Safety of nevirapine in pregnancy

Article (PDF Available)inHIV Medicine 8(1):64-9 · February 2007with10 Reads
DOI: 10.1111/j.1468-1293.2007.00433.x · Source: PubMed
Abstract
Nevirapine has been widely used in pregnancy for its efficacy, low pill burden, bioavailability and rapid transplacental transfer. Concern about nevirapine toxicity during pregnancy has emerged over recent years. The aims of the study were to document the frequency of cutaneous and hepatic toxicity secondary to nevirapine use during pregnancy and to compare rates in women starting nevirapine during the current pregnancy with those in women who had commenced nevirapine prior to the current pregnancy. This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997-2003. All HIV-1-infected women who received nevirapine as part of combination antiretroviral therapy (ART) during pregnancy were included in the study. Data on demographics, HIV infection risk, Centers for Disease Control and Prevention (CDC) status, surrogate markers at initiation of therapy, other medications hepatitis B and C virus coinfection and clinical data relating to potential toxicity were collated and analysed. Fifteen of 235 eligible women (6.4%) developed rash and eight (3.4%) developed hepatotoxicity, including four with coexistent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%). Alternative causes of rash/hepatotoxicity were suspected in seven cases and only 10 mothers (5.8%) discontinued nevirapine. Of the 170 women who commenced nevirapine during this pregnancy, 13 (7.6%) developed rash and eight (4.7%) hepatotoxicity, a combined incidence of 10%. Only two of 65 women with nevirapine exposure prior to this pregnancy developed rash (3.1%). Nevirapine-containing ART was well tolerated in this cohort of pregnant women. Although pregnancy did not appear to increase the risk of nevirapine-associated toxicity compared to published adult data, CD(4) count may be less predictive of toxicity in pregnancy.
ORIGINAL RESEARCH
Safety of nevirapine in pregnancy
U Natarajan,
1
A Pym,
2
C McDonald,
3
P Velisetty,
4
SG Edwards,
5
P Hay,
4
J Welch,
3
A de Ruiter,
1
GP Taylor
6
and J Anderson
2
1
Department of Genitourinary Medicine, Guy’s and St Thomas’ NHS Foundation Trust,
2
Centre for the Study of Sexual
Health and HIV, Homerton University NHS Foundation Trust,
3
Department of Sexual Health, Kings College Hospital,
4
Department of Genitourinary Medicine, St. George’s Healthcare NHS Trust,
5
Mortimer Market Centre, University College
Hospital, and
6
Department of GU Medicine & Communicable Diseases, Faculty of Medicine, Imperial College, London, UK
Background
Nevirapine has been widely used in pregnancy for its efficacy, low pill burden, bioavailability and
rapid transplacental transfer. Concern about nevirapine toxicity during pregnancy has emerged over
recent years.
Objectives
The aims of the study were to document the frequency of cutaneous and hepatic toxicity secondary to
nevirapine use during pregnancy and to compare rates in women starting nevirapine during the current
pregnancy with those in women who had commenced nevirapine prior to the current pregnancy.
Design
This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997–2003.
Methods
All HIV-1-infected women who received nevirapine as part of combination antiretroviral therapy
(ART) during pregnancy were included in the study. Data on demographics, HIV infection risk,
Centers for Disease Control and Prevention (CDC) status, surrogate markers at initiation of therapy,
other medications hepatitis B and C virus coinfection and clinical data relating to potential toxicity
were collated and analysed.
Results
Fifteen of 235 eligible women (6.4%) developed rash and eight (3.4%) developed hepatotoxicity,
including four with coexistent rash, giving a combined incidence of 19 potential cases of nevirapine
toxicity during pregnancy (8.1%). Alternative causes of rash/hepatotoxicity were suspected in seven
cases and only 10 mothers (5.8%) discontinued nevirapine. Of the 170 women who commenced
nevirapine during this pregnancy, 13 (7.6%) developed rash and eight (4.7%) hepatotoxicity, a
combined incidence of 10%. Only two of 65 women with nevirapine exposure prior to this
pregnancy developed rash (3.1%).
