Nevirapine versus efavirenz in 742 patients: no link of liver toxicity with
female sex, and a baseline CD4 cell count greater than 250 cells/μl
[Research Letters]

AIDS: Volume 20(17) 14 November 2006 p 2233-2236

Manfredi, Roberto; Calza, Leonardo
Department of Clinical and Experimental Medicine, Division of Infectious
Diseases, 'Alma Mater Studiorum' University of Bologna, S. Orsola-Malpighi
Hospital, Bologna, Italy

Abstract
Recent studies have reported increased nevirapine hepatotoxicity in female
patients with CD4 lymphocyte counts greater than 250 cells/μl (especially
pregnant women). However, our open-label comparison of 742 patients treated with
either nevirapine or efavirenz-based HAART as naive patients, experienced
subjects, or patients on salvage therapy, found no increased hepatotoxicity in
nevirapine-treated subjects, in particular with regard to both sex (females
versus males) and T-cell-mediated immunodeficiency (CD4 cell counts above versus
below 250 cells/μl).

A broad spectrum of mechanisms may sustain HAART hepatotoxicity. Non-nucleoside
reverse transcriptase inhibitors (NNRTI) is an easy class to explore, because it
includes two major compounds (nevirapine and efavirenz) that share genotypic
crossreaction, so that a previous failure with one component precludes the use
of the second derivative [1]. Although several studies have not shown remarkable
differences in major efficacy parameters compared with efavirenz [2-5], since
2002 efavirenz has retained its recommendation in antiretroviral-naive patients
as a result of its superior intrinsic activity [1,3,4], whereas nevirapine is
often suggested as a part of switch, simplification, or de-intensification
regimens in patients who have achieved sustained viral suppression and complete
immune reconstitution [1], but have suffered from adverse events or excessive
pill burden [1,3,6-8], as well as a component of rescue treatments [3]. All
these issues, together with convenient administration and a favourable
pharmacoeconomic profile (as represented by a 57.12% lower cost compared with
efavirenz, and even more difference compared with protease inhibitors) [9], are
valid reasons for the continued, extensive use of nevirapine in daily clinical
practice, just when a retrieved immune recovery is almost the rule, and the
female sex is increasingly represented in treated HIV-infected patients [3,8].
Since early 2005 some reports conducted on limited patient series showed
increased hepatotoxicity in pregnant women with CD4 cell counts greater than 250
cells/μl. Such reports were accompanied by a specific US Food and Drug
Administration advisory issued in January 2005 [10], which underlined and
apparently enlarged '… warnings against ongoing nevirapine treatment in women
with a CD4 count over 250, due to a greatly increased risk of serious liver
toxicity. The warnings do not apply to single-dose nevirapine, which does not
cause this problem'. This last statement does not seem to be well substantiated,
because most studies were conducted on pregnant women [11,12] (whereas the
advisory included all women, regardless of pregnancy) [10]. It was stated that
single-dose nevirapine was less toxic than twice daily administration, whereas
the large 2NN study demonstrated a slightly increased toxicity just for
once-daily administration [2], other non-comparative surveys failed in obtaining
reduced hepatotoxicity with once-daily nevirapine [4]. A very recent Cochrane
review showed a possible increased toxicity with once-daily nevirapine [5], and
pharmacokinetic studies also demonstrated greater Cmin/Cmax nevirapine levels
during once daily administration [13]. A large retrospective study in 2006,
conducted on 197 pregnant women exposed to nevirapine for 7 days or longer,
demonstrated a 5.6% overall toxicity rate, no fatalities, and especially no
serious hepatotoxicity, except one case of grade 4 cholestasis (attributable to
underlying conditions) [14]. In the meantime, some authors detected
unpredictable serum nevirapine concentrations, which could be responsible for
adverse events (including hepatotoxicity) in selected patients [13,15].

