highly active antiretroviral therapy ( haart ) has improved the prognosis of patients with human immunodeficiency virus ( hiv ) infection by significantly reducing related morbidity and mortality.1,2 early treatment protocols , many of which are still recommended , contain two nucleoside reverse transcriptase inhibitors ( nrti ) and one nonnucleoside reverse transcriptase inhibitor ( nnrti ) or a protease inhibitor ( pi).35 nnrtis currently included in treatment regimens comprise nevirapine ( npv ) , efavirenz , and rilpivirine .
although npv is used mostly to substitute pis in patients with high cardiovascular risk in developed countries,5 it is still included in first - line treatment regimens in low - income countries.3 given its short plasma half - life , nvp immediate - release ( nvp - ir ) must be administered twice a day to achieve a 24-hour effective plasma level.6 in order to simplify art regimens and improve adherence to prescribed medications , the extended - release formulation of nvp ( nvp - xr ) , which allows a single daily intake , has been developed and tested in two phase iii clinical trials .
the aim of the current review is twofold : ( 1 ) to highlight the clinical utility and efficacy of nvp - xr ; ( 2 ) to assess the impact of nvp - xr on patients safety by shedding light on the main side effects of nvp - xr and the expected gain in term of treatment adherence .
nevirapine is a member of the nnrti family that was introduced as a component of the triple art in 1996 ( viramune ; boehringer ingelheim pharmaceuticals , inc , ridgefield , ct , usa ) .
since then , it has been used in its immediate - release ( ir ) form alongside nrtis . following an induction phase at 200 mg in a single intake per day for 2 weeks
, nvp - ir is administered twice per day at 200 mg per intake during the continuation phase.7 early clinical trials comparing a single daily dose of nvp - ir 400 mg vs 200 mg twice per day , or vs another nnrti with longer half - life , revealed high rates of virologic failure among patients treated with single daily intake.810 for instance , in the daufin randomized , open - label trial,8 a twice - daily combination of zidovudine ( 300 mg ) , lamivudine ( 150 mg ) , and nvp - ir 200 mg was compared with an once - daily combination of lamivudine ( 300 mg ) , tenofovir ( 245 mg ) , and nvp - ir ( 400 mg ) .
this study was prematurely terminated after the inclusion of 35 and 36 patients respectively in each of the study arms , due to a treatment failure rate of 22.2% among those in the nvp - ir single daily intake arm of the study.8 by contrast , in a prospective nonrandomized study published in 2009 , assessing the efficacy and tolerance of a once - daily combination of nvp - ir ( 400 mg ) , tenofovir ( 300 mg ) , and emtricitabine ( 200 mg ) , weberschock et al11 found a virologic efficacy in 84.6% of patients who were still on treatment after 72 weeks of follow - up , and reported important side effects in 11.4% of patients . in spite of the nonrandomized nature and the lack of a control arm in the study by weberschock et al,11
there were suggestions for the efficacy and tolerability of regimens based on a once - daily nvp regimen .
therefore , in order to simplify treatment protocols , the nvp - xr ( viramune 400-xr ; boehringer ingelheim pharmaceuticals , inc ) , which allows a single daily intake of 400 mg , was approved by the us food and drug administration in march 2011.12
nevirapine belongs to the class of nnrti agents that act by inhibiting the reverse transcriptase ( rt ) of hiv-1 . unlike nrti
, nvp does not act through a competitive mechanism , but by directly binding to the catalytic site of rt , leading to the inhibition of the dna polymerase , which is essential for rna and dna activities.13,14 nvp - xr was developed from a hydrophilic polymer called hypromellose 2208 , to allow a controlled and extended release of nvp in the intestinal tract.15 nvp - ir is very well absorbed in the digestive tract , with a bioavailability rate as high as 90% .
compared with nvp - ir , nvp - xr is slowly absorbed in the digestive tract , with a bioavailability rate of 72%.12 the minimal plasmatic concentration of 2920 ng / ml achieved after a single dose of 400 mg of nvp - xr and the 24-hour time to maximum concentration , are compatible with a single daily intake using this formulation.12 nvp undergoes a biotransformation process involving cytochrome p450 to yield several hydroxylated metabolites .
the efficacy and tolerance of nvp - xr have been assessed in two major clinical trials : the verxve16 and tranxition17 trials .
