To the Editors:
Integrase strand transfer inhibitors (INSTIs) are potent and well-tolerated drugs for treating HIV infection.1–3 INSTI-based antiretroviral therapy (ART) regimen are now widely recommended as initial therapy for most patients, even in the setting of advanced HIV infection with opportunistic infections.4 The rapid decline of HIV viral load (VL) associated with INSTI-based ART might, however, potentiate the risk of immune reconstitution inflammatory syndrome (IRIS) in severely immunocompromised patients.5 Our aim was to determine if incidence of IRIS requiring hospitalization differs in immunocompromised patients who initiated ART containing or not an INSTI.
PATIENTS AND METHODS
Patients were retrospectively selected from a large prospective cohort including all patients in care in 15 French HIV centers (Clinicaltrials.gov ref NCT02898987). All patients received oral information and gave written consent to be enrolled in the cohort. According to French law, this cohort was approved by the French “Commission Nationale Informatique et Liberté” (CNIL). Data were prospectively collected via an electronic medical record. Selection criteria was having initiated first ART between January 1, 2010 and December 31, 2015 and CD4+ T-cell counts below 200/mm3 before treatment. Patients were classified as INSTI+ if an INSTI was included in their regimen and INSTI− otherwise. Age at ART initiation, sex, most probable way of HIV acquisition, pre-ART CD4+ T-cell count and VL, CD4+ T-cell count and VL 3 months after initiation were collected. Medical charts of patients hospitalized within the first 6 months of ART, the period associated with the greatest risk of IRIS occurrence,6 were examined blinded to the choice of first ART by 3 HIV specialists (M.D., G.M.B., and P.D.). Paradoxical worsening of opportunistic infections, or unmasking of a subclinical infection were classified by consensus as “paradoxical” or “unmasking” IRIS, according to adapted AIDS Clinical Trials Group IRIS criteria, when symptoms consistent with an infectious or inflammatory condition were associated with a drop of >2 log10 copies/mL of HIV VL, and not explained by a newly acquired infection, the expected clinical course of a previous infection, or side-effects.7 Continuous variables were described by medians, first and third quartiles, and compared between groups by Kruskal–Wallis rank sum test. Categorical variables were described by frequencies and compared between groups by χ2 test or Fischer exact when needed. Linear regression was used to estimate the OR of IRIS in INSTI+ patients. Generalized linear modelisation was performed to analyze baseline characteristics related with IRIS occurrence. All analyses were performed using R version 3.3.1 (The R Foundation for Statistical Computing).
During the study period, 2287 patients with CD4+ T-cell count below 200/mm3 initiated a first ART regimen. Of them, 398 were classified as INSTI+. Overall, the median age at ART initiation was 45 years (37–53), 63% were men and the most probable way of HIV acquisition was sexual (84%). Pre-ART CD4+ T-cell count was 83/mm3 (31–146) and pre-ART VL was 5.23 log10.copies/mL (4.78–5.66). INSTI+ and INSTI− groups were not significantly different at baseline (Table 1). The studied population represents 199 persons-year receiving an INSTI-based regimen and 945 person-year receiving a regimen without INSTI. An IRIS requiring hospitalization occurred in 41 patients with a median delay of 35 days (18–79) within 6 months after ART initiation. IRIS events were classified as unmasking in 22/41 patients (54%) and paradoxical in 19/41 (46%). IRIS was related to tuberculosis (12 cases), Mycobacterium avium complex (10 cases), progressive multifocal leukoencephalopathy (6 cases), cytomegalovirus (5 cases), Kaposi sarcoma (4 cases), toxoplasmosis (2 cases), cryptococcosis (1 case), and viral hepatitis B (1 case). CD4+ T-cell counts and VL were 103/mm3 (56–212) and 2.5 log10 copies/mL (1.6–3.1) when patients were hospitalized for IRIS, and 190/mm3 (114–272) and 1.97 log10 copies/mL (1.60–2.42) after 3 months of ART. IRIS occurred, respectively, in 1.5% (29/1889) of the INSTI− and 3% (12/398) of the INSTI+ groups (P = 0.05). Incidence of IRIS was 6.03 cases by person-year in the INSTI+ group and 3.06 cases by person-year in the INSTI− group. IRIS OR was 1.99 (1.09–3.47) (P = 0.04) for the INSTI+ group. Generalized linear modelisation showed that IRIS was associated with pre-ART HIV VL [for one log, OR 1.79 (1.23–2.65)], CD4+ T-cell counts [for one cell, OR 0.99 (0.98–0.99), and INSTI use OR 1.96 (1.07–3.43). HIV VL after 3 months of ART was lower in the INSTI+ group [1.68 log10 copies/mL (1.4–2.1)] compared with the INSTI− group [2.01 (1.6–2.5)] (P < 0.001)]. Repartition of opportunistic infections associated to IRIS (Table 1) and delay of IRIS after ART initiation [34.5 days (12.5–76) versus 35 days (20–79.5)] did not differ between groups.
