Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia

Katlama, Christine; Soulié, Cathia; Caby, Fabienne; Denis, Alexis; Blanc, Catherine; Schneider, Luminita; Valantin, M.A.; Tubiana, Roland; Kirstetter, M.; Valdenassi, E.; Nguyen, Thuy; Peytavin, Gilles; Cálvez, Vincent; Marcelin, Anne–Geneviève

doi:10.1093/jac/dkw186

Cited by 47 publications

(36 citation statements)

References 19 publications

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“…Dual therapy consisted of DTG + 3TC (seven studies) or RPV (four studies) or atazanavir (ATV, two studies) or darunavir (DRV, one study). Overall, 14 studies allowed the inclusion of patients with previous virological failure, including five monotherapy studies 18– 20, 22– 24 . In one study, patients with previous InSTI failure were also included 12 .…”

Section: Resultsmentioning

confidence: 99%

Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

Wandeler

Buzzi²,

Anderegg

et al. 2018

F1000Res

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Background: Dolutegravir-containing maintenance therapy is a promising simplification strategy for virologically suppressed HIV-infected individuals. However, most of the available data to inform this strategy come from small, uncontrolled studies. We estimated the proportion of HIV-infected patients experiencing virological failure (VF) and developing drug resistance on dolutegravir (DTG)-based maintenance therapy. Methods: We searched Medline, Embase, Cochrane Central, Web of Science, and conference abstracts for studies assessing VF on DTG-based maintenance therapy. Studies including ≥5 adults with an undetectable viral load on antiretroviral therapy (ART) who switched to a DTG-based mono- or dual therapy were included. Pooled proportions of VF were estimated using random-intercept logistic meta-regression and acquired drug resistance mutations described for each strategy. Results: Of 1719 studies considered, 21 met our selection criteria, including seven interventional and 14 observational studies. Eight studies including 251 patients assessed VF on DTG monotherapy and fourteen studies including 1670 participants VF on dual therapy. The participant’s median age ranged from 43 to 63 years, their median nadir CD4 count from 90 to 399 cells/µl, and 27.6% were female. The proportion of participants experiencing VF on DTG-monotherapy was 3.6% (95% confidence interval [CI] 1.9-6.7) at 24 weeks and 8.9% (95% CI 4.7-16.2) at 48 weeks. Resistance mutations developed in seven (3.6%) participants on DTG-monotherapy. Among patients on dual therapy, ten (0.7%, 95% CI 0.4-1.3) experienced VF by 48 weeks and none developed resistance to DTG. In adjusted analyses, VF at 24 weeks was less likely on dual therapy than on monotherapy (adjusted odds ratio: 0.10, 95% CI 0.03-0.30). Conclusions: Whereas VF is relatively common on DTG maintenance monotherapy, DTG-based dual therapy appears to be a promising simplification strategy for individuals with a suppressed HIV viral load on triple-ART.

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Section: Resultsmentioning

confidence: 99%

Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

Wandeler

Buzzi²,

Anderegg

et al. 2018

F1000Res

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“…As a matter of fact, a few recent communications have explored the possibility of dolutegravir monotherapy [33–36] and two of them reported 4 patients out of 61 (6.6%) who failed while on dolutegravir as monotherapy: all of them had been exposed to a first-generation INI (i.e. raltegravir or elvitegravir) [33, 34]. Better results have been obtained in some studies exploring the switch to a dual therapy using dolutegravir either in combination with rilpivirine [36, 37] or lamivudine [36, 38, 39], the latest being explored in naïve patients, too [40, 41].…”

