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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 Simplification

(Last updated:1/10/2011; last reviewed:1/10/2011)

Regimen simplification can be defined broadly as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy (ART) may be considered candidates for regimen simplification, especially if (1) they are receiving treatments that are no longer recommended as preferred or alternative choices for initial therapy; (2) they were prescribed a regimen in the setting of treatment failure at a time when there was an incomplete understanding of resistance or drug-drug interaction data; or (3) they were prescribed a regimen prior to the availability of newer options or formulations that might be easier to administer and/or more tolerable.

This section will review situations in which clinicians might consider simplifying treatment in a patient with virologic suppression. Importantly, this section will not review consideration of changes in treatment for reducing ongoing adverse effects. Regimens used in simplification strategies generally should be those that have proven high efficacy in antiretroviral (ARV)-naive patients (see What to Start) or that would be predicted to be highly active for a given patient based on the individual’s past treatment history and resistance profile.

Rationale

The major rationales behind regimen simplification are to improve the patient’s quality of life, maintain long-term adherence, avoid toxicities that may develop with prolonged ARV use, and reduce the risk of virologic failure. Systematic reviews in the non-HIV literature have shown that adherence is inversely related to the number of daily doses [1]. Some prospective studies in HIV-infected individuals have shown that those on regimens with reduced dosing frequency have higher levels of adherence [2-3]. Patient satisfaction with regimens that contain fewer pills and reduced dosing frequency is also higher [4].

Candidates for Regimen Simplification

Unlike ARV agents developed earlier in the HIV epidemic, many ARV medications approved in recent years have sufficiently long half-lives to allow for once-daily dosing, and most also do not have dietary restrictions. Patients on regimens initiated earlier in the era of potent combination ART with drugs that pose a high pill burden and/or frequent dosing requirements are often good candidates for regimen simplification. Patients without suspected drug-resistant virus. Patients on first (or modified) treatment regimens without a history of treatment failure are ideal candidates for regimen simplification. These patients are less likely to harbor drug-resistant virus, especially if a pretreatment genotype did not detect drug resistance. Prospective clinical studies have demonstrated that the likelihood of treatment failure is relatively low in patients after simplification and, indeed, may be lower than in patients who do not simplify treatment [5]. However, some patients may have unrecognized drug-resistant HIV, either acquired at the time of infection or as a consequence of prior treatment, such as patients who were treated with presumably nonsuppressive mono- or dual-nucleoside reverse transcriptase inhibitor (NRTI) regimens before the widespread availability of HIV RNA monitoring and resistance testing.

Patients with documented or suspected drug resistance. Treatment simplification may also be appropriate for selected individuals who achieve viral suppression after having had documented or suspected drug resistance. Often, these patients are on regimens selected when management of drug resistance, understanding of potentially adverse drug-drug interactions, and understanding of treatment options were relatively limited. Regimen simplification may also be considered for patients on two ritonavir (RTV)-boosted protease inhibitors (PIs). Although successful in suppressing viral replication, this treatment may cause patients to be on regimens that are cumbersome, costly, and associated with potential long-term adverse events. The ability to simplify regimens in this setting often reflects the availability of recently approved agents that have activity against drug-resistant virus and are easier to take without sacrificing ARV activity. Specific situations in which drug simplification could be considered in ART-experienced patients with viral drug resistance are outlined below. Simplifying regimens in patients who have extensive prior treatment histories is complicated. In such a case, a patient’s treatment history, treatment responses and tolerance, and resistance test results should be thoroughly reviewed before designing a new regimen. Expert consultation should be considered whenever possible.

Types of Treatment Simplification

Within-Class Simplifications.
Within-class substitutions offer the advantage of not exposing patients to still-unused drug classes, which potentially preserves other classes for future regimens. In general, within-class substitutions use a newer agent; coformulated drugs; or a formulation that has a lower pill burden, a lower dosing frequency, or would be less likely to cause toxicity.
  • NRTI Substitutions (e.g., changing from zidovudine [ZDV] or stavudine [d4T] to tenofovir [TDF] or abacavir [ABC]): This may be considered for a patient who has no history of viral resistance on an NRTI-containing regimen. Other NRTIs may be substituted to create a regimen with lower dosing frequency (e.g., once daily) that takes advantage of coformulated agents and potentially avoids some long-term toxicities (e.g., pancreatitis, peripheral neuropathy, lipoatrophy).

