HIV Articles  
Raltegravir, maraviroc, etravirine: an effective protease inhibitor and nucleoside reverse transcriptase inhibitor-sparing regimen for salvage therapy in HIV-infected patients with triple-class experience
27 March 2010 - Volume 24 - Issue 6 - p 924-928
Research Letters
Nozza, Silvia; Galli, Laura; Visco, Francesca; Soria, Alessandro; Canducci, Filippo; Salpietro, Stefania; Gianotti, Nicola; Bigoloni, Alba; Torre, Liviana Della; Tambussi, Giuseppe; Lazzarin, Adriano; Castagna, Antonella aDepartment of Infectious Diseases, San Raffaele Scientific Institute, Italy bUniversita Vita-Salute San Raffaele, Milan, Italy.
We prospectively evaluated 28 triple-class experienced HIV-1-infected patients harbouring R5 virus, who received maraviroc, raltegravir and etravirine. By on-treatment analysis, 26 (92%) had less than 50 copies HIV-RNA/ml at week 48. The median (interquartile range) 48-week increase in CD4+ cell counts was 267 (136-355) cells/µl. Three serious adverse events occurred: one recurrence of mycobacterial spondylodiscitis, one anal cancer, one Hodgkin lymphoma. Although long-term safety needs further study, this protease inhibitor and nucleoside analogue-sparing regimen showed sustained efficacy.
Recent phase III clinical trials investigating raltegravir [1], maraviroc [2] or etravirine [3,4] in HIV-1-infected patients with multiple previous failures have shown the best results when at least two active drugs were used in the optimized background regimen. Efficacy and safety data on the coadministration of raltegravir, maraviroc and etravirine without nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors are not available. The aim of our study was to evaluate the 48-week efficacy and safety of this novel NRTI and protease inhibitor-sparing salvage regimen.
Between May 2007 and May 2008, triple-class experienced HIV-1-infected patients regularly followed at the Department of Infectious Diseases, San Raffaele Scientific Institute, who were failing their current combination antiretroviral therapy (cART) after giving their written informed consent were co-screened for raltegravir (MK0518-023), maraviroc (A4001050) and etravirine (TMC125-C214) expanded access programmes and underwent genotypic drug-resistance testing and a coreceptor tropism test (Trofile, Monogram Biosciences, California, USA); a regimen of raltegravir, maraviroc and etravirine was planned for those with R5-tropic HIV-1, resistance or previous failures to non-NRTIs (NNRTIs), NRTIs and protease inhibitors. Genotypes were interpreted by Stanford genotypic algorithm [5], accessed at screening for each patient. Etravirine resistance score was calculated post hoc according to Vingerhoets et al. [6].
Patients enrolled in the study were given a regimen of raltegravir (400 mg b.i.d.) and maraviroc (600 mg b.i.d., due to the reduced plasma concentrations when combined with etravirine [7]) and etravirine (200 mg b.i.d.).
Only on-treatment analysis was applied because no patient discontinued treatment before week 48. All statistical tests were two-sided at the 5% level and were performed with SAS Software, release 9.1, SAS Institute, Inc., Cary, North Carolina, USA.
Twenty-eight out of 106 (26.4%) co-screened patients harboured a R5-tropic virus and were thus enrolled in the study: 26 (92.8%) were males, eight (28.6%) were co-infected with hepatitis C virus (HCV) and 16 (57%) were in C CDC stage. At baseline, the median [interquartile range (IQR)] age was 43.9 (42-49.4) years, the duration of HIV infection 16.6 (14-20.2) years, previous cART exposure 14 (12-16.7) years, CD4+ cell count 254 (76-399) cells/µl, and plasma HIV-RNA 4.16 (3.85-5.08) log10 copies/ml. All had been previously exposed to NRTIs, NNRTIs and at least three protease inhibitors, including lopinavir/ritonavir [28/28 (100%)], tipranavir/ritonavir [4/28 (14%)], and darunavir/ritonavir [10/28 (36%)]. Eleven (39%) patients had been previously treated with enfuvirtide.
