Excellent short-term CD4 recovery with a PI- and NRTI-sparing regimen in triple-class failure HIV-infected patients: raltegravir, maraviroc, etravirine

Abstract

Purpose of the studyWith the availability of new drug classes, the full suppression is a realistic goal even for heavily pre-treated patients. We prospectively evaluated the magnitude of CD4 recovery (CR) in this setting. MethodsWe decided to simultaneously screen triple class failing patients (pts) followed at San Raffaele Hospital in three Expanded Access Programs: raltegravir (MK0518-023), maraviroc (A4001050), etravirine (TMC125-C214). Salvage therapy was prescribed according to: viral tropism, screening genotype and previous resistance tests. Data were collected at baseline (BL) and at 4, 12, 24, 36 and 48 weeks. Generalized linear regression model was applied. Results are reported as median (Q1-Q3). Summary of resultsUp to date, 68 pts reached week 24 (W24) without modification of the initial regimen; age 44.5 (41.7-49.9) years, 17 (25%) women, 10 (17.2%) IVDU, infected since 15.0 (12.5-18.4) years, ARV exposure of 13.0 (11.6-15.4) years, CDC C stage 32 (47%). At BL: CD4 195 (87-306) cells//μL; CD4% 11.8 (7.0-17.5), HIV-RNA 4.2 (3.8-5.0) log10 copies/mL and CD4 nadir 73 (22-178) cells/μL. No difference in BL characteristics were found according to the group regimen prescribed. (Table 1.) At week 24, 14 (93%), 13 (76%), 14 (74%), 15 (94%) had HIV-RNA <50 copies/mL in group A, B, C, D, respectively (p = 0.238).At multivariable analysis, a significantly different CR was related to therapy group (p = 0.035) and positively related to BL HIV-RNA (p = 0.049). CR was higher in group A (adjusted mean: 214.8 ± 37.3) than group B (129.2 ± 33.5, p = 0.062) or group C (115.7 ± 30.5, p = 0.023) or group D (91.7 ± 33.3, p = 0.005). No independent effect of age (p = 0.834), gender (p = 0.392), HIV risk factor (p = 0.522), CD4% (p = 0.297) and CD4 nadir (p = 0.195) was observed. Despite the high pill number, RAL +MVC+ETR were very well tolerated; serious adverse events were diagnosed in two pts: spondylodiscitis (one), anal cancer (one). ConclusionSalvage therapy with RAL+ MVC+ETR showed an excellent short-term CD4 recovery. Reasons for this success could include: presence of active drugs blocking consecutive targets of viral replication, high doses of MVC required with this regimen, avoidance of ritonavir and NRTI toxicity.

Assessment of the pharmacokinetics of co‐administered maraviroc and raltegravir

“…Overall, it appears that reductions in maraviroc exposure observed due to co‐administration with raltegravir are unlikely to affect the antiretroviral activity of maraviroc. Notably, in a combination study with raltegravir, maraviroc and etravirine in heavily pretreated HIV‐infected patients harbouring R5 co‐receptor‐using virus, 90% of patients had undetectable viral load (<50 copies ml −1 ) at week 48 [15].…”

“…Raltegravir trough plasma concentration (ng ml -1 ) on day 3 (raltegravir) and day 14 maraviroc + raltegravir) patients harbouring R5 co-receptor-using virus, 90% of patients had undetectable viral load (<50 copies ml -1 ) at week 48 [15].…”

“…Maraviroc and raltegravir are two antiretrovirals with new mechanisms of action. It is likely that treatment-experienced patients will receive combination treatment that includes these two agents [15]. Hence, this study was undertaken to evaluate systematically the two-way pharmacokinetic interaction between maraviroc and raltegravir in healthy subjects.…”

Optimal Use of Raltegravir (Isentress®) in the Treatment of HIV‐Infected Adults – Canadian Consensus Guidelines

“…A number of nonrandomized studies have reported on the virological and immunological efficacy of raltegravir for treatment-experienced subjects (46)(47)(48)(49), including in combination with etravirine and darunavir (50-52). These primarily clinic-based studies further confirm the benefits observed in randomized clinical trials of raltegravir as a component of combination therapy for treatment experienced patients.…”

Use of Maraviroc-, Raltegravir-, and Etravirine-Containing Regimens in Treatment-Experienced Patients: A Case-Series Study

“…5-7 These 3 agents have been used in combination with other active ARV medications to create potent, fully suppressive regimens. 8 However, in some patient populations, the only remaining fully active ARV medications are these 3 agents. This case-series reviews patients from a large HIV patient cohort that were treated with these 3 agents in combination and reports on the tolerability and effectiveness of this regimen.…”