Nevirapine vs atazanavir/ritonavir in treatment-naive patients: ARTEN study

5 October 2009. Related: Conference reports, Antiretrovirals, IAS 5th Cape Town 2009.

Simon Collins, HIV i-Base

A late breaker poster from Soriano and colleagues presented 48-week results from the ARTEN study. This international non-inferiority trial randomised 569 treatment-naive patients to nevirapine 400mg once-daily (n=188), nevirapine 200mg twice-daily (n=188) or atazanavir/r (300/100mg) once-daily (n=193), all in addition to background tenofovir+FTC. [11]

The lower margin for non-inferiority was -12% and patients were recruited based on with CD4 counts below the upper recommended upper limit (250 and 400 cells/mm³ for women and men respectively).

The primary end-point was suppression to < 50 copies/mL at weeks 48 by Intent-to-treat (ITT) analysis, with a secondary sensitivity analysis looking at time to virological failure (TLOVR).

Baseline demographics and HIV-related characteristics were similar between groups. Mean CD4 and viral load were 183 cells/mm³ and 5.1 log copies/mL, respectively. Although <10% patients had a CD4 count <50 cells/mm³, 64%had viral load >100,000 copies/mL.

In the main analyses, nerirapine was non-inferior to atazanavir/r. For the primary endpoint, by ITT analysis the combined nevirapine groups were non-inferior to atazanavir/r (66.8% vs 65.3%; <50 copies/mL: difference 1.9% [95% CI -5.9% to 9.8%]). Using the TLOVR algorithm, the results were 70% and 74% of NVP and ATZ/r patients, respectively [difference 2.9% (95% CI -10.4% to 4.5%)].

CD4 responses were also similar (+170 vs +185 cells/mm³ in the NVP and ATZ/r groups, respectively).

Although side effects were similar, there were significantly higher discontinuations in the nevirapine arms: 22% in QD, 28% BID and 9% with ATZ/r.

Grade 3/4 events occurred in 12%/5% of NVP and 16%/3% of ATZ/r patients. Rash was reported in 16% of NVP and 12% of ATZ/r patients, but more NVP patients were discontinued due to rash compared with ATZ/r (5% vs 0%). Most nevirapine-associated rashes developed during the lead-in phase, with no Grade 4, SJS or TEN and no deaths due to liver or skin toxicity.

Nevirapine had a better impact on HDL-cholesterol and triglycerides (both p<0.0001) but not for for total cholesterol (p=0.41) or LDL-cholesterol (p<0.011). Overall though, the change in the TC:HDL ratio favoured nevirapine (-0.24 vs +0.13, p=0.0001).

Grade 3/4 increases in liver enzymes occurred in <5% patients but were higher in nevirapine patients, (see Table 1). Although exclusion criteria excluded active HBV or HCV infection, numbers of coinfected patients or response were not reported by this hepatitis status. Only one patient discontinued atazanavir/r due to increased bilirubin.

Table 1: Grade 3/4 liver enzyme elevations at week 48 (%pts)

* only 1 patient discontinued ATZ/r

Comment

It is reassuring that the high virological failure rate observed in smaller studies when nevirapine was used with tenofovir+FTC [12, 13] and which is highlighted in US guidelines [14], was not seen in ARTEN.

The data also support a reduced risk of nevirapine-associated severe reactions when prescribed to patients within the recommended CD4 thresholds. Although no cases were reported of fulminant liver failure, this remains the main reason for reduced use of nevirapine in Western countries.

The results are important, as nevirapine-based regimens remain widely used as first-line therapy, usually with d4T/3TC.

References:

11. Soriano V et al. Prospective comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naive HIV-1 infected patients: ARTEN study week 48 results. 5th IAS 2009, Cape Town. Late breaker poster abstract LBPEB07.
    http://www.ias2009.org/pag/Abstracts.aspx?AID=3709
12. Rey D et al. Early virolgic non-response to once daily combination of lamivudine, tenofovir, and nevirapine in ART-naive HIV-infected patients: preliminary results of the DAUFIN Study. 14th CROI, 2007, Los Angeles. Abstract 503.
    http://www.retroconference.org/2007/Abstracts/29768.htm
13. Lapadula G et al. Risk of early virological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine in antiretroviral therapy–naive HIV-infected patients. Clin Infect Dis 2008 Apr 1; 46:1127.
    http://www.journals.uchicago.edu/doi/full/10.1086/591802#rid_rf2
14. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; 1-139. Table 6, page 38.
    http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf