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Raltegravir, Etravirine, and Ritonavir-Boosted Darunavir: A Safe and Successful Rescue Regimen for Multidrug-Resistant HIV-1 Infection
  "At Weeks 4, 12, and 24, respectively, 63%, 81%, and 94% of patients achieved HIV1-RNA less than 50 copies/mL.....Fourteen (44%) and 16 (50%) patients had previously failed tipranavir and enfuvirtide-containing regimens, respectively."
High Rate of Virologic Suppression with Raltegravir plus Etravirine and Darunavir/Ritonavir among Treatment-Experienced Patients Infected with Multidrug-Resistant HIV: Results of the ANRS 139 TRIO Trial - (10/16/09) CID Nov 2009
JAIDS Journal of Acquired Immune Deficiency Syndromes:
November 2009
Imaz, Arkaitz MD; del Saz, Sara Villar MD; Ribas, M Angels MD; Curran, Adrian MD; Caballero, Estrella MD; Falco, Vicenc MD, PhD; Crespo, Manel MD, PhD; Ocana, Inma MD, PhD; Diaz, Marjorie MD; de Gopegui, Enrique Ruiz MD; Riera, Melcior MD, PhD; Ribera, Esteban MD, PhD
From the *Infectious Diseases Department, Hospital Universitari Vall d'Hebron and Departament de Medicina, Universidad Autonoma de Barcelona, Barcelona, Spain; Infectious Disease Unit, Hospital Universitari Son Dureta, Palma de Mallorca, Spain; Microbiology Department, Hospital Universitari Vall d'Hebron, Universidad Autonoma de Barcelona, Barcelona, Spain; and Microbiology Department, Hospital Universitari Son Dureta, Palma de Mallorca, Spain.
Background: Boosted darunavir (DRV/r) plus etravirine (ETR), in DUET trials, and raltegravir, in BENCHMRK trials, showed high rates of virologic response in patients with multidrug-resistant HIV-1 infection, particularly when associated with two more fully active antiretroviral drugs. No data from clinical trials, about this combination, are available.
Patients and Methods: Thirty-two consecutive heavily pretreated patients with multidrug-resistant HIV-1 infection who started a new salvage regimen with RAL (400 mg twice daily), ETR (200 mg twice daily), and DRV/r (600/100 mg twice daily) were studied. Clinical evaluation and immunologic, virologic, and biochemical parameters were collected at baseline and at Weeks 4, 12, and 24.
Results: Median baseline characteristics were age 44 years, 13 years on antiretroviral therapy, nine prior highly active antiretroviral therapy regimens, 261 CD4 cells/mL, and HIV-1 RNA 4.2 log10 copies/mL. Sixteen (50%) and 14 (44%) patients were enfuvirtide- and tipranavir-experienced, respectively. Three-class resistance mutations were present in all patients. Three patients (9%) had isolates with three ETR resistance mutations. All patients were DRV-naïve with a median of one DRV resistance mutation. At Weeks 4, 12, and 24, respectively, 63%, 81%, and 94% of patients achieved HIV1-RNA less than 50 copies/mL. Median CD4 cell count increased 30, 73, and 103 cells/mL at Weeks 4, 12, and 24, respectively. No patient had adverse events leading to discontinuation of the regimen.
Conclusion: The combination of raltegravir, ETR, and DRV/r was a highly effective and well-tolerated antiretroviral salvage regimen in patients infected with multidrug-resistant HIV-1.
The management of antiretroviral therapy failure in heavily treatment-experienced HIV-infected patients remains a challenge. Salvage therapeutic options are usually scarce because of the development of drug resistance to all antiretroviral drug classes and cross-resistance to agents within a class.1-3 In this setting, the development of new antiretroviral drugs, with novel mechanisms of action, as well as new drugs within the current classes with little intraclass cross-resistance has expanded rescue treatment options for heavily pretreated patients with multidrug-resistant HIV-1 infections.
Darunavir (DRV), a new protease inhibitor (PI) with a high genetic barrier and different resistance pattern than the other PIs, etravirine (ETR), a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) active against many HIV strains resistant to first-line NNRTIs, the integrase inhibitor raltegravir (RAL) and the CCR5 coreceptor antagonist maraviroc, are the newest drugs evaluated in randomized clinical trials in highly treatment-experienced patients.4-8 These studies, as well as prior trials with enfuvirtide and tipranavir,9,10 have shown that highest rates of virologic suppression are achieved in the subgroups of patients in whom two fully active agents, at least, can be added to the study drug in the regimen. Nevertheless, in these clinical trials, only current licensed drugs were allowed to be associated with the investigational drug in the regimen, so the possibilities of combining at least two fully active antiretroviral drugs were limited in many cases.
