(Last updated:14/7/2016; last reviewed:14/7/2016)
•Advances in antiretroviral (ARV) treatment and a better understanding of HIV drug resistance make it possible to consider switching an effective regimen to an alternative regimen in some situations.
•The fundamental principle of regimen switching is to maintain viral suppression without jeopardizing future treatment options (AI).
•It is critical to review a patient's full ARV history, including virologic responses, past ARV-associated toxicities, and cumulative resistance test results, if available, before selecting a new ART regimen (AI).
•Adverse events, the availability of ARVs with an improved safety profile, or the desire to simplify a regimen may prompt a regimen switch. Within-class and between-class switches can usually maintain viral suppression provided that there is no viral resistance to the ARV agents in the new regimen (AI).
•Consultation with an HIV specialist should be considered when considering a regimen switch for a patient with a history of resistance to one or more drug classes (BIII).
•More intensive monitoring to assess tolerability, viral suppression, adherence, and laboratory changes is recommended during the first 3 months after a regimen switch (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
With currently available antiretroviral therapy (ART), most HIV-infected patients are able to achieve and maintain HIV viral suppression. Furthermore, advances in treatment and a better understanding of drug resistance make it possible to consider switching an effective regimen to an alternative regimen in some situations (see below). When considering such a switch, clinicians must consider several key principles to maintain viral suppression while addressing concerns with the current regimen.
Reasons to Consider Regimen Switching in the Setting of Viral Suppression:
General Principles of Regimen Switching
The fundamental principle of regimen switching is to maintain viral suppression without jeopardizing future treatment options (AI). If a regimen switch results in virologic failure with emergence of new resistance mutations, the patient may require more complex, difficult to follow, or expensive regimens.
The review of a patient's full antiretroviral (ARV) history—including virologic responses, past ARV-associated toxicities, and cumulative resistance test results (if available)—is warranted before any treatment switch (AI).
If a patient with pre-ART wild-type HIV achieves and maintains viral suppression after ART initiation, one can assume that no new resistance mutation emerged while the patient was on the suppressive regimen.
Once selected, a resistance mutation is generally archived in the HIV reservoir and is likely to re-emerge under the appropriate selective drug pressure, even if not detected in the patient's most recent resistance test. If resistance data are not available, resistance may often be inferred from a patient's treatment history. For example, a patient who experienced virologic failure on a lamivudine (3TC)- or emtricitabine (FTC)-containing regimen in the past is likely to have the M184V substitution, even if it is not documented. For patients with documented failure on a non-nucleoside reverse transcriptase inhibitor (NNRTI) or an elvitegravir (EVG)- or raltegravir (RAL)-containing regimen, resistance to these drugs can also be assumed because these drugs generally have a lower barrier to resistance. If there is uncertainty about prior resistance, it is generally not advisable to switch a suppressive ARV regimen unless the new regimen is likely to be as active against potential resistant virus as the suppressive regimen. Consulting an HIV specialist is recommended when contemplating a regimen switch for a patient with a history of resistance to one or more drug classes.
A commercially available test amplifies viral DNA in whole blood samples to detect the presence of archived resistance mutations in patients with suppressed HIV RNA. Its value in clinical practice is still being evaluated (see Drug-Resistance Testing).
More intensive monitoring to assess tolerability, viral suppression, adherence, and laboratory changes is recommended during the first 3 months after a regimen switch (see below).
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This includes both documented resistance, and a history of treatment failure where it was not possible to perform resistance testing or results are not available.
