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Efficacy and safety of dolutegravir and rilpivirine dual therapy as a simplification strategy: a cohort study

2017; Wiley; Volume: 18; Issue: 9 Linguagem: Inglês

10.1111/hiv.12506

1468-1293

Pierre Gantner, Lise Cuzin, Clotilde Allavena, André Cabie, P. Puglièse, M.A. Valantin, Firouzé Bani‐Sadr, Véronique Joly, Tristan Ferry, Isabelle Poizot‐Martin, R. Garraffo, Gilles Peytavin, Samira Fafi‐Kremer, D. Rey,

Renal Transplantation Outcomes and Treatments

HIV-1 antiretroviral therapy (ART) is a life-long treatment. Its potential long-term adverse effects, in addition to the ageing process, may result in a higher incidence of non-AIDS-associated comorbidities than in general population 1, 2. To decrease pill and drug burden, reducing from standard triple therapy to a two drug-containing regimen is an option that continues to be investigated 3. An optimal dual therapy must have potency to maintain viral suppression, in combination with a low toxicity profile and simple administration to improve adherence. Dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), and rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), are two novel antiretroviral agents that are highly active and well tolerated in both ART-naïve and ART-experienced patients 4-7 DTG + RPV [50 + 25 mg once daily (qd)] dual therapy is a nucleoside reverse transcriptase inhibitor (NRTI) and boosted protease inhibitor (PI) sparing regimen which is still under evaluation in randomized studies (i.e. Switch to Rilpivirine + Dolutegravir, SWORD studies). The advantages of this combination include the lack of interactions between the two drugs and the simple qd administration 8, 9. The primary objective of this analysis was to assess viral suppression in ART-experienced patients with virological control switching to DTG + RPV in a real-life setting. Secondary objectives were to describe clinical and biological adverse events and plasma concentrations of DTG and RPV. The Dat'AIDS cohort study is a collaboration of major French HIV treatment centres (NCT02898987). These centres maintain prospective cohorts of HIV-1-infected individuals who provide written informed consent via a common electronic medical record 10. Anonymized data for clinical events, laboratory test results and therapeutic history collected by the networking organization have been submitted to the French National Commission on Informatics and Rights (CNIL Registration number: 2001/762876/nadiscnil.doc). The local Ethics Committee of the Faculty of medicine of Strasbourg, Strasbourg, France, approved the present study. We performed a retrospective analysis in individuals participating in the Dat'AIDS cohort with plasma HIV RNA < 50 HIV-1 RNA copies/mL on ART, without hepatitis B virus (HBV) coinfection, who were switched to DTG + RPV regimen between January 2014 and September 2015. The primary outcome measure was a mixed analysis of antiviral efficacy based on the loss of virological and therapeutic control on dual therapy at week 24. Secondary objectives were virological and therapeutic success over follow-up, immunological response, safety and steady-state drug level. The following data were collected for each participant: demographic data, HIV disease status, previous ART, reason for changing therapy and laboratory parameters. Laboratory abnormalities were graded using the 2003 Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) scale (http://www.anrs.fr). Steady-state trough plasma concentrations of DTG and RPV were determined in a subgroup of patients using liquid chromatography coupled with tandem mass spectrometry 11. Measured trough concentrations were considered adequate if above the protein-adjusted 90% inhibitory concentration (IC90) of 64 ng/mL and 12.1 ng/mL for DTG and RPV, respectively 12, 13. Dual therapy efficacy was analysed according to the time to loss of therapeutic and/or virological response (TLOVR) algorithm. The TLOVR was estimated using the Kaplan−Meier method. Confirmed loss of virological control was defined as a plasma HIV RNA > 50 copies/mL based on two consecutive measurements within 1 month or plasma HIV RNA > 1000 copies/mL for one sample. Therapeutic failure was defined as dual therapy discontinuation, whatever the reason. The Student's t-test was used to compare any changes in