Conclusions
Nevirapine-containing ART was well tolerated in this cohort of pregnant women. Although
pregnancy did not appear to increase the risk of nevirapine-associated toxicity compared to
published adult data, CD
4
count may be less predictive of toxicity in pregnancy.
Keywords: cutaneous side effects, hepatic side effects, nevirapine, pregnancy
Received: 16 March 2006, accepted 14 September 2006
Introduction
The use of antiretroviral therapy (ART) during preg-
nancy to minimize mother-to-child transmission of
HIV-1 infection is well established [1,2]. Ideally, ART
should be safe for mother and baby, effective and simple.
Nevirapine has been widely used in pregnancy both as
single-dose therapy during labour in resource-restricted
settings and as part of short- and long-term highly active
antiretroviral therapy (HAART). Physiological changes in
pregnancy can significantly alter pharmacokinetics but
nevirapine concentrations during pregnancy have been
Correspondence: Dr U. Natarajan, Department of GU Medicine & HIV, East
Surrey Hospital, Canada Avenue, Redhill RH1 5RH, UK. Tel: 01737 231725;
fax: 01737 231885; email: usharani.natarajan@sash.nhs.uk
HIV Medicine (2007), 8, 64–69
r
2007 British HIV Association
64
found to be comparable to those in nonpregnant adults
[3,4].
Recent safety data on the use of nevirapine in pregnancy
has given rise to concern. In the Paediatric AIDS Clinical
Trials Group 1022 study, five of 17 subjects (29.4%) were
reported to have an adverse event related to nevirapine,
including one fatality from fulminant hepatitis [5].
Furthermore, a number of deaths in pregnancy among
women taking nevirapine-containing ART have been
reported to the Food and Drug Administration [6]. Such
concerns have led to decreased use of nevirapine in
pregnancy in the UK.
The most common side effect associated with nevirapine
is rash [7]. In controlled trials the frequency of rash has
been found to be 14% and Stevens–Johnson syndrome
(SJS) has been estimated to occur in 0.3% of patients [8].
Nevirapine may also cause asymptomatic or severe clinical
hepatitis [9,10].
Skin complaints are common during normal pregnancy
[11,12] and causes include cholestasis, herpes gestationalis,
pruritic urticarial papules and erythema nodosum. Life-
threatening complications of pregnancy such as acute fatty
liver of pregnancy and the haemolysis, elevated liver
enzymes, low platelets (HELLP) syndrome that occur during
the third trimester [13] can potentially be confused with
nevirapine or nucleoside reverse transcriptase inhibitor
(NRTI)-related hepatotoxicity.
Risk factors for nevirapine-related adverse events
include higher CD4 counts at the start of therapy [14]
and female gender [15]. Whether pregnant women are
more susceptible to these adverse events is uncertain, but
pregnant women are more likely to commence ART, even
for short courses, at higher CD4 counts than nonpregnant
women.
The primary objective of this study was to document the
experience of pregnant women in London taking nevir-
apine and to examine the relationships between adverse
events and laboratory parameters, concomitant use of other
therapy, use of alcohol and timing of therapy.
Methods
All pregnant women attending five centres from 1 January
1997 who delivered by 31 December 2003 and who were
taking nevirapine as part of combination ART were
identified retrospectively from HIV/antenatal clinic records.
Women who had a single dose of nevirapine in labour only
(one woman), women whose pregnancies did not continue
into the second trimester as a result of either a spontaneous
miscarriage or medical termination of pregnancy (three
women), and women who were lost to follow up during
pregnancy (four women) were excluded from the study.
Case records and laboratory reports were individually
studied and relevant details collated according to an agreed
proforma. Demographic details, transmission risk group,
Centers for Disease Control and Prevention (CDC) staging,
hepatitis B and C virus coinfection, clinical side effects
potentially related to nevirapine, changes in liver enzymes,
ART history, gestation age at which nevirapine was started,
total duration of nevirapine exposure, CD4 count and
plasma HIV-1 viral load (measured using COBAS, Amplicor
HIV1RNA Version 1.5 Monitor Assay, Roche Diagnostics or
Bayer bDNA HIV-1, according to local practice) at the time
of starting nevirapine and at the closest point to delivery
were recorded. As nevirapine toxicity usually occurs during
the first few months of therapy, we analysed separately
mothers who commenced a nevirapine-containing regimen
during pregnancy (group 1: ‘during’) and those who had
commenced nevirapine before pregnancy (group 2: ‘be-
fore’). In this comparator group, CD4 counts and plasma
HIV-1 viral load measurements in the second trimester and
closest to delivery were recorded.
