Dolutegravir Update: Treatment-Naive and -Experienced Patients and Drug Resistance
Several studies presented new or updated information on dolutegravir.
This new integrase inhibitor has potential advantages over raltegravir by being a once rather than twice-daily drug, and over elvitegravir by not requiring PK boosting. Of note, dolutegravir with a twice-daily dose retains activity against early but not late resistance to raltegravir and elvitegravir and may rescue some patients who fail on first-line integrase inhibitors.
Dolutegravir also seems to have an interesting resistance profile that may limit the accumulation of further integrase mutations, although in vivo data are still scarce due to low numbers of patients who have experienced virological failure. Primary mutations to dolutegravir appear to significantly reduce viral fitness, but unlike with other antiretrovirals this does not seem to be restored by later development of compensatory mutations.
Dolutegravir has already been submitted to the US and EU regulatory authorities and a decision on approval is expected before the end of 2013.
SPRING-2 study: dolutegravir is non-inferior to raltegravir at 96 weeks in treatment-naive patients
Francois Raffi from Nantes University Hospital, presented 96-week results from the randomised, double-blind, placebo controlled phase 3 SPRING-2 study in 827 treatment-naive patients, with data presented for 411 patients in each arm. Results were stratified by baseline viral load above or below >100,000 copies/mL) and by investigator selected used of either tenofovir/FTC or abacavir/3TC (used by 60% and 40% of patients respectively). 1
This was a largely male and white study population in patients with early-stage HIV. Approximate baseline characteristics for the study included median age of 36 years, 85% male, 85% white and 10% African American. Median viral load and CD4 count were approximately 35,000 copies/mL and 360 cells/mm3 respectively. No figures for the range or IQR were provided for the median values. However, 28% of patients had baseline viral load >100,000 copies/mL and 12% had a CD4 count
At week 96, viral suppression in the dolutegravir (50 mg once daily) vs raltegravir (400 mg twice daily) arms was 81% versus 76% achieving undetectable viral load (
In the stratified analyses, responses were similar in each arm for patients with baseline viral load 100,000 copes/mL group (78% vs 63% achieving viral load to
There were no differences between arms when abacavir/3TC was used as the background RTIs but dolutegravir was significantly better when tenofovir/FTC was used (86% vs 77% respectively). When both baseline viral load and RTI choice were factored together dolutegravir was significantly more effective compared to raltegravir only with tenofovir/FTC use in the >100,000 copies/mL group: 81% (62/77) vs 61% (47/77), respectively.
Side effects were similar: 13-15% (nausea, headache, diarrhea, and nasopharyngitis) and 2% of patients in each arm discontinuing due to side effects, predominantly during the first year. From week 48, only three patients stopped due to tolerability (one case each of hepatitis C, suicide attempt and hepatotoxicity, all in the raltegravir arm).
Virologic non-response occurred less frequently on dolutegravir (5% vs 10%) and at virologic failure, with no resistance (from the limited resistance test results available) in the dolutegravir arms compared to n=1 (integrase resistance) and n=4 people (NRTI resistance) in the raltegravir arm. These results continued to support dolutegravir non-inferiority at week 96.
SAILING study: dolutegravir is superior to raltegravir in treatment-experienced, integrase naive patients
Week 48 results from the phase 3 randomised, placebo controlled, SAILING study comparing doultegravir to raltegravir in 715 treatment-experienced (with resistance to two or more classes) but integrase-naive patients were presented in a late breaker oral presentation by Pedro Cahn from Fundación Huésped, Buenos Aires. 2 The results were broadly similar to the 24-week interim analyses that was presented at CROI 2013. 3 The 48 week full study has also just been published in the Lancet. 4
Dolutegravir was dosed at 50 mg once-daily with raltegravir dosed at 400 mg twice-daily. Background combinations included up to two other drugs, one of which had to be fully active, and were individually optimised by baseline resistance test and treatment history. Approximately 30% were women, 50% white and 40% African/American.
At baseline, approximately half the patients in each arm had CD4 counts 50,000 copies/mL. Only 20% of patients using darunavir/ritonavir had no primary PI-associated mutations.