Section: Discussionmentioning

confidence: 99%

Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients

et al. 2017

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BackgroundLittle is known about the applicability of dual treatments based on integrase inhibitors. We explored the combination of lamivudine + dolutegravir as an option when switching from standard cART in virologically suppressed patients.MethodsIn this prospective cohort we enrolled patients previously switched to 3TC + DTG who were 18 years or older, with no previous resistance mutations to the used drugs, having a HIV-RNA <50 copies/ml for 6 months or longer, negative for HBsAg and on a stable (>6 months) cART.ResultsNinety-four individuals were included. They were mostly men (77.7%) with a mean age of 53 years. They presented 159 co-morbidities including cardiovascular, bone, hepatic, kidney, and CNS diseases. Because of these pathologies, they took 207 non-ARV drugs (mean 2.2 per patient). Median duration of viral suppression was 77.5 months (IQR 61). All subjects were prospectively followed up to week 24 and all remained on dual therapy during the whole period. Neither virological failure, nor viral blip was detected.The median CD4 count rose from 658 cells/mcl (IQR 403) to 724 cells/mcl (IQR 401) (P = 0.006) without a significant (P = 0.44) change in the CD4/CD8 ratio. A significant (P < 0.0001) increment of median creatinine from 0.87 mg/dl (IQR 0.34) to 0.95 mg/dl (IQR 0.29) was observed in the first 2 months but thereafter leveled on these values (1.00 mg/dl; IQR 0.35) (P = 0.111 compared to 2 months). The lipid profile slightly improved. The daily cost of cART was significantly (P < 0.0001) reduced of 6.89 euros (SD 6.10).DiscussionSwitching to a dual cART regimen based on lamivudine + dolutegravir maintains virological efficacy up to week 24, and is associated to slight improvements of the immunologic and metabolic status. The strategy allows to freely using concomitant medications for associated pathologies. The dual therapy is less expensive in economic terms.ConclusionAlthough still limited evidence exists, a dolutegravir-based dual therapy in combination with lamivudine shows promising results to be confirmed in larger controlled trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-017-2311-2) contains supplementary material, which is available to authorized users.

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“…In addition, treatment failure in such individuals was associated with the presence of various RAL/EVG resistance substitutions that predated DTG use, most notably at positions Q148 and N155H (11–13). Intriguingly, previous exposure to RAL or EVG can also compromise the efficacy of DTG when the latter drug is used as a single antiretroviral agent, even when exposed individuals were previously free of treatment failure with either of the former drugs (14). As remarkable was the absence of R263K in viruses isolated from individuals who experienced failure with DTG monotherapy (14).…”

Section: Introductionmentioning

confidence: 99%

“…Intriguingly, previous exposure to RAL or EVG can also compromise the efficacy of DTG when the latter drug is used as a single antiretroviral agent, even when exposed individuals were previously free of treatment failure with either of the former drugs (14). As remarkable was the absence of R263K in viruses isolated from individuals who experienced failure with DTG monotherapy (14). Altogether, those results suggest that R263K preferentially emerges upon ab initio DTG pressure and also points toward the potential involvement of residual replication in the emergence of drug resistance (discussed in reference 10).…”

Section: Introductionmentioning

confidence: 99%

The R263K Dolutegravir Resistance-Associated Substitution Progressively Decreases HIV-1 Integration

Mésplède

Leng

Pham

et al. 2017

mBio

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Human immunodeficiency virus (HIV) infection persists despite decades of active antiretroviral therapy (ART), effectively preventing viral eradication. Treatment decreases plasma viral RNA, but viral DNA persists, mostly integrated within the genome of nucleated blood cells. Viral DNA blood levels correlate with comorbidities and the rapidity of viral rebound following treatment interruption. To date, no intervention aiming at decreasing HIV DNA levels below those attained through ART has been successful. This includes use of some integrase inhibitors either as part of ART or in treatment intensification studies. We have argued that using the integrase inhibitor dolutegravir (DTG) in similar studies may yield better results, but this remains to be studied. In treatment-experienced individuals, the most frequent substitution associated with failure with dolutegravir is R263K in integrase. R263K decreases integration both in cell-free and tissue culture assays. We investigated here how integrated DNA levels evolve over time during prolonged infections with R263K viruses. To investigate a potential defect in reverse transcription with R263K, the levels of reverse transcripts were measured by quantitative PCR. We measured HIV type 1 (HIV-1) integration in Jurkat cells over the course of 4-week infections using Alu-mediated quantitative PCR. The results show that R263K did not decrease reverse transcription. Prolonged infections with R263K mutant viruses led to less HIV-1 integrated DNA over time compared to wild-type viruses. These tissue culture results help to explain the absence of the R263K substitution in most individuals experiencing failure with DTG and support studies aiming at longitudinally measuring the levels of integrated DNA in individuals treated with this drug.

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Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia

Abstract: Dolutegravir has the potency to be further investigated as a single ART in randomized studies, particularly in patients with no prior exposure to integrase inhibitors.

Cited by 47 publications

References 19 publications

Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients

The R263K Dolutegravir Resistance-Associated Substitution Progressively Decreases HIV-1 Integration

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