Dolutegravir in HIV-2-Infected Patients With Resistant Virus to First-line Integrase Inhibitors From the French Named Patient Program.

Dolutegravir has shown in vitro activity against human immunodeficiency virus type 2 (HIV-2). We report safety and efficacy data of regimens containing dolutegravir (50 mg twice daily) in antiretroviral-experienced, HIV-2-infected patients. HIV-2-infected patients experiencing virological failure to raltegravir received dolutegravir with optimized background antiretroviral combinations within the French Named Patient Program (NPP). Plasma HIV-2 RNA (pVL) was assessed at time of dolutegravir initiation (baseline), month 3, and month 6. Antiretroviral trough plasma concentrations (C12h) were determined using liquid chromatography coupled with tandem mass spectrometry. Thirteen HIV-2-infected-patients, with a median duration of 15 years' infection and given 16 previous antiretroviral regimens, were included in NPP. Median follow-up was 9 months (min-max, 3-15 months). Median baseline pVL and CD4 cell count were 9544 copies/mL (inter quartile range [IQR], 3096-23 120 copies/mL) and 100 cells/µL (IQR, 77-171 cells/µL), respectively. Available integrase genotypic resistance patterns were Y143C/G/H/R (n = 5), Q148R/K (n = 2), and N155H (n = 4). Optimized background antiretroviral regimens conferring a genotypic sensitivity score ≤2 in 10 patients included nucleoside reverse transcriptase inhibitors associated with darunavir/ritonavir (n = 12), saquinavir/ritonavir (n = 2), and maraviroc (n = 3). At months 3 and 6, pVL was undetectable in 6 of 13 and 4 of 12 patients, respectively, and median CD4 count was 161 (101-188) cells/µL and 167 (135-1353) cells/µL, respectively. Median dolutegravir C12h was 4086 (1756-5717 ng/mL) ng/mL in 9 patients. No serious events were notified except 1 death from progressive multifocal leukoencephalopathy at month 4. Optimized dolutegravir-containing antiretroviral regimens supported by good plasma exposure provide a substantial initial efficacy rate for salvage therapy in heavily antiretroviral-experienced HIV-2-infected patients with virus harboring resistance to first-generation integrase inhibitors. Larger numbers of patients and longer follow-up are needed to confirm these findings.

Descamps D ，Peytavin G ，Visseaux B ，Tubiana R ，Damond F ，Campa P ，Charpentier C ，Khuong-Josses MA ，Duvivier C ，Karmochkine M ，Lukiana T ，Matheron S ... -  《-》

Dolutegravir-based monotherapy or dual therapy maintains a high proportion of viral suppression even in highly experienced HIV-1-infected patients.

Dolutegravir is a powerful, well-tolerated integrase inhibitor with a high genetic barrier to resistance and may thus constitute the backbone of lightened regimens. This was a monocentric, retrospective study. HIV-1-infected patients receiving dolutegravir as monotherapy (mDGV) or dual therapy (dDGV) were systematically identified. The primary outcome was the proportion of patients who maintained undetectable (<50 copies/mL) plasma HIV RNA [plasma viral load (PVL)]. We identified 21 patients on mDGV (50 mg/day) and 31 on dDGV (50 or 100 mg/day, with atazanavir  ±  ritonavir, n = 12; rilpivirine, n = 11; maraviroc, n = 3; lamivudine, n = 3; darunavir/ritonavir, n = 1; or abacavir, n = 1). All of the patients were treatment experienced and 48% had experienced at least one virological failure. The baseline characteristics were as follows (for the mDGV/dDGV patients, respectively): 5%/29% had a history of AIDS; the median (IQR) highest PVL was 4.5 (4.3-5.5)/5.3 (4.7-5.6) log copies/mL; the median (IQR) nadir CD4+ count was 310 (280-468)/199 (134-281) cells/mm(3); 100% had undetectable PVL before the mDGV for a median (IQR) duration of 5.9 (3.5-9.9) years/81% had undetectable PVL before the dDGV for a median (IQR) duration of 3.7 (1.4-8.3) years; and the median (IQR) HIV DNA level was 2.7 (2.1-3.1)/2.9 (2.7-3) log copies/10(6) PBMCs. At the last follow-up visit, 100% and 97% of patients showed undetectable PVL following mDGV and dDGV, respectively [median (IQR) follow-up of 32 (29-45) and 50 (30-74) weeks, respectively]. In our experience, dolutegravir-based lightened regimens provided a high proportion of viral suppression, even in highly treatment-experienced patients.

