Once-daily dolutegravir superior to darunavir/ritonavir in 96-week follow-up

Jean-Michel Molina, speaking at HIV Glasgow. Image courtesy of HIV Drug Therapy Glasgow 2014 (hivglasgow.org)

Treatment with a triple antiretroviral combination containing once-daily integrase inhibitor dolutegravir (Tivicay) is superior to the ritonavir-boosted protease inhibitor darunavir (Prezista) over 96 weeks of follow-up, Jean-Michel Molina of the Hôpital Saint Louis, Paris, reported at the HIV Drug Therapy Glasgow conference last week.

Dolutegravir is also a component of the fixed-dose three-drug combination Triumeq, which contains abacavir and lamivudine.

The findings came from the FLAMINGO (or ING 114915) study, a multi-centre phase IIIb trial that compared dolutegravir to darunavir/ritonavir in a first combination of antiretrovirals. It recruited adults living with HIV who had a viral load over 1000 copies/ml, who had not taken treatment before, and who showed no sign of viral resistance. The study participants were randomised to receive dolutegravir or darunavir/ritonavir with an investigator-selected backbone nucleoside (NRTI) regimen: tenofovir/emtricitabine or abacavir/lamivudine. Participants were stratified by baseline viral load above or below 100,000 copies/ml and by backbone regimen.

Glossary

investigator

Scientific researcher.

endpoint

In a clinical trial, a clearly defined outcome which is used to evaluate whether a treatment is working or not. Trials usually have a single primary endpoint (e.g. having an undetectable viral load) as well as a few secondary endpoints, covering other aspects of treatment safety, tolerability and efficacy.

nausea

Feeling sick.

open-label

A clinical trial where both the researcher and participants know who is taking the experimental treatment. See also “blinded trial”.

primary endpoint

The main result that is measured at the end of a clinical study to see if a given treatment worked (e.g., proportion of participants with viral suppression). What the primary endpoint will be is decided before the study begins.

The doses administered were 50mg of dolutegravir once daily or darunavir/ritonavir 800/100mg once daily. The primary endpoint was the proportion of people with a viral load of less than 50 copies/ml at week 48 of treatment, and the secondary endpoints were the antiviral activity, safety, tolerability, health outcomes and viral resistance.

A total of 484 people were randomised and treated, with 242 in each of the two treatment groups. As reported in The Lancet in April 2014, 90% of participants receiving dolutegravir (217), and 83% of those receiving darunavir/ritonavir (200), had achieved a viral load of less than 50 copies/ml. The difference between the two groups being significant, investigators concluded that dolutegravir was superior to darunavir/ritonavir in treatment-naive patients.

The 96-week results of FLAMINGO were presented at the Glasgow congress. Eighty-six per cent of participants in the dolutegravir arm and 79% of participants in the darunavir/ritonavir arm completed the 96-week study. At week 96, the proportion of these remaining patients with a viral load of less than 50 copies/ml was 80% in the dolutegravir arm and 68% in the darunavir/ritonavir arm. Overall, virologic non-response to treatment (dolutegravir 8%; darunavir/ritonavir 12%) and non-response due to other reasons (dolutegravir 12%; darunavir/ritonavir 21%) occurred less frequently with dolutegravir.

Similarly to the week 48 results, the difference between arms was most pronounced in participants with high baseline viral load (>100,000 copies/ml) (82 vs 52% response through week 96) and in people taking the tenofovir/emtricitabine backbone (79 vs 64%).  

Responses were consistent in the abacavir/lamivudine stratum. Six participants (dolutegravir two, none post-week 48; darunavir/ritonavir four, including two post-week 48) experienced virologic failure, defined in the protocol as a viral load over 200 copies/ml at or after week 24, but none had treatment-emergent resistance to the study drugs.

As in the week 48 results, the most frequent drug-related adverse events were diarrhoea, nausea, and headache, with diarrhoea more common on darunavir/ritonavir (24%) than on dolutegravir (10%). Also, there were significantly more people with grade two fasting LDL cholesterol elevations on darunavir/ritonavir (22%) than on dolutegravir (7%) (p < 0.001); and creatinine levels for dolutegravir, higher than in darunavir/ritonavir as observed since week 2, remained stable through week 96.

In conclusion, at 96 weeks, dolutegravir 50mg once a day remained superior to darunavir/ritonavir 800/100mg once a day and maintained a good safety profile. Investigators concluded that dolutegravir 50mg once a day with either abacavir/lamivudine or tenofovir/emtricitabine is a suitable option for treatment-naive patients, a conclusion endorsed in the 2014 update of the European AIDS Clinical Society (EACS) antiretroviral treatment guidelines.

FLAMINGO is ongoing in an open-label extension to provide more long-term data from people taking dolutegravir.

References

Molina J-M et al. Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naïve HIV-1-infected individuals: 96-week results from FLAMINGO (ING114915). J Int AIDS Soc 17 (3): 6 (abstract 0153), 2014