In our open-label experience, conducted in over 1000 patients treated with HAART
for 12 months or longer, the hepatotoxicity pattern of both NNRTI was assessed
on the basis of three different backgrounds (as previously described) [7,16]:
antiretroviral-naive patients, starting NNRTI-based HAART; subjects experienced
with two to 10 therapeutic lines (but still NNRTI naive); and patients who added
an NNRTI only on late rescue therapies containing four or more different
anti-HIV drugs (and always including at least one protease inhibitor). Only
patients with nevirapine administered at a dose of 200 mg twice a day were
considered. Of 846 overall patients matching these characteristics, 64 were
excluded as a result of less than 90% adherence levels (as assessed by patients'
declarations and direct drug distribution accountability at our centre), 31 were
excluded because of subsequent efavirenz-nevirapine use, and nine patients were
excluded because they took once-daily nevirapine. Pregnant patients were not
admitted to the present study, because the use of efavirenz is not allowed. Of
742 evaluable subjects, 346 consecutive patients treated with nevirapine were
compared with 396 patients who took efavirenz, by a 12-36-month
univariate-multivariate analysis of serum liver abnormalities, on the grounds of
a spectrum of epidemiological, clinical, and laboratory parameters. Instead of
normal laboratory levels, we referred to the baseline value of each enrolled
patient. The two study groups were comparable with regard to the main
demographic-epidemiological features and clinical stage of HIV disease, whereas
a lower CD4 lymphocyte count was found in patients who started efavirenz (P <
0.00001), as well as greater HIV viraemia (P < 0.001). The last difference
concerned only the 93 antiretroviral-naive patients. Moreover, no differences
occurred as to the type-duration of eventual previous anti-HIV therapy, the
frequency-length of treatment with protease inhibitors or antitubercular
therapy, eventual co-infection with hepatitis C/B/D viruses, or other chronic
hepatobiliary-pancreatic disorders (biliary gallstones, cholecystitis,
pancreatitis), and alcohol-drug abuse or methadone administration. A twofold or
greater increase in serum transaminase levels compared with baseline was
significantly linked to the use of nevirapine compared with efavirenz (P <
0.00001). The time to peak transaminase alterations was shorter in the
nevirapine group (P < 0.00001), and hepatotoxicity represented the main
determinant of discontinuation in 20 nevirapine patients, compared with five
efavirenz subjects (P < 0.001; Table 1). More frequent alterations were also
detected for serum bilirubin (P = 0.05), gamma glutamyl transferase (P <
0.0004), alkaline phosphatase (P = 0.003), and albumin levels (P = 0.05) in the
nevirapine compared with the efavirenz group (data not shown). All differences
were carefully controlled for each available variable: a link between the
frequency of hepatotoxicity, time to peak transaminases, and NNRTI withdrawal
was disclosed for concurrent hepatitis C/B/D virus infection plus chronic
hepatobiliary-pancreatic disorders only at logistic regression multivariate
analysis (P < 0.03). In particular, when stratifying patients by sex and an
initial CD4 cell count greater than 250 cells/μl, no significant difference
emerged among patients taking either nevirapine or efavirenz, even after
controlling for all other variables. Finally, no differences were found when
analysing the three patient groups at enrolment (the 93 antiretroviral-naive
subjects, the 503 subjects treated with two to 10 lines, and the 146 patients on
four or more drugs, but NNRTI naive, data not shown).

Nevirapine-containing HAART remains more hepatotoxic than efavirenz-based
regimens [6,7,16], and a key role may be played by underlying chronic viral
hepatitis and hepatobiliary-pancreatic disorders, as previously demonstrated
[17]. As demonstrated in our study conducted on 742 patients who received an
NNRTI for the first time in different baseline conditions, female sex and a CD4
lymphocyte count greater than 250 cells/μl do not prompt any adjunctive risk of
hepatotoxicity. In the meantime, recent studies have also underlined the
long-term efficacy-safety profile of nevirapine [4,8]. In a multicentre
experience that recruited 613 patients treated with nevirapine for 2 years or
more (median follow-up 43 months) [4], fivefold or greater increases in
transaminase levels were observed in less than 2% of cases, whereas viral
suppression was achieved in approximately 75% of patients (including naive
patients, failing subjects, and those switching for toxicity). In their 2006
Cochrane revision, Siegfried et al. [5] assessed nevirapine-based regimens as
providing favourable efficacy and durability, associated with a low adverse
event profile and potential for drug-drug interactions. In both published series
[4,5], approximately 40% of patients were women, and no significant difference
with regard to toxicity or efficacy was found compared with efavirenz-treated
patients [5].

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