  • Switching of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (e.g., from nevirapine [NVP] to efavirenz [EFV]): This may be considered to reduce dosing frequency or to take advantage of coformulated agents.

  • Switching of PIs: This switch can be from one PI to another PI, to the same PI at a lower dosing frequency (such as from twice-daily to once-daily RTV-boosted lopinavir [LPV/r] or RTV-boosted darunavir [DRV/r]) or, in the case of atazanavir (ATV), to administration without RTV boosting [6]. (Unboosted ATV is presently not a preferred PI component and not recommended if the patient is taking TDF or if the patient has HIV with reduced susceptibility to ATV.) Such changes can reduce dosing frequency, pill count, drug-drug or drug-food interactions, or dyslipidemia or can take advantage of coformulation. These switches can be done with relative ease in patients without PI-resistant virus. However, these switches are not recommended in patients who have a history of documented or suspected PI resistance because convincing data in this setting are lacking.

Out-of-Class Substitutions. One common out-of-class substitution for regimen simplification involves a change from a PI-based to an NNRTI-based regimen. An important study in this regard was the NEFA trial, which evaluated substitution of a PI-based regimen in virologically suppressed patients with NVP, EFV, or ABC [7]. Although the baseline regimens in the study are no longer in widespread use, the NEFA findings are still relevant and provide information about the risks and benefits of switching treatment in patients with virologic suppression. In this study, 460 patients on stable, PI-based regimens with virologic suppression (<200 copies/mL for the previous 6 months) were switched to their randomized treatment arms. After 36 months of follow-up, virologic failure occurred more frequently in patients switched to ABC than in patients switched to EFV or NVP. The increased risk of treatment failure was particularly high in patients who had previous suboptimal treatment with mono- and dual-NRTI therapy. This emphasizes the need to consider the potential for drug-resistant virus prior to attempting simplification [8].

Newer agents that target different sites in the HIV life cycle, such as the integrase strand transfer inhibitor (INSTI) raltegravir (RAL) and the CCR5 antagonist maraviroc (MVC), also offer opportunities for out-of-class substitutions, particularly in patients who have a history of virus resistant to older HIV drugs. Three randomized studies have evaluated replacing a boosted PI with RAL in virologically suppressed patients. In two of these studies [9-10], the switch to RAL was associated with an increased risk of virologic failure in patients with documented or suspected pre-existing NRTI resistance; a third study did not find this higher risk, possibly due to a longer period of virologic suppression before the change [11]. Overall, these results suggest that in ART-experienced patients, RAL should be used with caution as a substitute for a boosted PI. This strategy should be avoided in patients with documented NRTI resistance unless there are other fully active drugs in the regimen.

Because enfuvirtide (T-20) requires twice-daily injections, causes injection-site reactions, and is more expensive than other available ARV agents, patients who are virologically suppressed on T-20-containing regimens may wish to substitute T-20 with an active oral agent. Because the majority of patients on T-20 have highly drug-resistant virus, substitution must be with another fully active agent. Data from one randomized trial and one observational study suggest that RAL can safely substitute for T-20 in patients not previously treated with INSTI [12-13]. Although this strategy generally maintains virologic suppression and is well tolerated, clinicians should be aware that any drug substitution may introduce unanticipated adverse effects or drug-drug interactions [14].

Other newer agents that might be considered as substitutes for T-20 are etravirine (ETR) or MVC. Use of ETR in this setting would optimally be considered only when viral susceptibility to ETR can be assured from resistance testing performed prior to virologic suppression and after carefully assessing for possible deleterious drug-drug interactions (e.g., ETR cannot be administered with several PIs [see Table 16b]). In the ETR early access program, switching from T-20 to ETR showed promise in maintaining viral suppression at 24 weeks, but only 37 subjects were included in this report [15]. MVC is only active in those with documented R5-only virus, a determination that cannot routinely be made in those with undetectable HIV RNA on a stable regimen. Although there is a commercially available proviral DNA assay to assess viral tropism in virologically suppressed patients, there are no clinical data on whether results of this test predict the successful use of MVC as a substitute for another active drug.

