Once-a-day dolutegravir may help in treatment-naive HIV

By Lorraine L. Janeczko

NEW YORK (Reuters Health) - Treatment-naive HIV patients may benefit from once-a-day dolutegravir, according to results at the halfway point of an open-label phase 3b study.

Once-a-day dolutegravir in combination with fixed-dose nucleoside reverse transcriptase inhibitors (NRTIs) was superior to once-a-day darunavir plus ritonavir at week 48 of the 96-week FLAMINGO non-inferiority trial, the authors reported online April 1 in The Lancet.

This drug regimen "represents an effective new treatment option for HIV-1-infected, treatment-naive patients," the authors wrote.

"The efficacy of both regimens was outstanding, indicating that the use of antiretroviral therapy in 2014 and beyond has become strikingly effective," said co-author Dr. Michael S. Saag, director of the Center for AIDS Research at the University of Alabama at Birmingham, in an email to Reuters Health.

"I fully expected that the regimens would be roughly equal to each other, but finding the dolutegravir group superior to boosted darunavir was a surprise. On close inspection of the results, dolutegravir showed better tolerability. Fewer subjects in the dolutegravir group stopped treatment due to intolerance, and that group demonstrated overall superiority using intent-to-treat analyses," he said.

"Dolutegravir was approved for use by the US Food and Drug Administration in 2013," he said. "Very soon, the agency likely will approve a 'triple combination' fixed-dose formulation in a single tablet containing dolutegravir, abacavir and lamivudine that can be taken once a day."

FLAMINGO was conducted at 64 research centers in nine countries.

Eligible patients aged 18 years and older had a plasma HIV-1 RNA concentration of 1,000 copies per mL or higher, no previous treatment with antiretroviral therapy, and no primary resistance to NRTIs or protease inhibitors.

Exclusion criteria included active disease of category C from the Centers for Disease Control and Prevention, estimated creatinine clearance of less than 50 mL/min, and malignancy within the past 5 years.

Over seven months, they screened 595 patients and included 484 in their analyses. One group (n=242) received dolutegravir 50 mg once daily, and the other group (n=242) received darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine.

At the 48th week, 217 patients (90%) receiving dolutegravir and 200 patients (83%) receiving darunavir plus ritonavir had HIV-1 RNA below 50 copies per mL. The adjusted treatment difference between groups was 7.1%, and dolutegravir was significantly superior to darunavir plus ritonavir (p=0.025).

In each group, two patients (<1%) had confirmed virologic failure. Discontinuation due to adverse events or stopping criteria occurred in four (2%) dolutegravir patients and 10 (4%) of those on darunavir plus ritonavir.

The most common adverse events were diarrhea (17% vs 29% with dolutegravir vs darunavir plus ritonavir); nausea (16% vs 18%); and headache (15% vs 10%). Patients on dolutegravir had fewer LDL values of grade 2 or above (2% vs 7%; p=0.0001).

"These results confirm that drugs only work when they are taken (!) - no one wants to take medicines that make them feel bad. Most newer antiretrovirals are roughly equally effective from a virologic perspective; where they differ, and where many of the newest drugs gain a foothold, is in their tolerability," said Dr. Saag in an email.

"Ritonavir-boosted darunavir is one of the best-tolerated protease inhibitor regimens (along with boosted atazanavir), but both regimens still require use of ritonavir, albeit at low doses (100 mg). Still, ritonavir is a tough drug to take, with side effects in some people, including nausea and diarrhea," he said.

"The integrase inhibitors, especially raltegravir and dolutegravir, do not require boosting and therefore are better tolerated than many other antiretroviral drugs," he said.

Dr. Cecilia M. Shikuma, director of the Hawaii Center for AIDS of the John A. Burns School of Medicine at the University of Hawaii at Manoa in Honolulu said in an email, "This study is important because it establishes an integrase inhibitor-based regimen as an extremely effective and simple once-daily alternative to more traditional antiretroviral regimens based on protease inhibitors or non-nucleoside reverse transcriptase."

"Besides being potent, dolutegravir can be taken with or without food at any time of day," added Dr. Shikuma, who was not involved in the study.

In an editorial, Dr. Anton L. Pozniak of Imperial College London and Dr. Jose R. Arribas of Instituto de Investigacion Hospital Universitario La Pa Paz (IdiPAZ) in Madrid wrote, "The only apparent management issue with dolutegravir is its effect on lowering the estimated, but not true, glomerular filtration rate due to its action on inhibiting organic cation transporter-1 in the tubule and decreasing creatine secretion."

The editorial continues: "Although this issue is not a true renal toxic effect, and in FLAMINGO no participant developed grade 3-4 increase in creatinine, physicians have to be aware of this phenomenon, especially in patients with underlying renal disease, so that any changes in creatinine can be interpreted correctly."

"Another note of caution is that long-term follow-up is needed to continue to look out for adverse events," they added.

Funding for the study was provided by ViiV Healthcare LLC and Shionogi & Co. Dr. Saag and several other authors have received funds from ViiV Healthcare and other companies or are employed by pharmaceutical companies, including Shionogi & Co. Three authors declared no conflicts of interest.

SOURCE: http://bit.ly/1k1cfGb

Lancet 2014.

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