2NN results – nevirapine and efavirenz in prospective randomised head-to-head study

Simon Collins, HIV i-Base

Among the most anticipated study results were those from the IATEC run and Boehringer sponsored 2NN study, and these were presented in the last session of oral poster presentations at the conference.

2NN is the first large randomised study to compare nevirapine (NVP, Viramune) and efavirenz (EFV, Sustiva) in a head-to-head study, and it was planned and run long after both drugs had been licensed. Such studies are generally rare and it is commendable that several important patient-centred questions were answered in one study.

The study also included a dual-NNRTI arm using both drugs together to look at whether similar benefits as dual-PI strategy were possible. A fourth arm was added and enrolment size significantly increased very early in the study to include once daily nevirapine. All four arms used a nucleoside backbone of stavudine (d4T, Zerit) and lamivudine (3TC, Epivir).

The multicentred international study enrolled 1,216 treatment naïve patients from 67 sites in 17 countries including from Europe, South Africa, Australia, Thailand, South America and the USA. Primary endpoints were the percentage of patients with treatment failure, defined as >1 log drop in viral load at week 12; virological failure after week 24, disease progression or change in assigned treatment. Secondary endpoints included percentage of patients with viral load <50 copies/ml; change in CD4 count and incidence of clinical or laboratory adverse events. All analyses were intent-to-treat (ITT) for all randomised patients at week 48. The four planned pair-wise comparisons were: NVP bd vs EFV; NVP bd vs NVP qd; NVP qd vs EFV+NVP and EFV qd vs EFV+NVP.

All arms were well matched and patient characteristics were relevant to people starting treatment today. Baseline median characteristics for the whole study included CD4 cell count just below 200 cells/mm3 (range 70-330), plasma viral load of 4.7 log (4.4-5.5), age 34 (29-40), 21% CDC class C. Over one third of patients were women, almost 60% acquired HIV heterosexually, and 5.3% and 9.5% were coinfected with hepatitis B and C respectively.

Results at 48 weeks

The only statistically significant difference by efficacy was between EFV QD and NVP+EFV arms (p<0.001).

CD4 increases for patients completing the study increased similarly and were 170, 160, 160 and 150 cell/mm3 at 48 weeks in the NVP QD, NVP BD, EFV QD and NVP+EFV arms respectively, with no statistically significant difference between arms.

As expected, differences were recorded in treatment arms when assessing side effects and grade 3/4 toxicities are shown below:

Twenty-five patients died during the study. Of these two were attributed to NVP use (one case of toxic hepatitis from Argentina without evidence of hepatic co-infection and one case of Steven’s Johnson syndrome from South Africa who died of MRSA septicaemia while recovering in hospital); one death was from lactic acidosis attributed to d4T; 11 deaths related to HIV-disease; 11 deaths non-Rx and non-HIV related.

The clearest conclusion achieving statistical significance was that dual NNRTI therapy results in statistically poorer virological response compared to efavirenz, and significantly greater grade 3/4 clinical toxicity than efavirenz. NVP once daily is associated with significantly greater grade 3/4 liver lab toxicity than efavirenz, which may have been a surprise, and that efavirenz is associated with greater CNS toxicity which wasn’t.

However the take home message stressed by the investigators, and in the many reports of this study, is that nevirapine and efavirenz both performed similarly with no statistical difference in potency or serious toxicity and that they should be considered equally when planning antiretroviral choices.

Lipid sub-study

A sub-study looked at the lipid samples obtained after a mandatory ≥3-hour fast with primary outcome being absolute change in plasma lipid concentrations adjusted for baseline value between start of treatment and week 48. The analysis was limited to patients who continued their randomised treatment for 48 weeks.

This showed a small but statistically significant benefit in favour of the patients receiving nevirapine alone over efavirenz alone. Change in plasma lipid concentrations over 48 weeks showed a larger increase in HDL-c (+0.37 vs + 0.24), larger decrease in TC:HDL-c ratio (-0.36 vs 0.04), both p<0.001; and a smaller increase in TG (+0.12 v +0.37), p=0.01.

The percentage of patients with dyslipidemia defined as TG>2.3mmol/l, TC >6.2mmol/l, LDL-c>4.1mmol/l, HDL-c <0.9 mmol/l and TC:HDL-c ratio >6.5 tended to be very slightly higher for efavirenz but in this analysis there was no significant statistical difference between treatment arms.

References

1. 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.

2. Van Leth F, Phanuphak P, Gazzard B et al. Lipid changes in 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 (2NN study). Abstract 752.

comment

Is there any importance to the several numerical differences between arms that showed greater EFV efficacy generally at >100k even though these were not statistically significant? P-values were not provided in order to comment on the importance of any trend and some questions are not answered as they were not included in the pairwise comparisons (ie NVP QD vs EFV QD)?

Absolute success rates were not high, but definition of failure was very strict and devised to show real-life results from each drug (ie switch = failure). This study certainly provides clinicians with data to support use of NVP-based combinations in first line therapy, although in the UK this is already common practice.

This study may not provide the clinical answer for when to choose one NNRTI over another as this will be guided by the approach to management of side effects, but for such a substantial non-registrational study it is as good as we are likely to see.

	HIV Treatment Bulletin Vol 4 No 3 April 2003