Reducing the number of active drugs in a regimen. This approach to treatment simplification involves switching a patient from a suppressive regimen to fewer active drugs. In early studies, this approach was associated with a higher risk of treatment failure than continuation of standard treatment with two NRTIs plus a PI [16]. More recently, studies have evaluated the use of an RTV-boosted PI as monotherapy after virologic suppression with a two-NRTI + boosted-PI regimen [17-18]. The major motivations for this approach are a reduction in NRTI-related toxicity and lower cost. In a randomized clinical trial [18], low-level viremia was more common in those on maintenance LPV/r alone than on a three-drug combination regimen. Viral suppression was achieved by resuming the NRTIs. Studies of DRV/r monotherapy, both as once- or twice-daily dosing, have reported mixed results [19-20]. In aggregate, boosted-PI monotherapy as initial [21] or as simplification treatment has been somewhat less effective in achieving complete virologic suppression and avoiding resistance. Therefore, this strategy cannot be recommended outside of a clinical trial.

Monitoring After Treatment Simplification

Patients should be evaluated 2–6 weeks after treatment simplification to assess tolerance and to undergo laboratory monitoring, including HIV RNA, CD4 cell count, and markers of renal and liver function. Assessment of fasting cholesterol subsets and triglycerides should be performed within 3 months after the change in therapy. In the absence of any specific complaints, laboratory abnormalities, or viral rebound at that visit, patients may resume regularly scheduled clinical and laboratory monitoring.

References

  1. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23(8):1296-1310.
  2. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354(3):251-260.

  3. Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses. 2007;23(12):1505-1514.

  4. Stone VE, Jordan J, Tolson J, et al. Perspectives on adherence and simplicity for HIV-infected patients on antiretroviral therapy: self-report of the relative importance of multiple attributes of highly active antiretroviral therapy (HAART) regimens in predicting adherence. J Acquir Immune Defic Syndr. 2004;36(3):808-816.

  5. Gatell J, Salmon-Ceron D, Lazzarin A, et al. Efficacy and safety of atazanavir-based highly active antiretroviral therapy in patients with virologic suppression switched from a stable, boosted or unboosted protease inhibitor treatment regimen: the SWAN Study (AI424-097) 48-week results. Clin Infect Dis. 2007;44(11):1484-1492.

  6. Squires KE, Young B, Dejesus E, et al. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients. AIDS. 2010;24(13):2019-2027.

  7. Martinez E. The NEFA study: results at three years. AIDS Rev. 2007;9(1):62.

  8. Ochoa de Echaguen A, Arnedo M, Xercavins M, et al. Genotypic and phenotypic resistance patterns at virological failure in a simplification trial with nevirapine, efavirenz or abacavir. AIDS. 2005;19(13):1385-1391.

  9. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375(9712):396-407.

  10. Vispo E, Barreiro P, Maida I, et al. Simplification From Protease Inhibitors to Once- or Twice-Daily Raltegravir: The ODIS Trial. HIV Clin Trials. 2010;11(4):197-204.

  11. Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. 2010;24(11):1697-1707.

  12. Harris M, Larsen G, Montaner JS. Outcomes of multidrug-resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. AIDS. 2008;22(10):1224-1226.

  13. De Castro N, Braun J, Charreau I, et al. Switch from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV-1-infected patients: a randomized open-label trial. Clin Infect Dis. 2009;49(8):1259-1267.

  14. Harris M, Larsen G, Montaner JS. Exacerbation of depression associated with starting raltegravir: a report of four cases. AIDS. 2008;22(14):1890-1892.

  15. Loutfy M, Ribera E, Florence E, et al. Sustained HIV RNA suppression after switching from enfuvirtide to etravirine in the early access programme. J Antimicrob Chemother. 2009;64(6):1341-1344.

  16. Havlir DV, Marschner IC, Hirsch MS, et al. Maintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. N Engl J Med. 1998;339(18):1261-1268.

  17. Swindells S, DiRienzo AG, Wilkin T, et al. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA. 2006;296(7):806-814.

  18. Pulido F, Arribas JR, Delgado R, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. AIDS. 2008;22(2):F1-9.

  19. Arribas JR, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010;24(2):223-230.

  20. 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.

  21. Delfraissy JF, Flandre P, Delaugerre C, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS. 2008;22(3):385-393.