Specific Regimen Switching Considerations (also see Adverse Effects of Antiretroviral Agents)
Strategies with Good Supporting Evidence
Within-class switches prompted by adverse events or the availability of in-class ARVs that offer a better safety profile, reduced dosing frequency, or lower pill burden usually maintain viral suppression provided there is no drug resistance to the new ARV. Some examples of within-class switch strategies are switching from efavirenz (EFV) to rilpivirine (RPV),2 from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF),3 from raltegravir (RAL) to elvitegravir/cobicistat (EVG/c)4 or dolutegravir (DTG), from ritonavir-boosted protease inhibitors (PIs/r) to PIs coformulated with cobicistat (PIs/c), or from boosted atazanavir (ATV/c or ATV/r) to unboosted ATV (when used with abacavir [ABC]/3TC).5-7
Between-class switches generally maintain viral suppression provided there is no resistance to the other components of the regimen. Some examples of between-class switch strategies are replacing a boosted PI with rilpivirine (RPV),8 or replacing an NNRTI or a boosted PI with an integrase strand transfer inhibitor (INSTI).9,10 However, such switches should be avoided if there is any doubt about the activity of the other agents in the regimen.
RTV-Boosted PI plus 3TC/FTC
There is growing evidence that a boosted PI-based regimen plus 3TC can maintain virologic suppression in ART-naive individuals without baseline resistance mutations11 and in patients with sustained viral suppression.12 Examples of such regimens include lopinavir/ritonavir (LPV/r) plus 3TC12 and atazanavir/ritonavir (ATV/r) plus 3TC.13 A study evaluating darunavir/ritonavir (DRV/r) plus 3TC is currently underway. A ritonavir-boosted PI plus 3TC may be a reasonable option when the use of TDF, TAF, or ABC is contraindicated or not desirable.
Strategies under Evaluation
Several strategies for switching regimens (described below) in patients with viral suppression are under investigation. These strategies cannot yet be recommended under most circumstances or at all until further evidence is available. If used, patients should be closely monitored to assure viral suppression is maintained.
RTV-Boosted PI plus 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.14 The efficacy of switching to DRV/r plus RAL in virologically suppressed patients with no resistance to either DRV or RAL has not been explored. 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.15 A regimen consisting of ATV/r plus RAL cannot currently be recommended.
EVG/c/TDF/FTC plus DRV
The single-tablet regimen EVG/c/TDF/FTC plus DRV has shown promising results as a simplification strategy in patients with complicated rescue regimens.16 A recent study enrolled 135 virologically suppressed patients who were receiving DRV-containing ART and had resistance to ≥2 ARV drug classes, but no INSTI resistance. The patients were then switched to a regimen of EVG/c/TDF/FTC plus DRV. At week 24, 97% of the patients maintained virologic suppression. The pill burden was reduced from an average of five tablets to two tablets. Currently, however, there is insufficient evidence to support this regimen switch other than in a well-controlled clinical trial or in special circumstances.
Dolutegravir plus 3TC or FTC
In a small (20-patient), single-arm study of DTG plus 3TC for ART-naive patients, all patients achieved and maintained viral suppression at 24 weeks.17 A clinical trial is underway to evaluate the role of this regimen as maintenance therapy in virologically suppressed patients who have no evidence of NRTI, INSTI, or PI resistance. Currently, however, there is insufficient evidence to support use of this regimen other than in a well-controlled clinical trial.
Strategies Not Recommended
RTV-Boosted PI Monotherapy
The strategy of switching virologically suppressed patients without PI resistance from one ART regimen to PI/r monotherapy has been evaluated in several studies. The rationale for this strategy is to avoid NRTI toxicities and decrease costs, while taking advantage of the high barrier to resistance of PIs. PI/r monotherapy maintains virologic suppression in most patients, but at slightly lower rates than standard therapy that includes 2 NRTIs.18,19 Low-level viremia, generally without the emergence of PI resistance, appears to be more common with monotherapy. In most studies, resumption of NRTIs in patients experiencing low-level viral rebound has led to re-suppression.20-23
On the basis of the results from these studies, PI/r monotherapy should generally be avoided (BI). No clinical trials evaluating the use of coformulated cobicistat-boosted PIs as monotherapy or comparing available PI/r monotherapy regimens have been conducted.