Ritonavir-boosted darunavir (DRV/r) has been combined successfully with ETR in DUET trials5,6 and with RAL in BENCHMRK trials.7 The association of these three novel antiretroviral drugs has not been studied in clinical trials.
The aim of the present study was to assess, in a real clinical setting, the effectiveness and safety of the combination of RAL, ETR, and DRV/r as salvage regimen in patients with advanced HIV-1 infection with prior multiple virologic failures and no viable treatment options resulting from resistance-associated mutations to current available antiretroviral classes.
All consecutive HIV-1-infected adults (age 18 years and older) who started a new salvage antiretroviral regimen with RAL (400 mg twice daily), ETR (200 mg twice daily), and DRV/r (600/100 mg twice daily) between April 2007 and January 2008 in two hospitals in Spain were studied. At the beginning of the analyzed period, these three drugs were available by compassionate use (ETR) or by expanded access programs (DRV and RAL).
Demographic data, prior AIDS-defining diseases, previous antiretroviral treatments, and genotyping data before starting the present salvage treatment were obtained. Highly active antiretroviral therapy was defined as the combination of three or more antiretroviral drugs. Any treatment change was considered as a new regimen. The antiretroviral drug combination was selected, after virologic failure, on the basis of both the treatment history and drug resistance testing. Genotypic resistance tests were performed using the VircoTYPE HIV1 test (Virco BVBA, Mechelen, Belgium). The last resistance test was performed while the patients were on treatment with the last failing regimen and all previous tests were taken into account to determine the potential susceptibility to antiretroviral drugs. Drug resistance-associated mutations (RAM) were considered as defined by the International AIDS Society-USA guidelines.11,12
The safety and tolerability of the study medications were assessed on the basis of clinical adverse events. World Health Organization toxicity grading scales were used to characterize abnormalities in analytical results and physical examination.13 Clinical evaluations were performed at baseline and at Weeks 4, 12, and 24, including, at each visit, physical examination and laboratory tests (CD4 cell count, HIV-1 RNA, hematology, liver and kidney function tests, and fasting blood lipids). Effectiveness was measured as the percentage of patients achieving viral suppression (HIV-1 RNA below 50 copies/mL) in both the intention-to-treat approach, in which any noncompletion equals failure, and the on-treatment approach. Virologic failure was defined as two consecutive determinations of RNA-HIV-1 above 50 copies/mL.
SPSS software for Windows (Version 12.0; SPSS, Chicago, IL) was used for statistical analyses. Categorical variables were described as number (proportion) and continuous variables as median (range or interquartile range). The nonparametric Wilcoxon rank test was used to compare related quantitative variables.
Thirty-two HIV-1-infected patients were included. Baseline characteristics are shown in Table 1. All patients were heavily treatment-experienced with prior failure to the three current antiretroviral oral drugs classes. Fourteen (44%) and 16 (50%) patients had previously failed tipranavir and enfuvirtide-containing regimens, respectively. At baseline, all patients had HIV-1 isolates harboring mutations related with resistance to nucleoside reverse transcriptase inhibitor (NRTI), NNRTI, and PI. The median of NRTI resistance-associated mutations was five. Twenty-one patients (66%) had etravirine resistance-associated mutations and three of these mutations were present in three patients (9%). The median PI RAMs were 11 with 75% of the isolates harboring four or more major PI RAMs. All patients were DRV-naïve and the median of DRV RAMs was 1 (range, 0-3).
Treatment efficacy is shown in Figure 1. After 24 weeks, 30 of 32 patients (94%) by intention-to-treat and 30 of 31 patients (97%) on treatment had viral load below 50 copies/mL. Only two patients did not reach virologic suppression; one stopped treatment voluntarily at Week 4 and the other had poor adherence overtime. CD4 cell count increased significantly by a median of 30 (interquartile range [IQR], -7 to 12), 73 (IQR, -8 to 144) and 103 (IQR, 50 to 217) cells/µL at Weeks 4, 12, and 24, respectively (P value for the differences 0.025, 0.005, and 0.005, respectively).
No patient had drug-related adverse events leading to discontinuation of the regimen. A nonsignificant increase was observed in serum levels of cholesterol (median, 44; IQR, 5 to 65) and triglycerides (median, 14; IQR, -15 to 146) at Week 24 compared with baseline (P = 0.48 and P = 0.18, respectively).
TABLE 1. Baseline Characteristics


The results obtained in the present study show the high and early efficacy of the combination of RAL, ETR, and DRV/r as salvage antiretroviral regimen for HIV-1-infected patients with scarce viable therapeutic options. All our patients were heavily pretreated and all of them had evidence of triple-class resistance. Even in this dramatic situation, 94% of patients achieved HIV RNA below 50 copies/mL after 24 weeks of therapy.
