Once-daily Nevirapine Has More Side-effects Than Twice-daily Dose

Once-daily nevirapine (Viramune) is associated with a higher risk of rash, leading to treatment discontinuation or interruption, than twice-daily dosing of the drug, according to Canadian research published in the January edition of HIV Medicine. The investigators also found that individuals who took nevirapine once daily were more likely to experience liver complications than patients who took the drug twice a day. For these reasons, the authors conclude that once-daily nevirapine cannot be recommended.

Once-daily dose of antiretroviral therapy is becoming increasingly available, and may be a way of improving patient adherence to treatment. Nevirapine has a long plasma half-life and high steady state plasma concentrations meaning that it may be a suitable candidate for once-daily use.

To determine how suitable the drug is for use on a once-daily basis, investigators from Ottawa conducted a literature review to establish the pharmacokinetics, efficacy and safety of once-daily nevirapine (400mg once a day) versus twice-daily (200mg twice a day) dose of the drug.

A Medline search was performed to identify published, peer-reviewed studies examining this question. Abstracts from major international HIV meetings were also reviewed.

The pharmacokinetic data suggested that once-daily nevirapine dosing resulted in lower minimum nevirapine plasma concentrations compared with twice-daily treatment. However these studies theoretically support once-daily dosing assuming that optimal adherence was maintained.

Several clinical trials have evaluated the safety and efficacy of nevirapine in a once-daily dosing regimen. The 2NN study is the largest and best known of these. The Canadian reviewers therefore focused on once-daily and twice-daily nevirapine recipients enrolled in the 2NN study.

The investigators found that the proportion of treatment failures by, or before, week 48 of the 2NN study were comparable between the once-daily and twice-daily treated patients.

However, they also found that there was a trend for patients who were taking the drug once daily to be more likely to change therapy than those who were taking a twice-daily dose of nevirapine (29% versus 22%). They suggest that this could be because of a greater incidence of side-effects.

More patients experienced liver abnormalities in the once-daily group compared with twice-daily nevirapine (14% versus 8%; p=0.036). Also more patients in the once-daily group temporarily or permanently discontinued therapy because of rash (12% versus 7%).

Other smaller clinical trials were considered in the review. Each found that there was no statistically significant difference in the efficacy of once-daily and twice-daily nevirapine. In two of these studies there were also no differences in the frequency of adverse events between once and twice-daily regimens. A further study did, however, highlight a difference in frequency of adverse events between once- and twice-daily dosing of nevirapine.

This study involved 196 patients to investigate the safety and efficacy of switching from various twice-daily regimens (with or without nevirapine) to once-daily nevirapine (400mg), ddI (400mg) and tenofovir (300mg). In this study, adverse events leading to treatment discontinuation were more common in the once-daily group. After 48 weeks, three patients (4%) who continued twice-daily dosing stopped therapy versus twelve individuals (14%) who switched to once-daily dosing. The reasons for treatment discontinuation were: five cases of nevirapine-related hepatitis, two of acute pancreatitis, two of skin rash, two of dry mouth and one of peripheral neuropathy.

“Unfortunately, when compared with twice-daily dosing, antiretroviral regimens in which nevirapine is dosed at 400mg once daily immediately after a 2-week lead-in period are associated with an increased risk of rash leading to treatment interruption or discontinuation”, comment the investigators, adding, “the risk of liver complications is another lingering concern. For these reasons, once-daily nevirapine cannot be recommended at this time.”

The investigators do not, however, rule out the possibility of once-daily nevirapine use. They suggest that longer-term use of the drug could yield improved tolerance of higher concentrations of the drug. They write, “it is theoretically possible that the benefits of once-daily dosing can be achieved without excess toxicity by switching to once-daily nevirapine only after several months of twice-daily administration.”

Source-Bio-Bio Technology