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2NN: compares nevirapine & efavirenz
Reported by Jules Levin
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At this morning's final session on "Clinical trials and Cohorts" results from several trials were reported. The results from 2NN have been highly anticipated, which compares prospectively nevirapine once daily, nevirapine twice daily, efavirenz, and the NNRTI double combination of nevirapine plus efavirenz. The study results from 2NN are for 48 weeks of following patients. All study participants also received d4T and 3TC. This is an international study in 17 countries at 65 study centers and was sponsored by Boerhinger Ingleheim. Also at this morning's session were studies on the new formulation of amprenavir called "908" compared to nelfinavir, the new protease for resistance tipranavir, and a comparison of 908 once or twice daily boosted by small dose ritonavir vs Kaletra. This report just covers 2NN. Beside the potency of a regiman when deciding which regimen to use other considerations include resistance (not reported in this study yet) and side effects & toxicities as it relates to the individual patients.
Here is brief synopsis. If you look below to the table reporting Treatment Success you will see a 5 percentage point benefit for efavirenz vs nevirapine (62% vs 56%), but this difference is not statistically significant.
Overall the virologic effectiveness of nevirapine was
comparable to efavirenz, as there appeared to be no significant statistical
differences when using the protocol defined paramater called "treatment
failure and success". As well, when comparing virologic success there was no
significant difference. When examining response to therapy by patients with
>100,000 copies/ml efavirenz trended to be more effective (61% vs 53 and
51%), although there was no mention as to whether this difference was
significant or not. Grade 3/4 hepatoxicity was more common in the nevirapine
patients with 2.1% of patients receiving NVP twice daily and 1.4% of those
receiving NVP once daily experiencing at least 1 grade 3/4 event compared to
0.3% in patients receiving efavirenz. Patients receiving efavirenz had a rate
of 4.5% of experiencing grade 3/4 lab abnormalities in liver function tests
(AST/ALT >5 times the upper limit of normal), compared to 7.8% for patients
receiving nevirapine twice daily and 13.2% for patients receiving nevirapine
once daily. Patients experiencing skin rash was 1.8% in the efavirenz group
and 3.1% in the nevirapine once daily group and 4.1% in the nevirapine twice
daily group. CNS/psychiatric (sleep disturbance, abnormal dreams, and
anxiety) grade 3/4 events were more common in the efavirenz patients, 5.5%
compared to 3.6% in the nevirapine twice daily group and 1.4% in the
nevirapine once daily group; and 7.7% in the double NNRTI group (EFV+NVP).
Overall the percent of patients experiencing at least 1 grade 3/4 event was
equivalent in the NVP once daily, NVP twice daily, and EFV groups; the
percent of patients discontinuing due to any adverse event was 15.5% in the
EFV patients and 21.2% in the NVP twice daily group and 24.1% in the NVP once
daily group. The double NNRTI group did not perform as well in these
categories, experiencing more grade 3/4 adverse events and discontinuing
therapy more often due to these adverse events. There were two deaths
attributed to NVP. One woman with toxic hepatitis who did not have hepatitis
coinfection. And a second person with Stevens Johnson Syndrome (severe skin
rash) and sepsis. Regarding lipid effects there were marginally better
effects on triglycerides, cholesterol and Chol./HDL ratio for the NVP arm and
worse for the double NNRTI arm.
In sum. Regarding side effects and toxicities this study demonstrated worse
hepatitis and skin related events for patients receiving nevirapine, and
worse CNS/psychiatric related events for patients receiving efavirenz. There
were 2 deaths related to nevirapine hepatitis and rash. And more patients
discontinued from nevirapine due to grade 3/4 events compared to efavirenz.
The use of the double NNRTI regimen was associated with more side effects,
toxicities, and discontinuations rates compared to the nevirapine and efavir
enz regimens.