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Monotherapy is not recommended
A systematic review of 10 randomised trials (comprising different boosted PI regimens), of 1964 patients with HIV-1 RNA suppression at baseline, PI monotherapy showed a higher risk of HIV RNA elevations, and small numbers with HIV RNA detectable in CSF and concomitantly in the plasma. However there was no increased risk of treatment-emergent drug resistance, neurocognitive endpoints were not different between the arms and HIV-1 RNA suppression rates after intensification were similar between PI monotherapy and triple therapy. These results argue against routine use of PI monotherapy as a switch strategy except in select cases where close monitoring is achievable
 Arribas, J, et al. Journal of the International AIDS Society, 17 (4Suppl 3), 19788. doi:10.7448/IAS.17.4.19788
Switching to Maraviroc
Co-receptor usage in virologically suppressed patients can be determined from proviral DNA obtained from peripheral blood mononuclear cells. If this testing identifies R5-tropic virus, a component of the patient’s regimen may potentially be switched to maraviroc (MVC).24,25 However, although the use of MVC after DNA tropism testing has potential, this strategy cannot be recommended until more data from larger clinical studies are available (see Co-receptor Tropism Assays).
Monitoring after Treatment Changes
After a treatment switch, patients should be evaluated more closely for several months (i.e., a clinic visit or phone call 1 to 2 weeks after the change, and a viral load test to check for rebound viremia 4 to 8 weeks after the switch). The purpose of more intensive monitoring is to assess medication tolerance and conduct targeted laboratory testing if the patient had pre-existing laboratory abnormalities or there are potential concerns with the new regimen. For example, if lipid abnormalities were present and/or were a reason for the ARV change, or if it is a concern with the new regimen, fasting cholesterol subsets and triglycerides should be assessed within 3 months after the change in therapy. In the absence of any new complaints, laboratory abnormalities, or evidence of viral rebound at this 3-month visit, clinical and laboratory monitoring of the patient may resume on a regularly scheduled basis (see Laboratory Testing for Initial Assessment and Monitoring of HIV-Infected Patients on Antiretroviral Therapy).
Changes in 2016 Guidelines
- Simplified to focus on switch strategies for virologically suppressed patients. The strategies are categorized as Strategies with Good Supporting Evidence, Strategies Under Evaluation, and Strategies Not Recommended.
- Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed June 15, 2016.
- Mills AM, Cohen C, Dejesus E, et al. Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens. HIV Clin Trials. Sep-Oct 2013;14(5):216-223. Available at http://www.ncbi.nlm.nih.gov/pubmed/24144898.
- Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV. Apr 2016;3(4):e158-165. Available at http://www.ncbi.nlm.nih.gov/pubmed/27036991.
- Mills A, Crofoot G, Ortiz R, et al. Switching from twice-daily raltegravir plus tenofovir disoproxil fumarate/emtricitabine to once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate in virologically suppressed, HIV-1-infected subjects: 48 weeks data. HIV Clin Trials. Mar-Apr 2014;15(2):51-56. Available at http://www.ncbi.nlm.nih.gov/pubmed/24710918.
- Squires KE, Young B, DeJesus E, et al. ARIES 144 week results: durable virologic suppression in HIV-infected patients simplified to unboosted atazanavir/abacavir/lamivudine. HIV Clin Trials. Sep-Oct 2012;13(5):233-244. Available at http://www.ncbi.nlm.nih.gov/pubmed/23134624.
- Ghosn J, Carosi G, Moreno S, et al. Unboosted atazanavir-based therapy maintains control of HIV type-1 replication as effectively as a ritonavir-boosted regimen. Antivir Ther. 2010;15(7):993-1002. Available at http://www.ncbi.nlm.nih.gov/pubmed/21041914.
- Wohl DA, Bhatti L, Small CB, et al. The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir. HIV Med. Feb 2016;17(2):106-117. Available at http://www.ncbi.nlm.nih.gov/pubmed/26176344.