Hepatotoxicity was defined as aspartate aminotransfer-
ase (AST) or alanine aminotransferase (ALT) 43 times the
upper limit of normal (ULN). Rash was defined as any new
cutaneous abnormality that might be caused by drug
toxicity.
Analysis
The groups were compared using t-tests (continuous
variables) and w
2
tests (categorical variables). It was not
possible to conduct several of the w
2
analyses, as there were
fewer than five cases in more than 20% of the cells. In
addition, CD4 count and log viral load were compared
between those who did and those who did not develop a
rash (t-tests). Analyses were carried out using the Statistics
Package for Social Sciences (SPSS) version 12.0 program.
Results
Two hundred and thirty-five pregnant women met the
inclusion criteria. One hundred and seventy started
nevirapine during the pregnancy, all of whom were
treatment naı
¨
ve except two who switched from nelfinavir
to nevirapine because of nelfinavir-associated side effects
and four who had initially started zidovudine monotherapy
but switched to HAART during the pregnancy (group 1).
Sixty-five commenced nevirapine prior to this pregnancy
(group 2). Group demographic details are shown in Table 1.
All the patients were on nevirapine 200 mg once daily
for 2 weeks, after which the dose was escalated to 200 mg
twice a day. Only two women were exposed to nevirapine
for less than 6 weeks, both of whom were in group 1. Two
Safety of nevirapine in pregnancy 65
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2007 British HIV Association HIV Medicine (2007) 8, 64–69
patients in each group consumed alcohol, but at less than
2 units/week.
Group 1
The outcomes and adverse events are summarized in Table
2. Thirteen patients were documented to have developed a
rash while on nevirapine, but in three cases this was
thought to be caused by cotrimoxazole, which had been
commenced concurrently. These patients had CD4 counts
of 80 cells/mL, 150 cells/mL and ‘not stated’ at the time of
starting nevirapine-based therapy.
Nevirapine was continued, and only cotrimoxazole was
discontinued in all three of these patients. Among the 10
patients in whom the rash was considered to be nevirapine-
associated, four had only a mild rash and continued
nevirapine safely, including two patients concomitantly
taking antituberculosis treatment. In these patients, the rash
was not considered severe enough to stop either treatment
or an association with nevirapine was not confirmed. Six
patients with severe generalized rash discontinued nevir-
apine, including one patient (0.6%) with Stevens Johnson
Syndrome (SJS) who made a full recovery with treatment.
Hepatotoxicity occurred in eight patients within 6 weeks
of starting nevirapine (Table 3). ALT ranged from 161 to
807 IU/L. Six out of the eight patients had grade 3/4 toxicity
(45 times the upper limit of normal), four had a coexistent
rash and all of them stopped nevirapine; they all had a
previously normal ALT measurement and had no evidence
of hepatitis B or C virus infection. All made a full recovery.