Here are the results presented by Joep Lange for the study team. 1216 treatment-naive patients were randomized to:
--nevirapine (NVP) 400 mg once daily (qd), n=220
--NVP 200 mg twice daily (bid), n=387
--efavirenz (EFV) 600 mg qd, n=400
--NVP+EFV 400/800 mg qd, n=209
--nuke backbone of d4T+3TC
Inclusion criteria were any CD4 count, HIV viral load >5000, any stage of CDC-classification of HIV/AIDS. The following definition of treatment failure at week 48 was used (primary outcome of study):
--less than 1 log decline in viral load in first 12 weeks
--2 consecutive viral load tests >50 copies/ml from week 24 onwards
--new CDC-C event or death
--change of allocated treatment
The baseline characteristics of the patients were relatively comparable in all study groups: 63% men, 34 yrs old, 190 CD4s, 4.7 log viral load (50,000 copies/ml), 21% CDC-class C, 5.3% had hepatitis B, and 9.5% had hepatitis C.
RESULTS
Treatment success:
--56.4% in NVP qd
--56.3% in NVP bid
--62% in EFV
--46.9% NVP+EFV
Percent with virologic success:
--NVP qd 65%
--NVP bid 63.6%
--EFV 67.8%
--NVP+EFV 61.7%
Virologic success for patients with baseline viral load >100,000 copies/ml:
--NVP qd 51.5%
--NVP bid 53.7%
--EFV 61%
--NVP+EFV 57.1%
Virologic success for patients with baseline viral load <100,000 copies/ml:
--NVP qd 71.1%
--NVP bid 68.2%
--EFV 71.1%
% <50 copies/ml (ITT):
--NVP qd 70%
--NVP bid 65.4%
--EFV 70%
--NVP+EFV 62.7%
Grade 3/4 clinical adverse events:
Hepatotoxicity-
--NVP qd 1.4%
--NVP bid 2.1%
--EFV 0.3%
--NVP+EFV 1.0%
Cutaneous Rash:
--NVP qd 4.1%
--NVP bid 3.1%
--EFV 1.8%
--NVP+EFV 3.8%
CNS/Psychiatric:
--NVP qd 1.4%
--NVP bd 3.5%
--EFV 5.5%
--NVP+EFV 7.7%
For anxiety, depression, and insomnia/abnormal dreams the incidence was 1.0 to 1.5% in the EFV group, 0 to 0.3% in the NVP groups and 0.5 to 2.4% in the NVP+EFV group.
Total % of patients experiencing grade 3/4 adverse events:
--NVP qd 15%
--NVP bd 20.4%
--EFV 18%
--NVP+EFV 24.4%
Total % of patients discontinuing due to any adverse event
--NVP qd 24.1%
--NVP bd 21.2%
--EFV 15.5%
--NVP+EFV 29%
Hepatobillary lab toxicity (elevated AST & ALT):
--NVP qd 13%
--NVP bd 7.8%
--EFV 4.5%
--NVP+EFV 8.6%
Non-hepatobillary lab toxicity*:
--NVP qd 8.2%
--NVP bd 3.9%
--EFV 8.8%
--NVP+EFV 9.6%
*These differences are not reported to be significant and neither are the differences regarding neutropenia, amylase, triglycerides, and alkaline phosphatase which ranged in incidence from 0.5% to about 5% in the EFV and NVP groups.
Deaths
There were 25 deaths during the study and 2 were attributed to NVP:
--female from Argentina with toxic hepatitis without evidence of hepatic co-infection
--Steven's Johnson Syndrome from S Africa. Died of MRSA septicaemia while recovering in hospital
--1 death attributed to d4T use: lactic acidosis
--11 deaths related to HIV
--11 deaths non-treatment and non-HIV related: none of the suicides were attributed to use of study medication
Changes in Lipids:
--both NVP only arms, compared to EFV had larger increases in HDL cholesterol
(0.37 vs 0.24 mmol)
--and larger decrease in total cholesterol:HDL-chol ratio: -0.36 vs 0.004), non-significant
The lipid sub-study was presented separately in a poster.
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