JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor
Raltegravir-Based Regimens Are Effective in HIV-1 Group O–Infected Patients
Depatureaux, Agnès MD, PhD*,†; Leoz, Marie MSc*,†; Le Moal, Gwenae MD‡; Pathé, Jean-Paul MD§; Pavie, Juliette MD‖; Batisse, Dominique MD¶; Daneluzzi, Vincent MD#; Genet, Philippe MD, PhD**; Gerard, Laurence MD‖; Lascaux-Cametz, Anne-Sophie MD††; Lambolez, Tessa MD‡‡; Chennebault, Jean-Marie MD§§; Plantier, Jean-Christophe PharmD, PhD*,†
*Laboratoire Associé au Centre National de Référence pour le VIH, CHU Charles Nicolle, Rouen, France
†GRAM, EA2656, Université de Rouen, Rouen, France
‡Service des Maladies Infectieuses, CHU La Milétrie, Poitiers, France
§Service de Médecine Interne, CHI Eure Seine, Evreux, France
‖Service des Maladies Infectieuses, CHU Saint Louis, Paris, France
¶Service d'Immunologie Clinique, Hôpital Européen Georges Pompidou, Paris, France
#Service des Maladies Infectieuses, CH Max Fourestier, Nanterre, France
**Service d'Hématologie, CH Victor Dupouy, Argenteuil, France
††Service d'Immunologie Clinique, CH Mondor, Créteil, France
‡‡Service de Médecine Interne et Infectiologie, CHG de Longjumeau, Longjumeau, France
§§Service des Maladies Infectieuses, CHU d'Angers, Angers, France
Financial Support Provided by the Agence Nationale de Recherches sur le SIDA et les hépatites virales and the Institut de Veille Sanitaire.
The authors have no conflicts of interest to disclose.
To the Editors:
HIV-1 group O (HIV-O), 1 of the 4 groups (M to P) of HIV-1, is endemic to Cameroon and circulates in countries with links to this region. It is characterized by high levels of antigenic and genetic diversity.1–3 The genetic polymorphism of antiretroviral (ARV) targets is known to have an impact on therapeutic management, with reports of natural resistance to nonnucleoside reverse transcriptase inhibitor,4,5 discordance between genotypic and phenotypic results for enfuvirtide,6 and incomplete prediction based on resistance algorithms validated for HIV-M.7 However, little is known about the impact of such polymorphism on the most recent classes of ARV drugs, such as integrase inhibitors. Raltegravir (RAL), the only integrase inhibitor currently available, proved effective against HIV-M.8,9 It is indicated for treatment-naive and treatment-experienced patients in association with other ARV drugs.10 This drug should be effective against HIV-O, despite higher levels of natural polymorphism than for HIV-M, due to absence of major resistance-associated mutations as previously described.11 However, only 1 study of a single patient treated with RAL has been published.12 In this study, we aimed to assess immunological and virological responses in the largest series of HIV-O patients treated with RAL-based regimens to date.
We analyzed data for 12 patients identified in a survey of HIV-O variants (RES-O) carried out by a French network13 and treated with RAL in addition to an optimized treatment based on the most recent resistance genotype. Immunological and virological responses were evaluated by determining CD4 lymphocyte counts and viral load (VL) before and after RAL initiation (defined as baseline). VL was determined with a Cobas Taqman v2 (Roche Diagnostics, Meylan, France), HIV-1 RealTime kit (Abbott Molecular, Rungis, France), or in-house HIV-O–specific technique, all validated for the monitoring of HIV-O14,15 and with lower limits of quantification of 20, 40, and 200, copies per milliliter, respectively. ARV targets were sequenced at baseline, as previously described.6,11,16 Baseline resistance was analyzed with the ANRS algorithm (V.21, October 2011) and a genotypic susceptibility score (GSS), defined as the number of effective ARV molecules in the RAL-based regimen.
The patients (8 women and 4 men) were living in France, had a median age of 48 years (35–72), had been infected with HIV for a median of 15 years (8–19), had severe immunodeficiency [nadir CD4 = 68 cells/mm3 (6–398)], and had received a median of 6 (2–10) lines of treatment (Table 1). At baseline, they had a median CD4 cell count of 180 (6–965) (Table 1); taking into account mutations associated to resistance to RAL, no major mutations were detected but some secondary mutations were naturally present, as previously described: 100% of the sequences harbored L74I and G163Q mutations and 2 sequences (BCF161 and BCF181) had V72I and T97A mutations, respectively (data not shown). RAL was included in salvage therapy in 9 patients due to multiple virological failures [baseline median VL of 3.9 log (2.3–4.7) copies/mL] or to replace another drug due to metabolic intolerance (high lipid level or lipodystrophy) in 3 patients (Table 1). Optimized therapy was defined by the most recent resistance genotype leading to a median of GSS of 3 (2–4); the most frequent ARV combination initiated with RAL (50% of cases) was tenofovir, emtricitabine, and darunavir (Table 1). Patients were followed up for a median of 20 months (11–41).
