeopardizing future treatment options [1].  One should consider prior documented resistance mutations, which are likely to persist in the viral reservoir.  A commercially available test can help to detect archived mutations, but its sensitivity and clinical utility is unknown.

Potential reasons to switch

  • Improve adherence (e.g., simplified regimens with fewer drugs, reduced pill burden or dosing frequency, minimize food requirements)

  • Improve tolerability (i.e. avoid toxicities of current regimen)

  • Mitigate Comorbidities

  • Avoid significant current or future drug-drug interactions

Evidence for Switching ART in patients that are virologically suppressed

The data from switch studies suggests that one should consider the drug class(es) of regimens to which a person is being switched, along with the number of agents in the future regimens, and prior treatment and resistance history.

There is some data to support simplifying to multi-drug regimens (including fixed dosed combinations) which contain an INSTI and/or PI.  In some instances, there is data to support 2 drug (class) regimens, but in other situations such strategies have been less successful (e.g., PI + EI). Strategies to simplify to monotherapy with INSTI or boosted PI have found success in niche circumstances, but data is lacking to recommend this strategy broadly.

General considerations

Score Modification Rule
Remaining on the current regimen when virally suppressed

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Regimens with equal or better pill burden and number of active drugs
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Treatment intensification in a virally suppressed patient
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Regimens with fewer than two active drugs

If one of the drugs was a fully active DTG or DRV:

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Switching for ART toxicities or side effects

Score Modification Rule
Switching for CNS toxicity

If EFV is in the current suppressive regimen, we consider it to be the likely offending agent.  There are clinical data in this setting of switching to 2NRTI + NVP [2], 2 NRTI + ETR [3], RAL [4], TAF/FTC/EVG/c [5], 2 NRTI + RPV [6].  We have extrapolated the data for RAL and EVG/c to DTG containing regimens as well.

Switching for dyslipidemia or cardiovascular toxicities/comorbidities

If ABC is in the regimen, we consider the potential for its contribution to the dyslipidemia. There are clinical data to support a switch to TDF/FTC in this setting (and we extrapolate this to include TAF) [7] [8].

If ritonavir-boosted PI is in the regimen, we consider its potential for contribution to dyslipidemia. There is data to support switch from LPV/r to ATV/r in this setting. There is also data to support switch from LPV/r to RAL [9], which we extrapolate to include DTG and other INSTIs.

Switching for diarrhea
If ritonavir boosted PI is in the regimen,we consider its potential for contribution to diarrhea. This was more frequent with LPV/r. There is data in this setting to switch to RAL(9), TDF/FTC/EVG/c [10], TDF/FTC/RPV [11], and ETR containing regimens [12]. As such, we prioritize these regimens.

 Switching or Simplifying to INSTI based regimens

Score Modification Rule
Switching to 3-drug fixed-dose combination regimens (2 NRTI + 1 INSTI)

DTG/ABC/3TC, from heterogenous pre-enrollment regimens



STRIIVING Study:  551 suppressed patients were randomized to switch pre-enrollment regimen to fixed dose ABC/3TC/DTG or remain on their pre-enrollment regimen.  Unpublished data (ICAAC 2015)—85% of those switching had Viral Load < 50 copies per mil at 24 weeks, vs 88% in the Control arm.  There were similar rates of side effects in both arms. Switching was associated with improved treatment satisfaction scores.

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 [13].
  • 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 [14] [15]. 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 [9].

Simplifying to DRV + EVG/c/TAF/FTC, from regimens with multi-class mutations

Early data suggests this may be an effective strategy

Unpublished data (IDweek 2015):  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.[16]

Simplifying to DTG + NRTI

There is some evidence from treatment naïve patients that DTG + 3TC may be effective.  18 of 20 patients receiving 3TC/DTG dual therapy for initial treatment of HIV achieved virological suppression at week 48 in the PADDLE study, results of which were presented at EACS 2015.  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.[17]  

--Unresolved question: whether this regimen would be effective in patients with baseline 3TC resistance.