DRV/r has been combined successfully with ETR in DUET trials5,6 and with RAL in BENCHMRK trials.7 No clinically significant pharmacokinetic interaction between ETR and DRV/r has been described.14 Systemic exposure to RAL, metabolized by uridine diphosphate-glucuronosyl-transferase, is not affected by coadministration of ETR or ritonavir and is not expected to interact with DRV.15 Thus, the combination of these three drugs does not seen to be limited by pharmacokinetic interactions.
In the POWER clinical trials, DRV showed improved virologic activity compared with current PIs in patients with prior failures to PI.4 The greater overall number of active antiretroviral agents in the optimized background therapy and de novo enfuvitide use were related with higher response rates. Eleven mutations in the protease gene were associated with resistance to DRV. The presence of three or more and even two mutations has been associated with diminished response to DRV/r,16-18 but each of these mutations could have different impact on DRV susceptibility.19 In our study, all patients were DRV-naïve with a median of one DRV resistance-related mutations, so this drug was considered to retain full activity in all cases.
ETR showed superior antiviral activity than placebo in DUET 1 and 2 trials among treatment-experienced patients with virologic failure and NNRTI and PI-resistant virus.5,6 In the subgroup of patients who received ETR plus two or more active drugs, 74% and 78% achieved HIV RNA below 50 copies/mL at Weeks 24 and 48, respectively.5,6,20,21 Furthermore, the addition of de novo enfuvirtide improved virologic response, underscoring the need for two or ideally three fully active agents in the regimen. The concurrent presence of three or more of 13 specific NNRTI mutations was associated with decreased virologic response to ETR. Recently, the identification of four additional mutations and the development of a weighted genotypic score have improved the correlation between the number of mutations and phenotypic resistance tests.22,23 In our study, 21 (66%) patients had HIV-1 isolates with ETR RAMs. Three patients (9%) had three mutations, but all of them achieved viral loads below 50 copies/mL at Week 24. This good virologic response could be the result of the association of ETR with two more fully active drugs as well as the low relative weight of some of the ETR RAMs.
BENCHMRCK 1 and 2 clinical trials demonstrated the better antiretroviral efficacy of RAL compared with placebo in HIV-1-infected patients failing therapy with triple-class-resistant virus. The greater virologic response was found when two new active drugs, enfuvirtide and DRV, were associated to RAL. In this subgroup of patients, 80% and 89% attained viral load below 50 copies/mL at Weeks 24 and 48, respectively.24,25
According to the previously reported good safety profiles of RAL, ETR, and DRV,4-7 in our patients, the combination of these three drugs was well tolerated and analytical abnormalities in liver function parameters and serum lipid levels were not observed, although it is worth of note the short length of follow up.
The adherence is usually a key issue for the success of any antiretroviral regimen. Despite good adherence, in general, along their whole treatment history, all of our patients had failed multiple highly active antiretroviral therapy regimens and one third of them never attained complete viral suppression. Most of these patients started treatment in the pre-HAART era with mono- or dual therapies and, sequentially, new drugs were added to a failing regimen as they became available. Thus, multiple resistance mutations to NRTIs, NNRTIs, and PIs were accumulated. During the study period, all but the two patients who did not achieve viral suppression had also excellent treatment adherence. The early virologic response as well as the good tolerance of the new regimen could also have influenced positively in the high adherence and, subsequently, in the success of the regimen.
The small number of patients and the absence of a control group are the main limitations of this study. However, our results show the impressive efficacy of this salvage regimen in a real clinical setting. Although only 24-week follow up is available, the efficacy is thought to be durable for a longer time as has been shown in trials cited.20,21,24,25 Moreover, these results suggest that it is possible to construct an effective rescue therapy without NRTI if three fully active drugs are included in the regimen.
Because new antiretroviral drugs with new mechanisms of action and new-generation drugs against classic targets are available, the maximal viral suppression is an attainable goal, even in patients with multidrug-resistant HIV-1 infection. Thus, current guidelines recommend the combination of three fully active antiretroviral drugs in the salvage regimen, including, if possible, new drugs from novel classes.26,27 Until now, most salvage regimens included recycled NRTIs in cases of fully or partially resistant virus to these drugs. With the new antiretroviral drugs, it is possible to build an effective rescue therapy without NRTIs if three fully active drugs are included in the regimen. Probably, the inclusion of NRTIs in this setting could only add toxicity and increase the expense without any improvement in the efficacy of the regimen.
In summary, RAL, ETR, and DRV/r is a well tolerated and highly effective antiretroviral combination in treatment-experienced and multidrug-resistant HIV-1-infected patients with few specific ETR and DRV resistance-related mutations.
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