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FLAMINGO: still in the pink?

Lancet HIV 2015; 2: e116–7

Refers to article:

Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study

Prof Jean-Michel Molina MD, Bonaventura Clotet MD, Prof Jan van Lunzen MD, Prof Adriano Lazzarin MD, Matthias Cavassini MD, Prof Keith Henry MD, Prof Valeriv Kulagin MD, Naomi Givens MSc, Carlos Fernando de Oliveira MD and Clare Brennan DPT on behalf of the FLAMINGO study team.

Integrase inhibitors are becoming more widely used in the treatment of HIV and data about their long-term effects are beginning to accumulate.1, 2, 3, and 4InThe Lancet HIV, Jean-Michel Molina and colleagues 5 present safety and efficacy data at 96 weeks from the FLAMINGO study. They assessed standard of care regimens of nucleosides plus a ritonavir-boosted protease inhibitor compared with standard treatment plus the integrase inhibitor dolutegravir. The primary analysis at 48 weeks 6 showed that the integrase inhibitor was superior to the protease inhibitor. This finding was mostly related to fewer withdrawals because of adverse events and better overall outcome for patients with a high viral load at baseline for those assigned to dolutegravir.

The findings at 96 weeks were much the same, with 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group having HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4 percentage points, 95% CI 4·7–20·2; p=0·002). Overall differences in treatment responses were attributed both to “virological and non-virological reasons” and the greatest difference in number of responses was in patients with high viral load at baseline.

Although the study was randomised, it was open-label and so liable to biases related to participant selection and the effect of the treatment allocation on post-randomisation treatment decisions and reporting of outcomes. Knowledge of the primary results at 48 weeks might have influenced outcomes at 96 weeks, because although a similar number of patients in each group withdrew consent at 48 weeks, more had withdrawn consent in the darunavir plus ritonavir group by 96 weeks.

Tolerability and safety at 96 weeks were much the same in each treatment group, with similar numbers of adverse events and diarrhoea, nausea, and headache being the most common, although diarrhoea was more common in the darunavir plus ritonavir group and headache was more common in the dolutegravir group. However, serious adverse events did differ between groups. At 96 weeks, the incidence of serious adverse events was higher in the dolutegravir group than in the darunavir plus ritonavir group (36/242 [15%]vs21/242 [9%]), a trend that was also noted at 48 weeks. 6 Between 48 and 96 weeks, ten patients reported 14 serious adverse events in the dolutegravir group versus eight patients reporting nine serious adverse events in the darunavir plus ritonavir group. In the dolutegravir group, three serious adverse events (two since 48 weeks) were deemed possibly drug related by the investigator (tendon rupture, polyarthritis, and suicide attempt), and might be a result of over-reporting of events for a new drug. No serious adverse events in the darunavir plus ritonavir group were classed as drug related.

There was good news about resistance. Few patients had virological failure up to 96 weeks and no treatment-emergent primary protease inhibitor, integrase inhibitor, or nucleoside reverse transcriptase inhibitor resistance mutations were detected in either group. Similar to SPRING-21 and 2and SINGLE,3 and 4dolultegravir developed no resistance mutations when given to treatment-naive pateints along with dual nucleoside reverse transcriptase inhibitors who had virological failure. These findings suggest that dolutegravir and ritonavir-boosted darunavir have a similar barrier to the development of resistance in treatment-naive patients but more data from outside of the controlled environment of clinical trials are needed to support this claim.

Could overall outcomes have been better if regimens were given as single tablet regimens? Integrase inhibitors are available in combined single tablet regimens and coformulated protease inhibitors with nucleosides are soon to follow. Few clinical trial data support better efficacy with single tablet regimens but they have advantages in terms of drug distribution, convenience for patients, and copayment.

If 30 million people worldwide are to be treated by 2030, then retention in treatment is key. Protease inhibitors might have a role for patients with baseline drug resistance or with suspected suboptimum adherence but generally, they have begun to fall out of favour as first-line treatment. Non-nucleoside reverse transcriptase inhibitors, particularly efavirenz, have remained at the forefront of first-line treatment recommendations in guidelines, but integrase inhibitors might begin to challenge that by virtue of their better tolerability and, in the case of dolutegravir, more favourable resistance patterns in patients who do have virological failure. Nonetheless, integrase inhibitors, despite their favourable attributes, have not improved overall long-term discontinuation; in the FLAMINGO study, 18% of participants had discontinued by 96 weeks. Although clinical trials have their difficulties, the real world can be a much more challenging place.

 

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© 2015 Published by Elsevier B.V.

TJB has received conference support and speaker's honoraria from Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, and ViiV Healthcare. AP has received conference support, speaker's honoraria, and advisory board fees from Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, and ViiV Healthcare.

References

  • 1 F Raffi, A Rachlis, HJ Stellbrink, et al., for the SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381:735-743 Crossref
  • 2 F Raffi, H Jaeger, E Quiros-Roldan, et al., for the extended SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13:927-935 Crossref
  • 3 SL Walmsley, A Antela, N Clumeck, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369:1807-1818 Crossref
  • 4 Walmsley S, Berenguer J, Khuong-Josses M, et al. Dolutegravir regimen statistically superior to efavirenz/tenofovir/emtricitabine: 96-week results from the SINGLE study (ING114467). 21st Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA; March 3–6, 2014. Abstract 543.
  • 5 JM Molina, B Clotet, J van Lunzen, et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015; published online March 10. http://dx.doi.org/10.1016/S2352-3018(15)00027-2
  • 6 B Clotet, J Feinberg, J van Lunzen, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383:2222-2231

Footnotes

a Chelsea and Westminster NHS Foundation Trust, London UK