Simplifying to DTG + NNRTI
  • There are two ongoing phase III RCTS (SWORD1 and SWORD 2) evaluating the strategy of switching from stable ARV regimens (2NRTIs + etiher PI, INSTI or NNRTI) to DTG plus RPV. Preliminary results were presented at CROI 2017 and suggested that of 513 patients switched from a 3 or 4 drug regimen, 95% maintained virus at undetectable levels, compared to 96% of 511 patients who remained on their original treatment regimen [18].
  • 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 [19].
  • 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 [20].


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).  

Simplifying to DTG Monotherapy 

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).
  • Unpublished, presented at CROI 2017: 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. After 24 weeks, continued-ART group also switched to DTG monotherapy (no comparator arm for weeks 24 to 48).  At 24 weeks DTG was non-inferior to continued therapy; 92/94 remained virally suppressed with no Integrase resistance among the two failures. However, among 77 patients reaching 48 weeks, viral failure occurred in 8 with 3 (of 6 in whom genotypes could be performed) developing DTG resistance. The study concluded that DTG monotherapy is insufficient to allow maintanence monotherapy. Wijting et al. Abstract 451 CROI 2017.[21]

Switching or Simplifying to PI based regimens

Score Modification Rule
Switching to PI/r + 3TC

There is evidence that a boosted PI with 3TC/FTC can maintain viral suppression in ART naïve patients without baseline resistance, and in patients with viral suppression.

ATV/r + 3TC, from ATV/r + 2 NRTI

  • The phase IV ATLASM study (Unpublished, EACS 2015), randomized virally suppressed patients receiving 2 NRTI + ATV/r to continue or switch to 3TC+ATV/r.  At 48 weeks, 90% switching maintained virologic suppression vs. 80% remaining on 2 NRTI + ATV/r.
  • The SALT trial randomly assigned 286 patients (143 [50%] to each group) with prior viral suppression, and no history of treatment failure or resistance, to 3TC+ATV/r vs 2NRTI+ ATV/r. At week 48 in the per-protocol population, 112 (84%) of 133 patients had virological response in the dual-treatment group versus 105 (78%) of 135 in the triple-treatment group (difference 6% [95% CI -5 to 16%), showing non-inferiority at the prespecified level. Treatment discontinuations were less frequent in the dual-treatment group (three [2%]) than in the triple-treatment group (ten [7%]; p=0·047) [22].

--Question: Would you consider this with baseline 3TC mutation?  There is data on maintaining viral suppression on PI monotherapy.  Retaining the 3TC appears to reduce rates of failure and blipping.

--Must consider need for TDF (Hep B).  Lose the cholesterol lowering effect of TDF.

DRV/r + 3TC

  • In a retrospective analysis of patients with at least six months of virological suppression (without evidence of resistance to 3TC or DRV) switched to 3TC plus DRV/r demonstrated continued virological suppression with a favorable safety profile [23].

LPV/r + 3TC

  • The OLE study randomized 250 patients that were virally suppressed to continue 2NRTI+LPV/r (127 [51%] patients) or switch to dual treatment with 3TC+LPV/r (123 [49%] patients). 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group, meeting the criteria for non-inferiority [24].
Switching to PI +INSTI
  • The combination of a boosted PI with an INSTI (DRV/r plus RAL) has been studied in ART-naive patients. At week 96, DRV/r plus RAL was noninferior to DRV/r plus TDF/FTC based on the proportion of patients achieving viral suppression. However, in patients with low pretreatment CD4 T lymphocyte counts (<200 cells/mm3) and high viral loads (>100,000 copies/mL), DRV/r plus RAL was inferior to DRV/r plus TDF/FTC.  The efficacy of this regimen in virally suppressed patients is not known. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised noninferiority trial [25].

  • KITE study:  60 HIV infected adults with plasma HIV-1 RNA <50 copies/ml were randomized to continue their NRTI based therapy or to start on LPV/r + RAL. At 48 weeks 92% of the LPV/r/RAL arm and 88% of the sHAART had HIV-RNA < 50 copies/ml. There were no serious adverse events in either arm. There were no differences between arms in bone mineral density, total body fat composition, creatinine clearance, or CD4 T cell counts at week 48.