quantitative variables. All tests were two-tailed and performed with a level of statistical significance of 0.05. During the study period, 152 patients were switched to DTG + RPV dual therapy. Patients were followed for a median of 36 weeks [interquartile range (IQR) 25–50 weeks]. The participants were primarily male (66%), 42% of individuals were men who have sex with men (MSM), and they had a median age of 55 years (IQR: 48–61 years). All had been virologically controlled on ART (plasma HIV RNA < 50 copies/mL) at the time of switch for a median of 10 years (IQR: 8–15 years). The patients had received a median of 9 different ART regimens (IQR: 5–14) for a median of 17 years (IQR: 5–14 years). Before dual therapy initiation, 41% of patients were INSTI-naïve. In addition, 52% of patients had experienced virological failure on a previous ART combination, but not on a previous DTG- or RPV-based regimen. Fifty-three patients (35%) had a history of AIDS-defining events. At baseline, the median CD4 T-cell count was 669 cells/μL (IQR: 523–867 cells/μL). Before switching to dual therapy, 43% of patients had been prescribed a standard ART regimen (two NRTIs + a third agent) and 37% were already taking another dual therapy. ART was switched to DTG + RPV primarily because of intolerance to the previous regimen (47%) or for treatment simplification (30%). As a primary outcome measure, the cumulative percentages of patients remaining free of confirmed virological failure and therapeutic failure at week 24 on dual therapy were 99.1% [115 of 116; 95% confidence interval (CI) 95.2–99.9] and 90.5% (105 of 116; 95% CI: 83.6–93.7), respectively. The TLOVR analysis over follow-up is depicted in Figure 1a,b. At the end of the study, confirmed virological failure had occurred in three patients (2%). Of these, two patients continued DTG + RPV [plasma HIV RNA: patient 1 (previously on successful maraviroc (MVC) + raltegravir (RAL)), 130 and 51 copies/mL, respectively, at weeks 38 and 43; patient 2 (previously on successful tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV)), 1147 copies/mL at week 39] and achieved virological suppression up to the end of follow-up. These patients harboured wild-type viruses as assessed by RNA Sanger sequencing at failure. The third patient, who had previously been on successful abacavir (ABC)/lamivudine (3TC)/zidovudine (ZDV), experienced early virological failure, with a single plasma HIV RNA measurement of 1259 copies/mL at week 15, and achieved virological suppression again on standard ART (ABC/3TC/DTG). No RNA resistance testing before the switch and at failure was available for this patient who has since been lost to follow-up. At the end of the study, 19 patients (13%) stopped dual therapy. Twelve patients discontinued DTG + RPV because of various and sometimes multiple adverse events: neurological disorders (n = 7), abdominal pain (n = 3), cutaneous effects (n = 1) and renal toxicity (n = 1). Other reasons for stopping DTG + RPV were: therapeutic simplification to a single-tablet regimen (n = 3), patient's decision (n = 1), virological failure (n = 1), pregnancy (n = 1) and drug−drug interaction (n = 1). In 106 evaluable patients after 24 weeks of DTG + RPV, no change in CD4 and CD8 T-cell counts was observed (Fig. 1c). At week 24, there was a significant increase from baseline values in creatinine (mean +/− standrad deviation, +11.1 ± 5.4 μmol/L; P < 0.001), but not in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentration (P = 0.4) (Fig. 1d). No grade 3 to 4 adverse events were observed. During follow-up, DTG and RPV steady-state plasma concentrations were assessed in 23 participants with virological success. DTG and RPV median trough concentrations were 2090 ng/mL (IQR: 1255–2965 ng/mL) and 130 ng/mL (IQR: 95–160 ng/mL), respectively. DTG and RPV concentrations were all measured above the protein-adjusted IC90. Simplified ART regimens are expected to reduce long-term toxicity and cost, while maintaining optimal immunological and virological efficacy. Potent dual therapy might be a good option as a drug-reducing strategy in ART-controlled patients 14. Evaluating the effects of two novel antiretroviral drugs in a prospective study of a French cohort (n = 152), we showed that DTG + RPV dual therapy is highly efficient in ART-controlled patients (90.5% therapeutic