Analysis of hepatic events in 2NN study by CD4 entry criteria, levels differences between nevirapine and efavirenz; excess hepatic events in once-daily nevirapine arm linked to single site in Thailand
Simon Collins, HIV i-Base
The 2NN study randomised over 1200 treatment naive patients to d4T/3TC plus one of four arms: nevirapine once daily, nevirapine twice daily, efavirenz once-daily, or nevirapine plus efavirenz. 
Baseline median characteristics included CD4 cell count just below 200 cells/mm3 [range 70-330] and plasma viral load of 4.7 log [4.4-5.5]). One of the key findings showed a higher rate of hepatobilary lab toxicity in the nevirapine once-daily compared to the twice-daily arm (13.2 vs 7.8, p=0.002), despite similar efficacy. The results, presented at the Retrovirus conference in February 2003, provided key comparative data for how NNRTIs have subsequently been used in clinical practice.
Later research into the risk factors for serious rash-associated hepatic toxicity led to regulatory changes in the product labeling, with an indication to only prescribe nevirapine in treatment naive patients with CD4 count <250 cells/mm3 in women and <400 cells/mm3 in men. 
At the 7th International Congress on HIV infection held in Glasgow last November, the higher incidence of nevirapine-related hepatic toxicity was reported as being driven by the Thailand sites, where patients also reported higher plasma nevirapine trough levels.  At the EACS meeting in Dublin, Stephen Storfer from Boehringer Ingelheim presented an analysis of hepatic events based on Thai and non-Thai patients who started treatment based on these new CD4 guidelines that tied the higher rates seen in the once-daily nevirapine arm to a single site in Thailand. 
The single Thai site contributed 167 patients of the 967 patients who received a single NNRTI in the 2NN study.
Rates of symptomatic (SymHAEs) and asymptomatic (AsymHAEs) hepatic adverse events are shown in Table 1 below.
Table 1: Rates of symptomatic (Sym) and asymptomatic (Asym) HAEs
% sym HAEs (% Asym HAEs)
|Population||CD4 criteria||NVP QD||NVP BID||EFV QD|
|Total 2NN||None||8.6 (7.0)||5.6 (4.9)||2.1 (3.8)|
|Thai||None||16.3 (10.2)||2.3 (9.3)||1.4 (5.8)|
|Thai||<250/<400||18.4 (7.8)||0.0 (9.3)||0.0 (5.8)|
|Non-Thai||None||6.2 (5.6)||6.3 (4.2)||2.6 (3.2)|
|Non-Thai||<250/<400||4.2 (2.8)||3.2 (3.9)||3.6 (3.9)|
The study concluded that all of the excess rates of symptomatic hepatic toxicity in the nevirapine once-daily arm could be attributed to the single Thai site and that both symptomatic and asymptomatic hepatic events outside Thailand were low and comparable in all the single NNRTI arms. The researchers also concluded that the new CD4 entry criteria appear to be effective.
It is unfortunate that these sub-analyses were not available earlier, and it is unclear why a single site driving toxicity responses also wasnt identified sooner. An earlier analysis of hepatic events based on baseline CD4 categorisation, would also have been very useful. Nevertheless, the information is very important, as it is the first and largest assessment of toxicity rates allowing for new CD4 criteria.
Although pharmacokinetics  and some clinical data generally support once-daily dosing, Boehringer Ingelheim have not yet applied to US or European regulatory agencies for a once-daily indication.
- Lange J, Van Leth F et al. Results of the 2NN study: A randomized comparative trial of first-line antiretroviral therapy with regimens containing either nevirapine alone, efavirenz alone or both drugs combined, together with stavudine and lamivudine. 10th CROI. February 10-14, 2003. Boston, MA, USA. Abstract 176. See HTB, April 2003:
- Boehringer Ingelheim Dear Doctor letter: Risk factors for severe, life-threatening and fatal hepatotoxicity with nevirapine. See HTB April 2003:
- van Leth H, Hall DB, Lange JMA et al. Regional differences in treatment failure in the 2NN Study. 7th ECAATH, Glasgow, 2004. Abstract P193.
- Storfer S, Leith J, Piliero P, Hall D. Analysis of hepatic events within the 2NN study: controlling for ethnicity and CD4+ count at initiation of nevirapine therapy. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE9.6/2.
- Kappelhoff BS, Huitema ADR, van Leth F et al. Pharmacokinetics of nevirapine: once daily versus twice-daily dosing in the 2NN study. HIV Clinical Trials 2005;6(5):254-261.