- Palella FJ, Jr., Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS. Jan 28 2014;28(3):335-344. Available at http://www.ncbi.nlm.nih.gov/pubmed/24670520.
- Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b noninferiority trial. Lancet Infect Dis. Jul 2014;14(7):590-599. Available at http://www.ncbi.nlm.nih.gov/pubmed/24908550.
- Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis. Jul 2014;14(7):581-589. Available at http://www.ncbi.nlm.nih.gov/pubmed/24908551.
- Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis. Jul 2014;14(7):572-580. Available at http://www.ncbi.nlm.nih.gov/pubmed/24783988.
- Arribas JR, Girard PM, Landman R, et al. Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis. Jul 2015;15(7):785-792. Available at http://www.ncbi.nlm.nih.gov/pubmed/26062880.
- Perez-Molina JA, Rubio R, Rivero A, et al. Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis. Jul 2015;15(7):775-784. Available at http://www.ncbi.nlm.nih.gov/pubmed/26062881.
- 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. Lancet. Nov 29 2014;384(9958):1942-1951. Available at http://www.ncbi.nlm.nih.gov/pubmed/25103176.
- van Lunzen J, Pozniak A, Gatell JM, et al. Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study. J Acquir Immune Defic Syndr. Apr 15 2016;71(5):538-543. Available at http://www.ncbi.nlm.nih.gov/pubmed/26605505.
- Huhn G, Tebas P, Gallant J. Strategic simplification: The efficacy and safety of switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamde (E/C/F/TAF) plus darunavir (DRV) in treatment-experienced HIV-1 infected adults. Presented at: ID Week. 2015. San Diego, CA.
- Figueroa MI, Sued O, Patterson P, Gun A, Rolon MJ, Cahn P. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naïve patients: First results of the PADDLE Trials. Presented at: 15th European AIDS Conference. 2015. Barcelona, Spain.
- Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS. Jan 28 2009;23(3):279-291. Available at http://www.ncbi.nlm.nih.gov/pubmed/19114854.
- Arribas JR, Clumeck N, Nelson M, Hill A, van Delft Y, Moecklinghoff C. The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load < 50 HIV-1 RNA copies/mL at baseline. HIV Med. Aug 2012;13(7):398-405. Available at http://www.ncbi.nlm.nih.gov/pubmed/22413874.
- Guiguet M, Ghosn J, Duvivier C, et al. Boosted protease inhibitor monotherapy as a maintenance strategy: an observational study. AIDS. Nov 28 2012;26(18):2345-2350. Available at http://www.ncbi.nlm.nih.gov/pubmed/22695301.
- Karlstrom O, Josephson F, Sonnerborg A. Early virologic rebound in a pilot trial of ritonavir-boosted atazanavir as maintenance monotherapy. J Acquir Immune Defic Syndr. Apr 1 2007;44(4):417-422. Available at http://www.ncbi.nlm.nih.gov/pubmed/17159658.
- Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. Sep 24 2010;24(15):2365-2374. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&;db=PubMed&dopt=Citation&list_uids=20802297.
- Vernazza P, Daneel S, Schiffer V, et al. The role of compartment penetration in PI-monotherapy: the AtazanavirRitonavir Monomaintenance (ATARITMO) Trial. AIDS. Jun 19 2007;21(10):1309-1315. Available at http://www.ncbi.nlm.nih.gov/pubmed/17545707.
- Bonjoch A, Pou C, Perez-Alvarez N, et al. Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: a pilot, prospective, randomized clinical trial. J Antimicrob Chemother. Jun 2013;68(6):1382-1387. Available at http://www.ncbi.nlm.nih.gov/pubmed/23354282.
- Vitiello P, Brudney D, MacCartney M, et al. Responses to switching to maraviroc-based antiretroviral therapy in treated patients with suppressed plasma HIV-1-RNA load. Intervirology. 2012;55(2):172-178. Available at http://www.ncbi.nlm.nih.gov/pubmed/22286889.