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Research Letters

Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus

Thuret, Isabellea; Chaix, Marie-Laureb,c; Tamalet, Catherined; Reliquet, Véroniquee; Firtion, Ghislainef; Tricoire, Joëlleg; Rabaud, Christianh; Frange, Pierrec,i; Aumaître, Huguesj; Blanche, Stéphanec,i

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doi: 10.1097/QAD.0b013e328331a456
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Abstract

There is a need for potent new antiretroviral (ARV) treatments for perinatally infected HIV adolescents who have developed highly drug-resistant viruses. Recently, three new drugs showed promising results for such adult patients: raltegravir, the first integrase inhibitor; etravirine, a new generation nonnucleoside reverse transcriptase inhibitor (NNRTI) and r-darunavir, a protease inhibitor often active despite protease inhibitor multiresistance [1–8]. Only darunavir has been licensed for children more than 13 years of age. Experience with the combined use of the three drugs in adults is growing [9]. No information has been reported for children or adolescents. ATU (Autorisation Temporaire d'Utilisation) is a permit, granted by the French health authority (AFSSaPS), which allows new drugs to be prescribed within a strict framework before commercialization on the drug market [10]. From October 2006 to December 2007, the French compassionate program allowed the prescription of this triple combination under the ATU for patients with active replication of a multiclass-resistant virus. A total of 12 adolescents under 18 years of age were treated in France. We describe the observation of these 12 adolescents who were monitored according to national guidelines [11].

The 12 patients had been perinatally HIV-1-infected. At the start of the ARV therapy with raltegravir, etravirine and r-darunavir, the median age was 15 years (range 12–17 years) and median weight was 48 kg (range 28.5–72 kg). Centers for Disease Control and Prevention (CDC) class C event had occurred for eight patients and all 12 were or had been immune class 3. CD4 cell counts ranged from 13–484 cells/ml (median of 124 cells/ml).

All patients had received extensive ARV therapy for a median duration of 15 years (range 10–17 years), including one or two NNRTIs, a median of six nucleoside reverse transcriptase inhibitors (NRTIs) and of four protease inhibitors. The entry inhibitor, enfuvirtide had been used in six patients. The 12 adolescents had genotype-documented triple-class (entry inhibitor not evaluated) drug resistance (Fig. 1).

F1-16
Fig. 1:
Percentage of patients with resistant virus according to each antiretroviral drug. Genotypic resistance test and drug resistance interpretation were done according to the French ANRS 2008 algorithm (http://www.hivfrenchresistance.org) on the basis of recent and historical genotypes prior to starting raltegravir, r/darunavir and etravirine combination.

The new combination was prescribed because of active viral replication with a HIV-1 RNA level ranging from 4.33 to 6.1 log10 copies/ml (median of 5.27 log10 copies/ml). Six patients had never experienced an undetectable viral load in their treatment history.

Raltegravir was administered as one 400 mg tablet twice daily (b.i.d.) for all patients, so individual doses ranged from 5.5–14 mg/kg/b.i.d. Adult doses were also prescribed in nine of 12 cases for darunavir (as 300 mg tablets at a dose of 600 mg b.i.d. with a 100 mg boost of ritonavir b.i.d.) and etravirine (as 100 mg tablets at a daily dose of 200 mg b.i.d.). Doses for darunavir and etravirine ranged from 8.3–15.8 and 2.8–5.3 mg/kg/b.i.d., respectively.

In eight cases, one or several additional drugs were added to the backbone triple combination, including one or two NRTIs in seven cases, tenofovir in four and enfuvirtide in three. Genotypic sensitivity scores of the new combination were 2, 3 and 4 for seven, two and three patients, respectively.

At the time of analysis (October 2008), the median treatment duration was 12 months (9–21). Enfuvirtide was rapidly stopped in three patients after viral control was obtained and darunavir was stopped in one patient because of gastrointestinal side effects.

No death or AIDS-defining clinical conditions occurred. One patient experienced a probable immune reconstitution inflammatory syndrome with transient worsening of a multifocal osteomyelitis. The median SD score for weight according to French references increased from −1.18 SD (−2.63 to +1.4) to −0.68 SD (−2.48 to +1.4) at the last follow-up evaluation (P = 0.033, Wilcoxon signed rank test).