The ongoing failing regimes, the screening genotypes and the calculated etravirine scores are reported in Table 1. below
At week 48, all patients had an HIV-RNA load below 400 copies/ml (P < 0.0001) and 26/28 (93%) had less than 50 copies HIV-RNA/ml (P < 0.0001) (Fig. 1a).
Unannounced pill counts at weeks 12, 24, 36, 48 were consistent with 100% adherence in 24 (86%), 26 (93%), 23 (82%) and 23 (82%) patients, respectively.
At week 48, the median increase in CD4+ cell count was 267 (136-355) cells/µl (Fig. 1b). The proportion of patients with CD4+ cell counts below 200 cells/µl was 36% (10/28) at baseline, and 7% (2/28) at week 48 (P = 0.0082).
Serious adverse events occurred in three (11%) patients: one anal cancer, one Hodgkin lymphoma, and one recurrence of mycobacterial spondylodiscitis, but no patient permanently discontinued treatment.
BMI [baseline: 23 (20.9-25.5); week 48: 24.5 (21.0-27.1); P = 0.0002], waist circumference [baseline: 85.2 (82.0-91.7); week 48: 88.0 (83.0-99.0); P = 0.002], and haemoglobin [baseline: 13.6 (12.3-15.1); week 48: 15.1 (14.5-15.9); P < 0.0001] increased significantly.
No significant changes in liver function tests were observed, except for one HCV-coinfected patient who experienced a grade 3 aspartate aminotransferase and alanine aminotransferase increase due to episodic alcohol abuse, which recovered without treatment interruption.
There was a significant decrease in plasma creatinine [baseline: 0.99 (0.87-1.22); week 48: 0.88 (0.78-0.99); P < 0.0001]. A significant increase in high-density lipoprotein-cholesterol [baseline: 39 (34-46); week 48: 41 (38-46); P = 0.027] was observed and four out of five patients who were using lipid-lowering agents at baseline stopped fibrates during follow-up, because of decrease of triglycerides levels; no patient introduced a lipid-lowering agent. There were no significant variations of glucose and insulin, except for one patient who experienced transient fasting glucose levels above126 mg/dl.
In our study, the combination of raltegravir and maraviroc, and etravirine led to an unexpected rate of virological success, with a rapid and robust CD4+ cell recovery, despite a high pill burden regimen and potentially negative drug-drug interactions.
In previous studies with salvage regimens, protease inhibitors and NRTIs were commonly added to novel antiretroviral compounds [8-13], despite minimal residual antiviral activity. Our results suggest that when raltegravir, maraviroc and etravirine are combined (in patients naïve for integrase inhibitors and CCR5 antagonists), their association with high genetic barrier drugs is not mandatory. Nevertheless, the long-term durability of this novel regimen must be confirmed.
In our study, the recovery of CD4+ cells was definitely higher than in other experiences when these drugs were differently combined [8-13]. This could be the direct consequence of the rate of virological success. However, raltegravir and maraviroc showed a higher CD4+ cell increase than efavirenz in head-to-head comparison in treatment-naïve patients despite similar or lower antiviral activity [14,15] and could have had a synergistic effect in our patients, for unknown reasons. Another possible explanation could be the removal of NRTI-related bone marrow toxicity [16,17].
The increase of abdominal waist circumference needs to be properly addressed, but it was not associated with an increase in insulin resistance. Moreover, we observed an improvement of lipid profile.
Two patients developed non-AIDS-related malignancies: a relationship with treatment is difficult to establish in this fragile population. Data from trials in treatment-naïve and treatment-experienced patients are reassuring [14,15,18], but, as the risk of cancer when these three drugs are used in combination is unknown, the long-term safety of this regimen will be strictly monitored.
In conclusion, our results suggest that a protease inhibitor and NRTI-sparing regimen of raltegravir and maraviroc, and etravirine is potent and well tolerated. Although long-term toxicity needs to be accurately evaluated, this regimen may represent a powerful option to regain full viral control and robust CD4+ cell recovery in patients with extensive drug resistance and R5-tropic HIV.

  iconpaperstack view older Articles   Back to Top