Patients who take once-daily antiretroviral therapy based upon nevirapine (Viramune) do not have better adherence to their treatment than patients who take the drug twice-daily, according to a French study published in the October edition of AIDS. The study also found that patients who took once-daily therapy were four times more likely to miss taking their anti-HIV treatment for two or more consecutive days, a risk factor for the development of drug-resistant virus.
Antiretroviral therapy requires high levels of adherence. The best results are seen in patients who take at least 95% of their doses correctly. Adherence below this level has been associated with an increased risk of drug resistance.
For many patients such rigorous adherence is a challenge and once-daily anti-HIV therapy has been developed with the aim of improving patient adherence.
However, evidence that taking once-daily rather than twice-daily treatment leads to improved adherence remains scarce.
Investigators in France hypothesised that switching to once-daily treatment would improve adherence amongst patients who had initiated anti-HIV therapy with a regimen that included twice-daily doses of the NNRTI, nevirapine. Studies have shown that this drug can be taken once- or twice-daily, although the 2NN study of nevirapine versus efavirenz showed a higher rate of grade 3 and 4 liver toxicity in the once-daily group. This finding has discouraged once-daily use of nevirapine despite the drug's long half-life.
The investigators also wanted to see if there were differences between once- and twice-daily dosing in terms of safety, efficacy and patient preference.
A total of 52 patients were therefore included in analysis of the POSOVIR study. The mean age of these patients was 48 years. The patients were receiving their HIV care at four Parisian hospitals. All had had received potent antiretroviral therapy, including twice-daily nevirapine, resulting in a viral load below 400 copies/ml for a minimum of six months before entry to the study.
The study lasted for one year and was in three stages. For the first three months patients continued to take twice-daily nevirapine. At the end of this period they were randomised on an equal basis to take the drug either once- or twice-daily for a further four months. For the final five months of the study patients were given the option of taking once- or twice-daily therapy.
Adherence was electronically monitored and blood tests were used to check plasma levels of nevirapine. Furthermore, patients were asked to validate the electronic records of their adherence.
All patients had their clinical, biological and immunovirological parameters monitored at weeks 12, 28 and 52.
During the randomised phase, adherence was a non-significant 0.5% better amongst patients taking once-daily nevirapine. However, the odds of a treatment-free day were increased by 70% for patients taking once-daily therapy (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.0 – 2.8, p = 0.04). Furthermore, in longitudinal analysis, once-daily dosing was significantly associated with having two or more consecutive days without HIV therapy (OR, 4.4, 95% CI, 1.9 – 10.3, p
But patients did nevertheless seem to prefer once-daily treatment. At the end of the randomisation period, fifteen patients taking twice-daily treatment opted to switch to once-daily therapy as opposed to eight patients randomised to the once-daily arm who wished to change back to twice-daily treatment.
“We found no evidence of improved adherence rate with once-daily dosing”, write the investigators, adding, “once-daily dosing was associated with an increased number of drug interruptions.”
They continue, “our result…has potentially important implications for supporting continuous therapy, including in low-income countries, because antiretroviral drug interruptions, and the emergence of drug resistance are both associated with the risk of death.”
Although the investigators acknowledge that once-daily therapy is popular with some patients, they caution that their findings suggest that patients “prone to drug holidays” should be encouraged to take twice-daily therapy to reduce their risk of resistance. They conclude, “our findings suggest that the effect of once-daily versus twice-daily dosing doses increase the number of drug interruptions and is compatible with modest improvements in adherence rates”.
Parienti J-J et al. Effect of twice-daily nevirapine on adherence in HIV-1-infected patients: a randomised controlled study. AIDS 21: 2217 – 2222, 2007.