Using a prospectively collected multicenter cohort, we found that IRIS events requiring hospitalization were twice more frequent among patients with CD4+ T cells below 200/mm3 who initiated INSTI-based ART regimen. IRIS events were also related with high VL and low CD4+ T-cell count at baseline.
Patients with advanced HIV infection, low CD4+ T-cell count, high HIV VL, and a high likelihood of opportunistic infection with high-antigen burden cumulate risk factors for IRIS occurrence.6 A rapid decline of HIV VL has also been considered as a risk factor for IRIS.5,8 IRIS results from the recovery of a protective but unbalanced cell-mediated immunity driven by pathogen-derived antigens that cause disproportionate tissue damage to the host.9 IRIS occurs mostly during the first 3–6 months after the initiation of ART when the control of HIV replication allows redistribution of CD45RO+ memory CD4+ and CD8+ T cells from lymphoid tissues to the periphery.10 It is therefore conceivable that a sharper control of HIV replication during this period by more potent ART regimens, as reported for INSTI-based regimens, increases the risk of IRIS.1–3 The lower HIV VL observed after 3 months of ART in the INSTI+ group experiencing more IRIS events supports this hypothesis. Those results are particularly important in the setting of a still frequent late presentation to HIV care worldwide. Late presentation refers to HIV-infected patients entering care with a CD4+ T-cell count below 350/mm3 (as patients included in our study) or with an AIDS-defining event.11 In a 2013 cross-European update, 48.7% of HIV-infected patients presenting to care were late presenters, most of them coming from countries with high prevalence of tuberculosis.12 We believe that in late presenters, particularly those being treated for a mycobacterial disease, INSTI-based regimens might be associated with an increased risk of IRIS. Although achievement of viral replication control is obviously instrumental and highly desirable, patients with extensive opportunistic infections at high risk of IRIS, or infections affecting the brain that may be associated with life-threatening IRIS, warrant close monitoring when starting an INSTI-based ART regimen during the 3–6-month period usually associated with IRIS occurrence.
The large sample size of the cohort and independent review of cases with a homogeneous definition are strengths of our study. However, IRIS cases were infrequent and did not allow us to further analyze differences between pathogens associated with IRIS. Although it had been considered that 16.1% of unselected patients starting ART develop any type of IRIS,6 the relatively low frequency of IRIS events in our study (1.8%) may be explained by the strict definition of IRIS we used and by our exclusive focus on severe IRIS events requiring hospitalization and treatment, avoiding thereby less relevant IRIS events such as darts or Herpesviridae-related IRIS.
On the other end our study has some limits. Some indication bias could exist in our study. Because of known interactions between protease inhibitors and rifampicin, it is possible that in case of pre-existing mycobacterial diseases, leading most of the IRIS cases, patients were more prone to receive an INSTI-based regimen, although alternatives such as efavirenz were largely prescribed. As shown in the table, we could not show that this was the case, but we may lack power to find any significant difference in the choice of first ART in IRIS cases. We do not consider relevant enough the tendency for the CD4+ T-cell counts to be lower in the INSTI+ group to have influenced clinicians toward INSTI prescription. The results of the multivariate analysis showed that the INSTI effect was independent of the CD4+ T-cell value.
