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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
Management of the Treatment-Experienced Patient
Regimen Switching in the Setting of Virologic Suppression
(Last updated: May 1, 2014; last reviewed: May 1, 2014)
With use of currently available antiretroviral therapy (ART), most HIV-infected patients are able to achieve sustained HIV viral suppression. Furthermore, advances in treatment and better understanding about drug resistance make it possible to consider switching an effective regimen to an alternative regimen in some situations (see below). When contemplating such a switch, clinicians must consider several key principles to maintain viral suppression while addressing concerns with the current treatment.
Reasons to Consider Regimen Switching in the Setting of Viral Suppression:
To simplify the regimen by reducing pill burden and dosing frequency to improve adherence
To enhance tolerability and decrease short- or long-term toxicity (see Adverse Effects section)
The cardinal principle of regimen switching is to maintain viral suppression without jeopardizing future treatment options. 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. Principles for successful regimen switching are highlighted below:
It is critical to review a patient’s full antiretroviral (ARV) history (including virologic responses, resistance test results, and past adverse events) before any treatment switch.
Once a particular resistance mutation has been selected, it is generally archived in the HIV reservoir and is likely to reappear under the appropriate selective drug pressure, even if not detected in the most recent resistance test. If resistance data are unavailable, resistance may often be inferred from a patient’s treatment history. For example, a clinician should assume that patients who have failed a cytosine analogue (e.g., a lamivudine (3TC)- or emtricitabine (FTC)-containing regimen), likely have the M184V substitution, even if the substitution is not documented. The same assumption of resistance may also apply to patients with documented failure to an non-nucleoside reverse transcriptase inhibitor (NNRTI)- or an integrase strand transfer inhibitors (INSTI)-based regimen 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 resistant virus as the suppressive regimen.
Consultation with an HIV specialist is recommended when considering a regimen switch for a patient with a history of resistance to one or more drug classes.
Switching from a ritonavir (RTV)-boosted protease inhibitor (PI) regimen to a regimen composed of drugs with a lower barrier to resistance generally maintains viral suppression provided there is no resistance to the other components of the regimen. However, such switches should be avoided if there is any doubt about the activity of the other agents in the regimen.
Within-class switches prompted by adverse events usually maintain viral suppression provided that there is no drug resistance to the other ARV agents in the same drug class.
In the absence of any likely drug resistance, switching from complex regimens, parenteral drug (i.e., enfuvirtide), or drugs known now to be more toxic (e.g., zidovudine, stavudine, or didanosine) or with higher pill burden or dosing frequency to simpler regimens (e.g., from a regimen including ritonavir-boosted saquinavir [SQV/r] to one including ritonavir-boosted darunavir [DRV/r]) or to ARVs in a new drug class (e.g., an INSTI) generally results in similar or improved adherence, continued viral suppression and possibly improved quality of life.
More intensive monitoring of tolerability, viral suppression, adherence, and laboratory changes is recommended during the first 3 months after a regimen switch.
Alternative Switch Strategies for Patients with Virologic Suppression
RTV-Boosted PI Monotherapy
The strategy of switching virologically suppressed patients without PI resistance from one ART regimen to RTV-boosted PI monotherapy has been studied. The rationale for this strategy is to avoid nucleoside reverse transcriptase inhibitor (NRTI) toxicities and decrease costs, while taking advantage of the high barrier to resistance of RTV-boosted PIs. RTV-boosted PI monotherapy maintains virologic suppression in most patients, but at slightly lower rates than standard therapy that includes 2 NRTIs.2,3 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.
No clinical trials comparing available RTV-boosted PI monotherapy regimens have been conducted. Findings from an observational study suggest that the rate of treatment failure is higher in patients on RTV-boosted atazanavir (ATV/r) than in those on RTV-boosted lopinavir (LPV/r) or DRV/r.4 Another pilot study reported early viral rebound with use of ATV/r monotherapy.5 There are rare reports of central nervous system virologic escape, sometimes with clinical symptoms, in patients on RTV-boosted PI monotherapy.6,7
On the basis of the results from these studies, RTV-boosted PI monotherapy should generally be avoided. Other strategies to avoid use of NRTIs (i.e., use of a RTV-boosted PI plus a NNRTI, an INSTI, or maraviroc [MVC]) are also being studied, but data on these strategies are limited.
Switching from a Ritonavir-Boosted Protease Inhibitor to Unboosted Atazanavir
Several clinical studies have evaluated switching a RTV-boosted PI to unboosted atazanavir (ATV) in virologically suppressed patients without NRTI resistance. Two comparative clinical trials reported that ATV/r and ATV, both in combination with 2 NRTIs (mostly ABC/3TC), demonstrated comparable levels of virologic suppression and a similar lack of treatment-emergent resistance. The benefits of the unboosted ATV regimen included a slightly improved lipid profile and a lower incidence of hyperbilirubinemia.8,9 An additional study of 296 patients with virologic suppression on tenofovir disoproxil fumarate (TDF)/FTC plus ATV/r showed that patients switched to ABC/3TC plus ATV maintained viral suppression and showed improvements in certain bone and renal biomarkers.10 The results of these and other non-comparative studies suggest that a regimen of ABC/3TC plus ATV can be considered in virologically suppressed patients, especially in those who have adverse effects from TDF or RTV.
Switching to Maraviroc
Co-receptor usage in virologically suppressed patients can be determined from proviral DNA obtained from peripheral blood mononuclear cells. Individuals found to have R5-tropic virus by this technique could potentially have a component of their regimens switched to MVC.11,12 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 Tropism Testing section).
De-intensification of a standard RTV-boosted PI regimen from three to two active drugs (e.g., to a boosted PI plus one NRTI,13 a boosted PI plus an INSTI,14,15 or an NNRTI such as etravirine15 or the CCR5 antagonist MVC12) may be more effective virologically than RTV-boosted PI monotherapy, but, thus far, comparative data on this approach are limited. In general, switching a regimen —even in a patient without known drug resistance—from an effective three-drug regimen to a two-drug regimen has not been validated and is not recommended.
Monitoring after Treatment Changes
Patients should be evaluated more closely for several months after a treatment switch (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 goal of the 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 are a concern with the new regimen, fasting cholesterol subsets and triglycerides should be assessed within 3 months after the change in therapy. Absent any specific 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 section).
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.
Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS. 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. 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. 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. 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. 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 Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial. AIDS. 2007;21(10):1309-1315. Available at http://www.ncbi.nlm.nih.gov/pubmed/17545707.
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. 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 D. Simplification to abacavir/lamivudine (ABC/3TC) + atazanavir (ATV) from tenofovir/emtricitabine (TDF/FTC) + ATV/Ritonavir (RTV, /r) maintains viral suppression and improves bone biomarkers. Abstract H-556c. Paper presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; 2012.
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. 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.
Di Giambenedetto S, Fabbiani M, Colafigli M, et al. Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitors + atazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study). J Antimicrob Chemother. 2013;68(6):1364-1372. Available at http://www.ncbi.nlm.nih.gov/pubmed/23372058.
Ofotokun I, Sheth AN, Sanford SE, et al. A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study. AIDS Res Hum Retroviruses. 2012;28(10):1196-1206. Available at http://www.ncbi.nlm.nih.gov/pubmed/22364141.
Burgos J, Crespo M, Falco V, et al. Simplification to dual antiretroviral therapy including a ritonavir-boosted protease inhibitor in treatment-experienced HIV-1-infected patients. J Antimicrob Chemother. 2012;67(10):2479-2486. Available at http://www.ncbi.nlm.nih.gov/pubmed/22729925.