success at 24 weeks). Two patients experienced transient and low-level viral replication, 9 months post-switch, without emergence of resistance mutations, and returned to suppressed viral load without ART modification 15. Only one patient had to stop DTG + RPV treatment early because of virological failure, but resistance was not documented. Switching to a dual DTG + RPV regimen in virologically suppressed patients seems to be as efficient as switching to a combination of two NRTIs plus RPV (therapeutic success at week 24, 94%) or DTG (therapeutic success at week 24, 79%) 5, 7, and showed similar efficacy to other dual therapy 3. Antiviral efficacy was observed whatever the type of previous ART. Information on previous genotyping, and on possible previous virological failure on the NNRTI or INSTI drug class, is essential to obtain before starting DTG + RPV, to rule out any resistance to these drugs. Compared with DTG monotherapy, a dual DTG + RPV regimen would offer a higher genetic barrier 16-18. This dual combination was well tolerated with few discontinuations because of adverse events, mostly neurological disorders 19, showing a relatively good tolerability of DTG + RPV, compared with 47% discontinuations for adverse events on previous treatment. Only grade 1 to 2 laboratory abnormalities were observed. An elevation of serum creatinine level has been associated with DTG use in previous studies 4, 5. Moreover, adequate expected trough plasma concentrations of DTG and RPV demonstrated the favourable drug interaction profile of these two drugs in such a maintenance strategy 9. To the best of our knowledge, there is no published study that has assessed immuno-virological outcomes of switching to DTG + RPV in a large cohort of ART-controlled patients. This study has several limitations inherent to the Dat'AIDS cohort study design 10. Our 'real life' data have to be compared with the future results of ongoing prospective randomized studies comparing DTG + RPV dual therapy to maintenance of standard ART. These clinical studies should also assess the dynamics of HIV replication in reservoirs under DTG + RPV dual therapy 20. We thank all the patients and staff of the HIV clinical centres who participated in the study and Thomas Jovelin for database management. Conflicts of interest: PG has received honoraria for travel/accommodation/meeting expenses from Bristol-Myers Squibb. MAV has received honoraria for travel/accommodation/meeting expenses from Janssen-Cilag, Gilead Science, ViiV, Bristol-Myers Squibb, and Merck-Sharp & Dohme-Chibret. DR has received honoraria for travel/accommodation/meeting expenses from Gilead Science, ViiV, Bristol-Myers Squibb, and Merck-Sharp & Dohme-Chibret. Members of the Dat'AIDS study group: C. Allavena, E. Billaud, C. Biron, B. Bonnet, S. Bouchez, D. Boutoille, C. Brunet, T. Jovelin, N. Hall, C. Bernaud, P. Morineau, V. Reliquet, O. Aubry, P. Point, M. Besnier, O. Grossi, M. Lefebvre, H. Hüe, M. Cavellec, A. Soria, S. Pineau, E. André-Garnier and A. Rodallec (Nantes); S. Brégigeon, O. Faucher, V. Obry-Roguet, M. Orticoni, M. J. Soavi, I. Luquet-Besson, E. Ressiot, I. Pinot, M. J. Ducassou, H. Bertone, S. Gallie, S. Trijau, A. S. Ritleng, A. Ivanova, M. Guignard, C. Blanco-Betancourt and I. Poizot-Martin (Marseille); M. Alvarez, N. Biezunski, L. Cuzin, A. Debard, P. Delobel, C. Delpierre, C. Fourcade, B. Marchou, G. Martin-Blondel, L. Porte, M. Mularczyk, D. Garipuy, K. Saune, I. Lepain, M. Marcel and E. Puntis (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); Ph. Choisy, S. Vandame, Th. Huleux, F. Ajana, I. Alcaraz, V. Baclet, T. H. Huleux, H. Melliez, N. Viget, M. Valette, E. Aissi, Ch. Allienne, A. Meybeck and B. Riff (Tourcoing); R. Agher, C. Katlama, M. A. Valantin, C. Duvivier, V. Joly, Y. Yazdanpanah, R. Landman, C. Mackoumbou-Nkouka, F. Louni, Z. Julia, C. Charpentier and D. Descamps (Paris); L. Cotte, D. Peyramond, C. Chidiac, T. Ferry, F. Ader, F. Biron, A. Boibieux, P. Miailhes, T. Perpoint, I. Schlienger, F. Dahoud, J. Lippmann, E. Braun, J. Koffi, C. Longuet, V. Guéripel, C. Augustin-Normand and S. Degroodt (Lyon); D. Rey, M. L. Batard, C. Bernard-Henry, C. Cheneau, E. de Mautort, P. Fischer, M. Partisani, M. Priester and P. Gantner (Strasbourg); F. Bani-Sadr, C. Rouger, J. L. Berger, Y. N'Guyen, D. Lambert, I. Kmiec, M. Hentzien and D. Lebrun (Reims).