Dolutegravir update: drug resistance in people who are treatment-naive and -experienced

25 July 2013. Related: Conference reports, Antiretrovirals, Drug resistance, IAS 7th Kuala Lumpur 2013.

Simon Collins, HIV i-Base

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 <200 cells/mm3. Approximately 2% and 10% were coinfected with hepatitis B and C respectively.

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 (<50 copies/mL (difference 4.5%; 95% CI: -1.1%, 10.0%). This compared to rates of 88% vs 85% patients respectively at week 48 (difference was 2.5%; (95% CI: -2.2% to 7.1%). Median CD4 cells/mm3 increases from baseline were also similar between arms (+276 vs +264 cells/mm3).

In the stratified analyses, responses were similar in each arm for patients with baseline viral load <100,000 copies/mL but were significantly better for dolutegravir in the >100,000 copes/mL group (78% vs 63% achieving viral load to <50 copies/mL).

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 <200 cells/mm3 and 50% had resistance to three or more classes. Baseline viral load for patients on currently failing therapy was approximately 15,000 copies/mL with 30% failing at >50,000 copies/mL. Only 20% of patients using darunavir/ritonavir had no primary PI-associated mutations.

Viral efficacy (<50 copies/mL) at week 48 (primary endpoint) favoured dolutegravir over raltegravir (71% vs 64%; difference (95% CI): 7.4% (0.7%, 14.2%); p=0.03), adjusting for baseline viral load, darunavir/r use without primary PI mutations and baseline phenotypic sensitivity score for the background regimen. CD4 changes were similar at +162 vs +153 cells/mm3 in the dolutegravir vs raltegravir arms.

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 <1% vs 5% for virologic non-response and 5% vs 7% for viral rebound.

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 <2-fold change in IC50) vs raltegravir (n=10/361) groups. [5]

Tolerability was good in both arms, with <1% reporting grade 4 events: one case each of hepatotoxicty and renal failure in the dolutegravir arm and one case each of rash, pancreatitis, hepatitis and suicide ideation in the raltegravir arm. Mean increases in serum creatinine were greater with dolutegravir (+11.1 vs +5.1 umol/L).

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 <50 copies/mL was achieved by 69% of patients at week 24 and 56% at week 48, with virologic non-response of 27% and 39% at week 24 and 48 respectively.

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<0.001), but a less clear relationship with OSS. The active drug in most cases was an NRTI.

Response by dolutegravir sensitivity at baseline was 82%(98/120), 56% (14/25) and 11% (1/9) in the < 4-fold, 4-10 fold and >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. [9, 10]

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.

References:

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.

1. Raffi F et al. Dolutegravir is non-inferior to raltegravir and shows durable response through 96 weeks: results from the SPRING-2 trial. 7th IAS, Kuala Lumpur, 2013. Poster abstract TULBPE17.
   http://pag.ias2013.org/abstracts.aspx?aid=3021
2. Cahn P et al. Dolutegravir (DTG) is superior to raltegravir (RAL) in ART-experienced, integrase naive subjects: week 48 results from SAILING (ING111762). 7th IAS, Kuala Lumpur, 2013. Late breaker oral abstract WELBB03.
   http://pag.ias2013.org/abstracts.aspx?aid=3071
3. Pozniak A et al. Dolutegravir vs raltegravir in ART-experienced, integrase-naïve subjects: 24-Week interim results from SAILING (ING111762). 20th CROI, 2013, Atlanta. Late breaker poster 179LB.
   http://www.retroconference.org/2013b/Abstracts/47950.htm
4. Chan P et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. The Lancet, Early Online Publication, 3 July 2013, doi:10.1016/S0140-6736(13)61221-0.
   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61221-0/abstract
5. Underwood MR et al. Analysis and characterization of treatment-emergent resistance in ART-experienced, integrase inhibitor-naïve subjects with dolutegravir (DTG) versus raltegravir (RTG) in SAILING (ING111762). Onternational Workshop on HIV & hepatitis virus Drug Resistance and Curative Strategies. 4-8 June 2013, Toronto. Oral abstract 21.
6. Nichols G et al. Phase 3 assessment of dolutegravir (DTG) 50mg twice daily in HIV-1-infected subjects with raltegravir (RAL) and/or elvitegravir (EVG) resistance in VIKING-3: week 24 results of all 183 patients enrolled. 7th IAS, Kuala Lumpur, 2013. Late breaker poster TULBPE19.
   http://pag.ias2013.org/abstracts.asp?aid=3069
7. Vavro C et al. Integrase genotypic and phenotypic predictors of antiviral response to dolutegravir (DTG) in subjects with resistance to integrase inhibitors (INIs). International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies, 4-8 June 2013, Toronto. Oral abstract 29. See HTB report.
   https://i-base.info/htb/22022
8. Curtis LD et al. Once-daily dolutegravir (DTG; S/GSK1349572) has a renal safety profile comparable to raltegravir (RAL) and efavirenz in antiretroviral (ART)-naïve adults: 48 week results from SPRING-2 (ING113086) and SINGLE (ING114467). 7th IAS, Kuala Lumpur, 2013. Poster abstract TUPE282.
   http://pag.ias2013.org/abstracts.aspx?aid=1634
9. Mesplede T et al. Secondary resistance mutations in the R263K integrase inhibitor resistance pathway. 7th IAS, Kuala Lumpur, 2013. Poster abstract MOPE022.
   http://pag.ias2013.org/abstracts.aspx?aid=1761
   http://pag.ias2013.org/EPosterHandler.axd?aid=1761 (PDF)
10. Mesplede T et al. HIV resistance to dolutegravir (DTG) simultaneously diminishes viral DNA integration into host cells and viral replication fitness: implications for HIV reservoirs. Poster abstract MOPE014.
    http://pag.ias2013.org/abstracts.aspx?aid=350