A clear immunological response was observed in all patients, with large increases in CD4 cell counts [median of +161 cells (87–515)]; this increase was similar for patients with CD4 counts above and below 200 cells per microliter at baseline (data not shown). Surprisingly, 2 patients (BCF013 and RBF127) in switch situations displayed the largest increases as follows: +392 and +344, respectively (Table 1).
At end point, 7 of the 9 patients with virological failure on inclusion had sustained undetectable VL for a median of 19 months (7–41). Two patients (RBF130 and RBF132) had a detectable VL (Table 1). For RBF132, this was due to the voluntary interruption of treatment after almost 2 years of undetectable VL (data not shown). For RBF130, VL decreased strongly 7 months after RAL introduction (from 4.2 to 1.6 log copies/mL) but subsequently increased due to poor compliance with treatment (Table 1). Despite these poor virological results, both patients displayed significant increases in CD4 cell counts (+87 and +309 cells/mm3, for RBF132 and RBF130, respectively).
This study constitutes the first report of immunological and virological responses to a RAL-based regimen for a large series of HIV-O–infected patients. Responses were excellent and sustained over a long period of follow-up. Although comparison, in the strict sense of the word, with the BENCHMRK 1 and 2 reference studies8 is impossible, we obtained similar, conclusive, immunological and virological results, indicating that RAL-based regimens were also effective in HIV-O–infected patients. Indeed, the patients studied here displayed very large increases in CD4 cell counts (mean of +231 vs. +123 CD4 cells/μL) and 78% of patients in failure displayed a virological response to RAL, versus 62% for BENCHMRK 1 and 2. Our study included only a small number of patients, but these patients were comparable to the BENCHMRK 1 and 2 patients in terms of their considerable experience of treatment and duration of HIV infection, although they had better prognostic factors at baseline, including better GSS (58% with a GSS ≥ 3 vs. 51%), higher CD4 cell count at baseline (42% with CD4 count >200 cells/μL vs. 31%), and lower VL (median of 3.9 log vs. 4.84 log copies/mL).
Furthermore, 8 patients, including RBF132 (who responded to treatment for 2 years before deciding to stop treatment), reached undetectable VL for the first time. Our results thus indicate that optimized treatment including, in most cases, the latest efficient drugs can lead to virological success in HIV-O–infected patients similar to that observed for HIV-M–infected patients.8 RBF130 proved an exception to this rule, with virological failure at end point. However, despite the lack of complete virological response, VL decreased significantly, demonstrating a probable initial efficacy of RAL introduction. The subsequent increase in VL may be accounted for in part by treatment being stopped, as observed by the reversion of some resistance-associated mutations and the lack of RAL resistance-associated mutations in the endpoint genotype. Two other lines of treatment were tried after the first course of RAL, but poor compliance and a low GSS led to repeated failures in this patient (data not shown).
Our findings also demonstrate the efficacy of switching to RAL therapy as follows: the 3 patients maintained an undetectable VL and displayed large increases in CD4 cell counts. For BCF013, this significant increase was associated with secondary immune reconstruction after chemotherapy for lymphoma.
We observed naturally high levels of polymorphism in the integrase region, as previously described11 and as reported for non-B HIV-M strains17–20 or HIV-221–23; this polymorphism does not seem to interfere with virological response because the region corresponding to the catalytic site of the enzyme remains highly conserved.18–20 However, this baseline polymorphism may favor resistance mutations by lowering the genetic barrier, as already suggested by other authors.17,24,25
In conclusion, RAL-based regimens consistently resulted in high immunological and virological response rates in HIV-O–infected patients in switch or with considerable experience of treatment, regardless of CD4 cell count or VL at baseline. Follow-up should be continued to check that these treatments remain effective in these particular patients. These results also suggest that RAL-based regimens are of potential value for treating naive patients, as recommended for HIV-M.
The authors thank the Agence Nationale de Recherches sur le SIDA et les hépatites virales and the Institut de Veille Sanitaire for financial support; all the clinicians and biologists of the RES-O network; and the technical staff of the virology laboratory of Rouen's hospital.
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