Laboratory, immunological and virological results were available for all patients at M1, M3 and every 3 months thereafter following a treatment switch, as recommended in French guidelines. Plasma HIV-1 RNA levels (log 10 copies/ml) significantly decreased from a median of 5.27 (range 4.33–6.10) at baseline to 2.32 (<1.60–3.65), 2.00 (<1.60–4.71), 1.69 (<1.60–4.01) and 1.66 (<1.6–2.50) at M1, M3, M6 and M9 (P < 0.001, Friedman test). The number of children with less than 400 copies/ml of HIV-1 RNA was nine, ten, 11 and 12, and the number of those with less than 50 copies/ml was one, three, five and five, at the same points in time. At the last follow-up evaluation, virological failure, defined as viral load more than 400 copies/ml at two consecutive measurements, occurred in only one patient and was clearly related to suboptimal adherence to the program documented by repeated undetectable levels of ARV drugs.

The median CD4 cell count (range) regularly increased from 124 cells/ml (13–484) at baseline to 500 (18–1239) at M9 (P < 0.001, Friedman test).

No clinical symptoms of intolerance were noticed except in one patient in whom darunavir was stopped because of diarrhea and vomiting. No grade 3 or 4 biological dysfunctions [in terms of hematology, fasting total cholesterol, fasting triglycerides, serum creatinine, total bilirubin, aspartate transaminase, alanine transaminase (ALT), creatinine phosphokinase and lipase] occurred. All baseline perturbations, including anemia grade 2 (n = 1), neutropenia grade 1 (n = 1), increased ALT values grade 1 (n = 1) and elevated gamma-glutamyl transferase (grade 3, n = 1) remained unchanged or resolved. Mild increase (grade 2) in fasting triglyceride levels appeared in two patients, whereas improvement in three others previously treated with lopinavir was noticed.

In this first pediatric observational analysis, the tolerability and efficacy of a combination of raltegravir, r-darunavir and etravirine appear remarkable. Although these data do not carry the same weight as a controlled trial, potential bias was limited by the use of standardized follow-up guidelines and analyses based on all French children treated during the ATU period. Virological results were impressive. Viral load less than 400 copies/ml was obtained and maintained upto the last evaluation for all patients except one. This demonstrates that, as in adults, the majority of extensively treated adolescents can be virologically controlled by a salvage regimen consisting of a combination of new drugs, despite a long record of suboptimal treatment and viral multiresistance. In addition to virologic control, we observed immunological and clinical improvements. No unusual events were observed during tolerance evaluation, though the size of the group and the follow-up were too limited to draw definitive conclusions.

In these adolescents with multiclass drug-resistant HIV, the use of a new class of drug such as raltegravir offers considerable potential benefits because of the absence of cross resistance. However, the efficacy of raltegravir in experienced patients improved when combined with other fully or partially active agents [3]. The opportunity to use etravirine and r-darunavir (two new drugs not yet licensed in France for patients under 18 years of age) in association with raltegravir, as part of the expanded access program, contributed to the sustained virological suppression. Dosage and pharmacokinetic data from pediatric clinical trials are still to be published [12], but a combination of raltegravir, r-darunavir and etravirine demonstrated a potent ARV effect with a good safety profile for adolescents in urgent need of treatment. Optimal treatment for these adolescents is sometimes precluded because of long delays in obtaining marketing authorization for new pediatric drugs.

Acknowledgements

We acknowledge the contribution of Anderson D. Loundou, Biostatician, PhD, Medicine School University, Department of Public Health, AP-HM (Marseilles University Hospital System) for performing the statistical analysis. The present analysis was independent of drug manufacturers (Merck Sharp Dohme-Chibret, Paris, France and Tibotec/Janssen-Cilag, Issy-les-Moulineaux, France) and the Agence Francaise de Securité Sanitaire et des Produits de Santé (AFSSaPS) who managed the expanded access programs. An unrestricted grant was received from Merck-France to cover editing fees.

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© 2009 Lippincott Williams & Wilkins, Inc.