Viral efficacy (
None of the subgroup analyses favoured raltegravir, but dolutegravir was statistically superior in patients with viral load greater than 50,000 copies/mL in the darunavir/r group with primary PI mutations and in patients with a PSS score of 2 or higher.
Virologic failure occurred less frequently in the dolutegravir arm (6% vs 12%) with
Although resistance occurred at low levels in each arm, fewer patients failed with integrase resistance (1% vs 5%; p=0.003) or to background regimen (1% vs 3%) in the dolutegravir (n=2/354; both with R263K, one also with V260I, but this conferred 5
Tolerability was good in both arms, with
VIKING-3 study: dolutegravir in integrase experienced patients
Perhaps the most important dolutegravir study at IAS 2013 was the single-arm VIKING-3 in integrase-experienced patients. 6 This provided information on likely options for people with more extensive drug resistance, including people who have failed on raltegravir or elvitegravir containing combinations. Dolutegravir was added to current failing regimens (integrase inhibitors were stopped) at 50 mg twice-daily for the first 8 days before background treatment was optimised at day 8 and dolutegravir was continued.
Baseline characteristics included 23% women, 21% HBV or HCV coinfection and 27% African American, with a median CD4 count of 140 (range 19-1110) cells/mm3, 56% with CDC class C, and a median 13 years prior ART (range 0.3 25 years).
Participants had previously used a median of 14 ARVs (range 3-25) including prior darunavir/r (73%), etravirine (56%), T20 (49%) and maraviroc (32%). Class resistance included >/=2 NRTIs (75%), >/+ 1 NNRTI (70%) and >/+ 2 PIs (62%). All patients had evidence of integrase resistance (68% at baseline, 32% documented).
This analysis provided results for 183 patients at week 24 and 114 patients with data at week 48. Overall, viral load
Results by primary integration mutations and Overall Susceptibility Score (OSS) at baseline are detailed in Table 1 and showed reduced responses when Q148 was present with two or more other integrase mutations (p
Response by dolutegravir sensitivity at baseline was 82%(98/120), 56% (14/25) and 11% (1/9) in the 10-fold reduced sensitivity groups respectively.
In a separate analysis, phenotypic response cut-offs for dolutegravir of <9.45, 9.45-25.99 and >25.99 were derived for full (>1 log), intermediate and non-responses. See later report in HTB from the Drug Resistance Workshop. 7
Tolerability was generally good with side effects similar to earlier reports using 50 mg once-daily dosing.
A separate poster reported renal safety from two Phase 3 studies. Renal events in the dolutegravir arms were comparable to control arms. Dolutegravir produces a small non-progressive increase in serum creatinine in the first two weeks of treatment that remains stable afterwards that can affect eGFR. However, no increases in median urinary albumin/creatinine ratios were observed over 48 weeks. 8
Drug resistance in integrase-naïve patients
Very few treatment-naïve or integrase-naïve patients have experienced virologic failure using dolutegravir. However, it is notable that even when suboptimal responses or viral rebound occurs, that mutations in the integrase gene are rare even out to 96 weeks in the SPRING-2 study reported above. Information on the potential resistance profile for dolutegravir is therefore largely based on in vitro studies.
Mespléde and colleagues from Mark Wainberg's group at McGill University, Québec rather than ViiV or GSK are suggesting that this may be related to dolutegravir's long intracellular half-life. In vitro, multiple pass selection studies in the presence of increasing concentrations of dolutegravir, generate the R263K mutation, which is often associated with the secondary mutation H51Y which further decreases susceptibility to the drug and is associated with reduced integration and impaired viral replication. Other secondary mutations in vitro include M50I and E138K. These secondary mutations not only do not compensate for reduced replication but, in further in vitro assays, both R263K and R253K/H51Y impaired the development of resistance to 3TC and nevirapine. 910
Two patients in the dolutegravir arm in the SAILING study developed R263K at virological failure however, and this should caution that resistance can develop in naïve patients, even though this had <2 fold impact on IC50 (and perhaps might be overcome by increasing to a 50 mg twice-daily dose).5
If the resistance profile continues to be strong in clinical practice, when monitoring is less intense and so viral failure is detected later, this could have important implications for using dolutegravir in first-line therapy.
Unless stated otherwise, references are to the Programme and Abstracts for the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 30 June 3 July 2013, Kuala Lumpur.
This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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