Although relatively rare, the risk of severe IRIS requiring hospitalization seems greater in severely immunocompromised HIV-infected patients receiving INSTI-based regimens as first ART than in those not receiving an INSTI. This risk should be balanced with the benefit of these treatments in patients with advanced disease.
The authors thank the entire centres' technical staff for data quality assessment.
Dat'AIDS Study Group: S. Brégigeon, O. Faucher, M. Orticoni, M.J. Soavi, P Geneau de Lamarlière, H Laroche, E. Ressiot, M Carta, M.J. Ducassou, I Jacquet, S. Gallie, A Galinier, A.S. Ritleng, A. Ivanova, C. Blanco-Betancourt, C Lions, C Debreux, V Obry-Roguet, and I. Poizot-Martin (Marseille); Alvarez M, Biezunski N, Cuzin L, Debard A, Delobel P, Delpierre C, Garipuy D, Lansalot P, Lelievre L, Lepain I, Marcel M, Marchou B, Martin-Blondel G, Metsu D, Mularczyk M, Porte L, Puntis E, and Saune K (Toulouse); P. Pugliese, C. Ceppi, E. Cua, J. Cottalorda, P. Dellamonica, E. Demonchy, B. Dunais, J. Durant, C. Etienne, S. Ferrando, J. G. Fuzibet, R. Garraffo, K. Risso, V. Mondain, A. Naqvi, N. Oran, I. Perbost, S. Pillet, B. Prouvost-Keller, C. Pradier, S. Wehrlen-Pugliese, E. Rosenthal, S. Sausse, and P.M. Roger (Nice); C. Allavena, C. Bernaud, E. Billaud, C. Biron, B. Bonnet, S. Bouchez, D. Boutoille, C. Brunet-Cartier, N. Hall, T. Jovelin, P. Morineau, F. Raffi, V. Reliquet, H. Hue, L. Larmet, So. Pineau, V. Ferré, E. André-Garnier, A. Rodallec, F. Vivrel, M. Lefebvre, O. Grossi, C. Biron, P. Point, and O. Aubry (Nantes); F. Ajana, E.Aissi, I. Alcaraz, V. Baclet, P. Choisy, T. Huleux, H. Melliez, A. Meybeck, A. Pasquet, B. Riff, O. Robineau, M. Valette, and N. Viget, (Tourcoing); Y. Yazdanpanah, R. Landman, C. Duvivier, M.A. Valantin, R. Agher, C. Katlama, O. Lortholary, F. Lanternier, C. Charlier, C. Rouzaud, B. Henry, V. Avettand-Fenoel, C. Rouzioux, P.H. Consigny, G. Cessot, F. Touam, R. Usubillaga, and C. Louisin (Paris); A. Cabié, S. Abel, S. Pierre-François, Mathilde Pircher, and Benoit Rozé (Fort de France); D. Rey, P. Fischer, M. Partisani, C Cheneau, M Priester, ML Batard, C Bernard-Henry, and E de Mautort (Strasbourg); C. Chirouze, C. Drobacheff-Thiébaut, J.P. Faller, J.F. Faucher, A. Foltzer, H. Gil, L. Hustache-Mathieu (Besançon), and B. Hoen (Pointe à Pitre); C Jacomet, H Laurichesse, O Lesens, M Vidal, N Mrozek, C Aumeran, O Baud, J Beytout, D Coban, S Casanova (Clermont-Ferrand), F. Bani-Sadr, C. Rouger, J.L. Berger, Y. N'Guyen, D. Lambert, I. Kmiec, M. Hentzien (Reims), C. Chidiac, F. Ader, F. Biron, A. Boibieux, L. Cotte, T. Ferry, P Miailhes, T. Perpoint, F Valour, and S. Degroodt (Lyon).
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