2NN study shows nevirapine equal to efavirenz, but has better lipid profile

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A major international randomised study has challenged a widespread assumption amongst clinicians, by showing that nevirapine and efavirenz have equivalent effects on viral load over 48 weeks.

Nevirapine and efavirenz, both NNRTIs, are the most commonly used drugs in first line therapy in Europe, in combination with two nucleoside analogues. However, some doctors believe that efavirenz is more potent than nevirapine due to analyses of several large cohorts (click here for further details).

The 2NN study set out to compare the two agents, and to compare the strategy of single NNRTI treatment with dual NNRTI treatment. The study also compared the strategies of dosing nevirapine once or twice daily.



A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).


Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.

intent to treat analysis

All participants in a clinical trial are included in the final analysis, in the groups they were originally assigned to, whether or not they actually completed their course of treatment. This method provides a better estimate of the real-world effect of a treatment than an ‘on treatment’ analysis.

central nervous system (CNS)

The brain and spinal cord. CNS side-effects refer to mood changes, anxiety, dizzyness, sleep disturbance, impact on mental health, etc.

equivalence trial

A clinical trial which aims to demonstrate that a new treatment is no better or worse than an existing treatment. While the two drugs may have similar results in terms of virological response, the new drug may have fewer side-effects, be cheaper or have other advantages. 

Twelve hundred and sixteen patients in Europe, Australia, Thailand, Argentina, British Columbia and the United States were randomised to receive either:

  • Nevirapine 400mg once daily plus d4T/3TC twice daily (n=220)
  • Nevirapine 200mg twice daily plus d4T/3TC twice daily (n=367)
  • Efavirenz 600mg once daily plus d4T/3TC twice daily (n=400)
  • Efavirenz 800mg plus nevirapine 400mg once daily (plus d4T/3TC twice daily) (n=127).

Treatment failure was defined as a treatment change, discontinuation due to toxicity, or virologic rebound (two consecutive HIV RNA measurements above 50 copies/ml after week 24) or failure of treatment to suppress viral load by at least 1 log10 copies/ml by week 12).

After 48 weeks, 56.4% of the NVP qd group, 56.3% of the NVP bid group, 62.3% of the EFV group and 46.9% of the NVP + EFV group were counted as treatment successes, and the only significant difference was between the efavirenz group and the nevirapine plus efavirenz group (p

There was no significant difference in the proportion of patients with viral load below 50 copies/ml at week 48 by intent to treat analysis.

The median increase in CD4 cells over 48 weeks was

comparable across all treatment arms in the ITT analysis: a median increase of 170

cells/mm3 in the nevirapine once-daily arm, 160 cells/mm3 in both the nevirapine twice daily

arm and the efavirenz arm, and 150 cells/mm3 in the nevirapine + efavirenz arm.

There were significantly more grade 3 or 4 liver enzyme elevations in the once daily nevirapine-treated patients compared to the efavirenz-treated patients, but a similar trend amongst twice daily nevirapine recipients did not reach statistical significance (p=0.06). Grade 3 or 4 adverse events were significantly more common among patients treated with nevirapine and efavirenz together when compared to patients treated with nevirapine once daily, and central nervous system toxicities were significantly more common amongst efavirenz-treated patients.


Two deaths were attributed to nevirapine use (one hepatitis and one death from MRSA septicaemia following hospital admission for Stevens Johnson Syndrome). One death from lactic acidosis attributed to d4T treatment was also reported.

A full Powerpoint presentation of the 2NN study is available at the IATEC website here.

Presenting the findings, Prof. Joep Lange of the University of Amsterdam Academic Medical Centre said that the study showed that nevirapine and efavirenz should not be used together

Findings of the 2NN lipid sub-study were also presented. In this sub-study, the nevirapine

once-daily and twice-daily regimens were analysed together. In patients who remained on

their allocated treatment (n=833), nevirapine regimens were shown to provide an improved

lipid profile compared to efavirenz at 48 weeks. Patients in the nevirapine regimens

experienced a greater increase in HDL-c (“good”) cholesterol than those in the efavirenz

regimen over 48 weeks. Specifically, a 37.0 percent increase was seen in the nevirapine

regimens, versus a 24.0 percent increase in the efavirenz regimen. Additionally, treatment

with nevirapine resulted in a significantly improved total cholesterol: HDL-cholesterol

ratio, which has been associated with a reduced cardiovascular risk profile in non-HIV

infected individuals.

Participating centres in the UK included: Chelsea and Westminster Hospital, London, North Manchester Hospital, Royal Free Hospital, London, and Royal Sussex County Hospital, Brighton.


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. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 176, 2003.