Raltegravir versus efavirenz in treatment-naïves at 96 weeks: continued efficacy and fewer adverse effects

The integrase inhibitor raltegravir continues to show strong efficacy "almost identical" to that of efavirenz at 96 weeks, in combination with tenofovir and 3TC, and a side-effect profile that continues to be favourable, Dr Marty Markowitz of the Aaron Diamond AIDS Research Center reported on Tuesday at the XVII International AIDS Conference in Mexico City.

Raltegravir (Isentress) is an integrase inhibitor currently being studied in both treatment-experienced and in treatment-naïve patients. Owing to its significant and durable effects in highly treatment-experienced patients, raltegravir has already received approval in Europe and the United States for use in this population.

Meanwhile, raltegravir is also being studied in an ongoing Phase II trial in patients who have not previously been on HIV treatment. In this multicentre, double-blind, randomised study, the efficacy, safety and tolerability of raltegravir is being compared to efavirenz, in combination with tenofovir (TDF) and lamivudine (3TC).

A total of 198 patients were enrolled, with 160 randomised to raltegravir and 38 to efavirenz. The study was originally designed to compare raltegravir doses of 100, 200, 400 or 600mg twice daily. Raltegravir and efavirenz have been comparably effective at suppressing viral load to undetectable levels up to 48 weeks, and raltegravir has appeared more tolerable, with a better lipid profile. Baseline information on the participants and detailed 48-weeks results have already been reported.

After 48 weeks, as there was little appreciable difference in performance between the different raltegravir doses, doses were standardised to 400mg twice daily for all 160 patients in the raltegravir arm.

Now, at week 96, raltegravir and efavirenz remain neck-and-neck in terms of efficacy, with what Dr Markowitz called "almost superimposable results." HIV viral load was suppressed to below 400 copies/ml in 84% of patients in each group, and to below 50 copies/ml in 83% versus 84% in the raltegravir and efavirenz groups, respectively. (This was in an intent-to-treat analysis, with non-completers treated as treatment failures.) In an observed-failure analysis of only those patients who completed treatment to 96 weeks, the suppression rates to below 50 copies/ml were 92% for raltegravir and 91% for efavirenz.

Increases in CD4 cell counts were also very similar in both treatment arms: 221 cells/mm³ for raltegravir versus 232 cells/mm³ for efavirenz.

Dropout rates in both arms were similar, at about 16%.

Fewer drug-related clinical adverse experiences (AEs) were reported in the raltegravir than in the efavirenz group (51% versus 74%, respectively). (These included any AEs reported by study investigators.) In raltegravir and efavirenz respectively, reported rates of nausea were 12.5% vs 13.2%, dizziness 8.8% vs 28.9%, headache 8.8% vs 23.7%, diarrhoea 6.9% vs 10.5%, abnormal dreams 6.3% vs 18.4%, insomnia 8.1% vs 10.5%, and nightmares 0% vs 10.5%. Neuropsychiatric AEs overall remained less frequent with raltegravir (16%) than with efavirenz (32%).

There were ten reports of grade four elevations in creatine phosphokinase (CPK) in patients on raltegravir. Otherwise, serious laboratory abnormalities remained infrequent in both arms. Raltegravir had significantly less effect on total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides. In raltegravir and efavirenz respectively, the mean change in TC levels were +1.1 vs +24.0 mg/dl (p=.002), in LDL-C levels -5.8 vs +4.4 mg/dl (p=.045), and in triglycerides -10.8 vs +13.4 mg/dl (p=0.145). Raltegravir also resulted in smaller increases in the beneficial HDL cholesterol (+7.4 vs +13.0 mg/dl, p=.017).

Dr Markowitz concluded that, "at 96 weeks, raltegravir had sustained antiretroviral effect similar to 48-week data and to efavirenz, in ART-naïve patients in combination with tenofovir and 3TC. Raltegravir was generally well tolerated; drug related AEs appeared less frequent in patients treated with raltegravir compared to efavirenz."

In questions following the presentation, Dr. Markowitz commented on the initial, very rapid decline in viral load seen with raltegravir as compared to other agents, saying that whether this rapid suppression would have any longer-term clinical significance is still an open question.

In terms of drug resistance, viral rebound was seen in one patient on raltegravir between 48 and 96 weeks, with no well-characterised viral resistance mutations reported. (One other patient rebounded on efavirenz treatment, with mutations identified at M184V and K103N).

Asked about the potential to develop a once-daily dose of raltegravir, Markowitz replied that "the 400 mg bid (twice-daily) dose was chosen for this study based on lots of pharmacokinetic (PK) data… there is a huge amount of variability in raltegravir levels, both between patients and within single patients. The 200 mg bid exposure is probably similar to that of a qd (once-daily) 800 mg, so that is a possibility on the menu for further development."