Gubavu C ，Prazuck T ，Niang M ，Buret J ，Mille C ，Guinard J ，Avettand-Fènoël V ，Hocqueloux L ... -  《-》

Efficacy and tolerance of dolutegravir-based combined ART in perinatally HIV-1-infected adolescents: a French multicentre retrospective study.

To assess the safety and efficacy of a dolutegravir-based regimen in perinatally HIV-1-infected adolescents. We conducted a retrospective multicentre study of 50 adolescents beginning dolutegravir-based treatment regimens between January 2014 and December 2015. Clinical and biological data collected before and after dolutegravir initiation were analysed. The primary endpoint was the proportion of patients achieving a plasma viral load (PVL) <50 copies/mL within 3 months of dolutegravir initiation (for patients with detectable viraemia at baseline) and maintaining virological suppression (PVL <50 copies/mL) until the last follow-up visit (for all patients). Virological suppression was noted for 17/50 adolescents at baseline. Dolutegravir-based regimens maintained virological success in 14/17 patients (82%). The other three patients experienced a transient viral rebound, before PVL fell to < 50 copies/mL again, with no need to change the antiretroviral regimen. Thirty-three viraemic adolescents were enrolled. All but one had already received antiretroviral drugs. Virological success was achieved and maintained in 19/33 subjects (58%). Another three adolescents with initial virological failure had an undetectable PVL at the end of follow-up, with reinforced measures to improve compliance. Overall, sustained virological success was observed in 66% of patients and 78% of patients had an undetectable PVL at the last visit. Dolutegravir was well tolerated. Only one patient stopped treatment for severe drug-related adverse effects (dizziness and sleep disturbance). No emergence of resistance mutations was observed in patients with virological failure. Dolutegravir was safe and virologically effective in these patients, for whom multiple interventions were required to improve compliance.

Briand C ，Dollfus C ，Faye A ，Kantor E ，Avettand-Fenoel V ，Caseris M ，Descamps D ，Schneider V ，Tabone MD ，Vaudre G ，Veber F ，Blanche S ，Frange P ... -  《-》

Dolutegravir for the treatment of HIV-2 infection.

Therapeutic options are limited for HIV-2 infected persons, largely in part due to the lack of susceptibility to HIV-1 non-nucleoside reverse transcriptase inhibitors and poor susceptibility to some HIV-1 protease inhibitors. This is particularly worrisome for HIV-2 patients with prior antiretroviral failure. Report the virological response to dolutegravir in HIV-2-infected individuals. Retrospective observational assessment of all HIV-2 individuals treated with dolutegravir in Spain. From 297 HIV-2-infected individuals recorded at the Spanish national registry, 26% received antiretroviral therapy. Six out of 8 failing on raltegravir selected for integrase resistance mutations N155H (4), Y143G (1) and Q148R (1). Two patients bearing N155H subsequently received dolutegravir. Both experienced initially more than 1.5 log drop in plasma HIV-2 RNA and significant CD4 gains. Whereas one kept on undetectable viremia 6 months later, the other experienced viral rebound. Dolutegravir may be a good therapeutic option for patients with HIV-2 infection, including those that previously failed other integrase inhibitors.

Treviño A ，Cabezas T ，Lozano AB ，García-Delgado R ，Force L ，Fernández-Montero JM ，Mendoza Cd ，Caballero E ，Soriano V ... -  《-》

Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.

Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir). Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. ViiV Healthcare.

Cahn P ，Pozniak AL ，Mingrone H ，Shuldyakov A ，Brites C ，Andrade-Villanueva JF ，Richmond G ，Buendia CB ，Fourie J ，Ramgopal M ，Hagins D ，Felizarta F ，Madruga J ，Reuter T ，Newman T ，Small CB ，Lombaard J ，Grinsztejn B ，Dorey D ，Underwood M ，Griffith S ，Min S ，extended SAILING Study Team ... -  《-》