  • In another study, virologically suppressed patients switched to a regimen consisting of ATV/r plus RAL or ATV/r plus TDF/FTC. This regimen switch was associated with higher rates of virologic failure and treatment discontinuations than switching to ATV/r plus  TDF/FTC. A regimen consisting of ATV/r plus RAL cannot currently be recommended [26].

  • In an observational cohort in Italy, 113 patients on DTG + DRV/r were followed, most of whom had baseline NRTI mutations, and PI mutations (12 also had INSTI mutations). The percentage of viremic patients declined from baseline to week 24 from 43% to 6% [19].

Simplifying to PI Monotherapy

The DHHS guidelines recommend against simplification to a boosted PI monotherapy regimen.

  • Monet: 256 patients with a viral load of < 50 HIV-1 RNA currently on XXXX for at least 6 months were switched to either DRV/r monotherapy or DRV/r plus two NRTI’s. By week 144, viral suppression was was 69% vs. 75% in the DRV/r monotherapy and triple therapy arms [difference= -5.9%; 95% confidence interval (CI) -16.9%, +5.1%]; by a strict ITT analysis (switches not considered failures), viral suppression was 84% vs. 83.5%. There was non-inferiority in strict ITT, but not in TLOVR (switch=failure) analysis.
  • In the MONOI-ANRS 136 trial of maintenance monotherapy in patients with suppressed HIV RNA viremia 225 patients were randomized to receive DRV/r monotherapy or DRV/r triple drug regimen. Three patients experienced virological failure on DRV/r monotherapy and none on the triple drug regimen. No resistance emerged to protease inhibitors and the two groups did not differ in the number of serious adverse events.
  • Of 529 patients virologically suppressed who switched to a boosted protease inhibitor monotherapy individuals with less than 1 year of prior sustained virological suppression were more likely to experience virological failure on boosted protease inhibitor monotherapy (BPIMT) for a duration of 12-23 months and 24 months or more. Rates of failure were similar for BPIMT with lopinavir-ritonavir or darunavir-ritonavir, but increased for BPIMT with atazanavir-RTV [27].
  • In another study 131 HIV-1 infected patients who switched to a maintenance dual antiretroviral regimen containing a boosted PI were followed for a median of 14 months. Virological failure rate was 90.1%. Two patients had virological failure and 11 discontinued treatment due to side effects or were lost to follow-up [28]

Switching or Simplifying to NNRTI based regimens

Score Modification Rule
Switching to RPV based regimens from EFV or boosted PI regimens

Switching from EFV to RPV

A phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (≥3 months duration) to RPV/FTC/TDF. At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance [6].

Switching from a boosted PI to RPV

In an RCT of switching from 2NRTI +PI/r in virally suppressed patients to TDF/FTC/RPV, primary objective of noninferiority at week 24 was met(11): 93.7% of RPV/FTC/TDF versus 89.9% of protease inhibitor+RTV+ Through week 48, 89.3% of participants in the immediate switch group maintained virologic suppression. High rates of suppression were maintained with RPV/FTC/TDF regardless of participant's pre-antiretroviral HIV-1 RNA level. Overall development of resistance mutations after switching to RPV/FTC/TDF was low. Decreases in total cholesterol, low-density lipoprotein (LDL), and triglycerides were significantly greater among RPV/FTC/TDF recipients than those in the protease inhibitor+RTV+ two NRTIs group [11]

Switching from boosted PI or NNRTI therapy to EFV/TDF/FTC
The A1266-073 study randomized suppressed patients on NNRTI or PI based therapy to stay on their regimens or switch to TDF/FTC/EFV, and found that switching to TDF/FTC/EFV was non-inferior with regards to virologic suppression, and had benefits of improvements in TG and quality of life measurements [29].

Switching or Simplifying to EI based regimens

Score Modification Rule
Switching to a Boosted PI + Maraviroc, from Boosted PI + 2 NRTI 
Not recommended.  In the MARCH study (EACS 2015), patients with R5 tropic virus, who were virally suppressed on 2NRTI + 1 PI/r, were randomized to MVC + PI/r.  Patients switched to the MVC + PI/r regimen had lower rates of maintaining viral suppression (84%) at XXX weeks, compared to 98% who continued on the 2 NRTI + 1  PI regimen.