To the Editors:
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). We also observed a significant increase in the CD4+ to CD8+ ratio from 0.21 (0.13-0.35) at baseline to 0.44 (0.28-0.62) at week 96 (P < 0.0001).
CD4 cells count, CD4 percentage, and CD4 to CD8 ratio increased until week 48, afterward their level was stable. Serious adverse events occurred in 4 patients (14%): one anal cancer, 2 Hodgkins lymphomas with 1 death, and 1 recurrence of mycobacterial spondylodiscitis (probably due to the rapid immune reconstitution).
Two patients did not complete treatment: they stopped therapy at week 72 (one for aspartate transferase and alaninoaminotransferase increase due to alcohol abuse and one for chemotherapy for Hodgkin lymphoma). During the 96 weeks, there was a significant increase in the median body mass index from 23.1 (20.5-25.5) to 24.2 (22.5-26.6) (P = 0.0002) and waist circumference from 86 cm (82-92 cm) to 92 cm (88-100 cm) (P < 0.0001). We observed an improvement of the hematological profile, with a significant increase in hemoglobin from 13.6 g/dL (12.3-14.8 g/dL) to 15.3 g/dL (14.6-15.9 g/dL) (P < 0.0001), platelets from 181 × 109 per cubic millimeter (151-204 × 109/mm3) to 185 × 109 per cubic millimeter (164-217 ×109/mm3) (P = 0.028), white blood cells from 5.0 × 109 per cubic millimeter (3.9-5.6 × 109/mm3) to 6.2 × 109 per cubic millimeter (5.3-7.8 × 109/mm3) (P = 0.0002) and a nonsignificant increase in lymphocytes from 1.7 (1.2-2.0) 109/mm3 to 2.3 (1.9-3.0) 109/mm3 (p=0.125) and neutrophils from 2.4 × 109 per cubic millimeter (2-3.7 × 109/mm3) to 3.2 × 109 per cubic millimeter (2.7-4.3 × 109/mm3) (P = 0.068).
No significant changes in aspartate transferase (P = 0.370), alaninoaminotransferase (P = 0.300), γglutamyl transferase (P = 0.479), and creatinine phosphokinase levels (P = 0.142) were recorded. With respect to the lipid profile, we observed a significant increase in high-density lipoprotein cholesterol from 39 mg/dL (35.5-45.5 mg/dL) to 43 mg/dL (39-55 mg/dL) (P = 0.029). Conversely, triglycerides and low-density lipoprotein cholesterol decrease, although not significantly, from 139 mg/dL (99.5-190 mg/dL) to 100 mg/dL (76-186 mg/dL) (P = 0.223) and from 114 mg/dL (82-129 mg/dL) to 104 mg/dL (88-128 mg/dL) (P = 0.847), respectively. We did not observe changes in glucose or insulin levels; 2 patients, however, developed diabetes.
There was a significant median decrease in plasma creatinine levels from 1.01 mg/dL (0.87-1.25 mg/dL) to 0.88 mg/dL (0.83-1.03 mg/dL) (P < 0.0001) and an increase in serum urate levels within normal ranges from 5.44 mg/dL (3.8-6.14 mg/dL) to 6 mg/dL (4.5-6.9 mg/dL) (P = 0.008).
New drug classes and new combinations of antiretrovirals have been allowed to reach high rates of virological and immunological response in patients with multidrug-resistant HIV.
Current treatment guidelines suggest the use of new drug classes to achieve maximal virological suppression in salvage patients.8 Long-term efficacy and safety of new regimens including more new compounds are under observation.9 There are few data on efficacy and safety when we combined in a novel regimen drugs, such as maraviroc, raltegravir, and etravirine. This NRTIs-sparing and PIs-sparing regimen was associated with high rates of virological success, which was sustained over 96 weeks and associated with a marked and persistent increase in CD4+ cells count. The new combination of maraviroc, raltegravir, and etravirine showed durability of the response despite high pill burden and concerns on the potentially low genetic barrier of such compounds. This highlights the importance of a combination of active drugs, rather than an individual's genetic barrier, in obtaining virological success.
The recovery of CD4+ cells in our patients was sustained, and its magnitude was definitely greater than in other studies in which the drugs were combined differently1-4; this may have been a direct consequence of the concomitant use of maraviroc and raltegravir, which has been associated to greater immunological recovery in experienced and naive subjects. Another possible explanation is the avoidance of NRTI-related toxicity on bone marrow, and this is reinforced by a significant improvement in almost all the hematological parameters. The clinical implications of such a high rate of CD4+ cell recovery need to be investigated further as it may provide better protection against AIDS and non-AIDS illnesses.
During the treatment, 3 patients developed non-AIDS-related malignancies, whose relationships with drug use is unlikely. No data are currently available concerning the risk for cancer when the 3 drugs are used in combination, and the long-term safety of this regimen will be strictly monitored.
A favorable and lasting trend of bone marrow function and renal could be explained with the removal of NRTIs, in particular tenofovir. Despite the removal of PIs, there was only a modest improvement in metabolic parameters.
This was a single-center uncontrolled trial in a small patient sample, and it may be difficult to generalize the maintenance of results to the heavily pretreated HIV-1-infected population. However, encouraging results at week 96 suggests that this regimen can be a sustainable therapy in HIV-1-infected patients with very limited treatment options and may be considered in salvage patients.
In conclusion, this new PI-sparing and NRTI-sparing regimen of maraviroc plus raltegravir plus etravirine has durable efficacy, allowing full viral control and CD4+ cell recovery in patients with extensive drug resistance.
The authors are grateful to all the patients for their commitment and thank all the staff for their invaluable help in conducting the study, particularly the colleagues of the Department of Infectious Diseases, the virologists (Filippo Canducci, Enzo Boeri, and Massimo Clementi), the study coordinators (Vega Rusconi, Clara Ronchetti, and Elisabetta Carini), and the research nurse (Concetta Vinci). They are also grateful to Merck, Pfizer and Tibotec for allowing to co-screen the patients within their expanded access programs and for, respectively, the raltegravir, maraviroc, and etravirine.
Silvia Nozza, MD
Laura Galli, MSc
Alba Bigoloni, SN
Gianotti Nicola, MD
Manuela Pogliaghi, MD
Francesca Cossarini, MD
Stefania Salpietro, MSc
Andrea Galli, PhD
Liviana Della Torre, SN
Giuseppe Tambussi, MD
Adriano Lazzarin, MD
Antonella Castagna, MD
San Raffaele Scientific Institute Milan, Italy
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8. Panel of Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
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