Durability and Safety of a Novel Salvage Therapy in R5-Tropic HIV-Infected Patients: Maraviroc, Raltegravir, Etravirine
Data on long-term efficacy and safety of maraviroc,1 raltegravir,2 darunavir/ritonavir,3 or etravirine4 in combination with optimized background therapy are now available. Several combinations of these new drugs in novel regimens are under study, but data about their combination after 48 weeks are lacking. In the TRIO trial (etravirine, darunavir/ritonavir and raltegravir), 86% of patients had HIV RNA<50 copies per milliliter at week 485; in etravirine early access program, 62.3% of patients achieved HIV RNA <75 copies per milliliter at week 48.6 We recently published data on 48-week outcome of a novel protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs)-sparing regimen including maraviroc, raltegravir, and etravirine for salvage therapy in a small sample size of 28 HIV-infected patients harboring an R5-tropic virus: at week 48, 92% had HIV RNA <50 copies per milliliter.7
Here we report 96-week efficacy and safety data.
Triple-class experienced HIV-1-infected patients attending the Department of Infectious Diseases of San Raffaele Scientific Institute in Milan, Italy, who were failing on their current continuous antiretroviral therapy, were co-screened for entry into the raltegravir (MK0518-023), maraviroc (A4001050), and etravirine (TMC125-C214) expanded access programs after giving their written informed consent. A regimen with raltegravir, maraviroc, and etravirine was planned for those with R5-tropic HIV-1, resistance or previous failures to non-NRTIs, nonnucleoside reverse transcriptase inhibitors, and PIs. This is an ongoing prospective study; as previously described,7 at each visit (baseline and weeks 4, 12, 24, 36, 48, 60, 72, 84, and 96), they underwent a physical examination, recording of adverse events and fasting blood collection for hematological, biochemistry, immunological, and virological analyses. HIV-1 genotyping for resistance to protease and reverse transcriptase inhibitors, integrase, and fusion inhibitors when appropriate and HIV-1 coreceptor tropism test were performed at screening and at any time HIV RNA reached >50 copies per milliliter.
Results are described as median (Q1-Q3). Changes between week 48 and week 96 were evaluated by the Wilcoxon sign test or by the McNemar test. Trends of laboratory parameters were tested by analysis of variance for repeated measures, and Greenhouse-Geisser probabilities were calculated.
Twenty-eight patients were enrolled. Twenty-six (92.8%) were men, 6 (21.4%) were intravenous drug users, and 8 (28.6%) were coinfected with hepatitis C virus; their median age (interquartile range was 43.9 years (42-49.4 years), duration of HIV infection 16.6 years (14-20.2 years), previous continuous antiretroviral therapy, exposure 14 years (12-16.7 years), nadir CD4+ count 74 cells per cubic millimeter (28-195 cells/mm3), CD4+ count 254 cells per cubic millimeter (76-399 cells/mm3), CD4% 13.6% (8.1%-19.6%), the CD4+ to CD8+ ratio 0.21 (0.12-0.36), and the plasma HIV RNA load 4.16 log10 copies per milliliter (3.85-5.08 log10 copies/mL). Sixteen patients (57%) had previously been diagnosed with a Center for Disease Control and Prevention category C HIV-related illness.
Twenty-five (89%) enrolled patients completed 96 weeks of treatment. By week 96, 24 (96%) of 25 patients attained HIV RNA <50 copies per milliliter (P < 0.0001); 14 (56%) of 25 had HIV RNA below 1 copy per milliliter detected by a ultrasensitive method (Fig. 1A). The remaining patient showed a decrease from 111,380 copies per milliliter at baseline to 71 copies per milliliter at week 96 without changes in repeated resistance profile or in viral tropism.
Overall, the median (interquartile range) CD4+ cell count rose from 247 cells per cubic millimeter (66-355 cells/mm3) at baseline to 472 cells per cubic millimeter (398-562 cells/mm3) at week 96 with a median increase of 211 cells per cubic millimeter (114-302 cells/mm3) by week 96 (P < 0.0001) (Fig. 1B).
There was also a significant median increase in CD4 percent from 12.6% (8.1%-19.5%) at baseline to 19.7% (14.2%-26.2%) at week 96 (P < 0.0001).