verxve was a phase iii multinational , randomized , single - blinded parallel arms trial , comparing the efficacy and tolerance of nvp - xr ( 400 mg once - daily ) with nvp - ir ( 200 mg twice - daily ) ; each arm augmented with emtricitabine ( ftc ) and tenofovir ( tdf ) among 1011 adult patients ( 505 in the nvp - xr arm and 506 in the nvp - ir arm ) with hiv infection and nave to art drugs.16 the primary outcome of the study was a sustained virologic response at 48 months of treatment .
sustained virologic response was defined by two consecutive hiv viral load < 50 copies / ml at least 2 weeks apart and without relapse or change in the art regimen.16 after 48 weeks of treatment , this study showed a noninferiority of once - daily nvp - xr 400 mg compared with twice - daily nvp - ir , for a predefined margin of 10% .
the proportion of patients with sustained virologic response at 48 weeks was 81% ( 409/505 ) in the nvp - xr group and 75.9% ( 384/506 ) in the nvp - ir group with an adjusted difference of 4.9% favoring the nvp - xr arm.16 the tranxition trial was conducted to assess the efficacy and tolerance of once - daily nvp - lp 400 mg , subsequent to a transition from an initial twice - daily regime of nvp - ir 200 mg in patients with virologic efficacy .
this was a randomized trial ( 2:1 , nvp - xr : nvp - ir ) in multinational , double- blinded , noninferiority , and paralleled groups.17 this study enrolled 295 patients in the nvp - xr group and 148 patients in the nvp - ir group .
the main primary outcome was a sustained virologic response at 24 weeks following randomization and was based on a viral load < 50 copies / ml.17 persisting virologic response was observed in 93.6% of patients in the nvp - xr arm and 92.6% in the nvp - ir arm , with an adjusted difference of 1% favoring the nvp - xr arm .
nvp - xr was noninferior to nvp - ir , based on a margin of 10%.17 the two phase iii clinical trials16,17 have demonstrated the clinical efficacy of nvp - xr compared with nvp - ir ( suppression of the viral load or maintenance of a nondetectable viral load ) among hiv patients nave to art or initially treated with a regimen containing a nvp - ir .
other indicators of comparable efficacy between the two formulations are : the time to the loss of virologic response and increase in cd4 count from the baseline levels.16
in the verxve trial , the incidence of a skin eruption considered to be drug - related was 5.7% in the nvp - xr arm and 4.9% in the nvp - ir arm , with nonsignificant difference .
the majority of patients had mild or moderate skin eruption , usually within the first 4 months of starting the treatment .
three patients in the nvp - ir arm developed stevens johnson syndrome against none in the nvp - xr arm.16 the proportion of patients who developed symptomatic hepatitis was 1.6% and 2.4% in the nvp - xr and nvp - ir arms , respectively ( p > 0.05).16 drug side effects were reported in 11.9%17 and 19.8%16 of patients on nvp - xr , and in 2%17 and 24%16 of those on nvp - ir in the two published clinical trials , respectively.16,17 it is also of note that grade 3 and 4 side effects attributable to the trial medications were comparable in the two arms in the two studies .
therefore , the reported frequency of side effects during treatment with nvp - xr is comparable to those observed during treatment with nvp - ir .
the reduction of the pill burden significantly improves the adherence to art.18 therefore , transition to nvp - xr formulation , which allows a single daily intake would improve the adherence of patients initially on nvp - ir twice daily , or those directly started on the new formulation .
in the two clinical trials of nvp - xr , adherence was similar in the two arms , which in some ways is expected in rigorously conducted randomized controlled trials .
the xr formulation of nvp is effective and well tolerated in both hiv patients who are nave to art therapy and those initially treated with nvp - ir .
the incorporation of nvp - xr in the treatment armamentarium for hiv infection would likely allow a simplification of treatment protocols through single daily intake of the medications and therefore contributing to improving adherence to art .
 an extended - release formulation of nevirapine ( nvp - xr ) has been developed with the aim of simplifying antiretroviral treatment regimens and improving patients adherence with a single daily intake . 
 the verxve and tranxition clinical trials have demonstrated the noninferiority of nvp - xr compared with nevirapine immediate - release ( nvp - ir ) on viral load after 24 and 48 months of treatment . 
 the tolerance profiles of nvp - xr and nvp - ir are similar . simplifying the treatment dosage for nvp would likely improve adherence to antiretroviral treatments . 
Introduction
Historical perspective
Pharmacology of nevirapine extended-release formulation
Clinical efficacy of nevirapine extended-release
Tolerance and side effects of nevirapine extended-release
Impact of nevirapine extended-release on the patient: improvement of the adherence to antiretroviral treatment
Conclusions