One patient, who started nevirapine at 21 weeks,
developed abdominal pain, proteinuria, low platelet levels
and deranged liver enzyme levels. She had evidence of
intrauterine growth retardation (IUGR) and the clinical
features suggested HELLP syndrome. Although her condi-
tion was not thought to be nevirapine-related, nevirapine
Table 1 Demographic and clinical characteristics of the groups
Variable
First exposed
to nevirapine
in current
pregnancy
(
n
5 170)
First exposed
to nevirapine
prior to current
pregnancy
(
n
5 65)
Age (years)
Mean 28.2 31.2
Median 28.4 31.0
Transmission risk group
Heterosexual 165 (97.0) 64 (98.5)
IVDU 5 (3) 1 (1.5)
Ethnic group
Black African 211 (89.8%) 153 (90.0) 58 (89.2)
Black Caribbean 7 (2.9%) 6 (3.5) 1 (1.5)
Caucasian 15 (6.4%) 9 (5.3) 6 (9.2)
Mixed/others 2 (0.9%) 2 (1.2) 0
CDC status
A 170 (79.3%) 136 (80.0) 34 (52.3)
B 33 (14%) 23 (13.5) 10 (15.4)
C 32 (13.6%) 11 (6.5) 21 (32.3)
Nadir CD4 count
Mean (cells/mL) 361 167
Known [n (%)] 184 (78.3%) 142 (83.5) 42 (64.6)
Unknown [n (%)] 51 (21.7%) 28 (16.5) 23 (35.4)
CD4 count at initiation
of nevirapine
Mean (SD) (cells/mL) 276.52 (159.73) 188.98 (152.45)
o 200 cells/mL[n (%)] 80 (34%) 51 (30) 29 (44.6)
200–349 cells/mL[n (%)] 71 (30.2%) 60 (35.3) 11 (16.9)
4 350 cells/mL[n (%)] 48 (20.4%) 42 (24.7) 6 (9.2)
Unknown [n (%)] 36 (15.3%) 17 (10) 19 (29.2)
Viral load at inclusion
Median (copies/mL) 17 400 10 715
Log viral load (log
copies/mL) [mean (SD)]
4.17 (0.82) 3.32 (1.47)
Undetectable (o50
copies/mL) [n (%)]
20 (8.5%) 2 (1.2) 18 (27.7)
Detectable (450
copies/mL) [n (%)]
184 (78.3%) 152 (89.4) 32 (49.2)
Unknown [n (%)] 31 (13.2%) 16 (9.4) 15 (23)
Number of weeks on
nevirapine
Mean 11.5 (n 5 168) 33.4
*
Median 15.0 28.0
Hepatitis coinfection [n (%)] 11 (4.6%)
Hepatitis B 3 (1.8) 1 (1.5)
Hepatitis C 6 (3.5) 1 (1.5)
Results shown in bold are significant at the Po0.05 level (two-tailed) (i.e.
the two groups differed in CDC status, CD4 count and viral load when
starting treatment).
*
Fifty patients conceived on nevirapine, and the reminder recommenced
nevirapine during the pregnancy.
CDC, Centers for Disease Control and Prevention; IVDU, intravenous drug
user; SD, standard deviation.
Table 2 Outcomes and adverse events in the patient groups
Group 1
(‘during’)
(
n
5 170)
Group 2
(‘before’)
(
n
5 65)
CD4 count at delivery
Mean (SD) (cells/mL) 384 (218) 373 (188)
o 200 cells/mL[n (%)] 26 (15.3) 8 (12.3)
200–349 cells/mL[n (%)] 54 (31.8) 20 (30.8)
4 350 cells/mL[n (%)] 81 (47.6) 34 (52.3)
Unknown [n (%)] 9 (5.3) 3 (4.6)
Viral load at delivery
Median (copies/mL; plasma) 49 49
Undetectable (o50 copies/mL) [n (%)] 95 (55.9) 50 (76.9)
Detectable (450 copies/mL) [n (%)] 68 (40) 11 (16.9)
Unknown [n (%)] 7 (4.1) 4 (6.2)
Log viral load [mean (SD)] (log copies/mL) 2.07 (0.73) 1.81 (0.34)
Highest ALT/AST (IU/L)
Mean (SD) 43.8 (104.7) 23.9 (29.5)
Median 20.5 17.0
Developed rash [n (%)] 13 (7.6) 2 (3.1)
Developed hepatotoxicity [n (%)] 8 (4.7) 0
Developed rash and/or hepatotoxicity [n (%)] 17 (10) 2 (3.1)
Developed both rash and hepatotoxicity [n (%)] 4 (2.4) 0
Results shown in bold are significant at the Po0.05 level (two-tailed).
The two groups differed in their viral load at delivery but not in their CD4
count.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; SD,
standard deviation.
66 U Natarajan et al.
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2007 British HIV Association HIV Medicine (2007) 8, 64–69
was stopped in view of raised liver enzymes and she was
delivered by emergency caesarean section at 30 weeks,
following which she made a full recovery.
Group 2
Two out of 65 patients who had commenced nevirapine
prior to their current pregnancy developed rash. One was
on nevirapine for 20 weeks prior to this pregnancy,
continued nevirapine through early pregnancy and devel-
oped a mild rash in her 20th week of pregnancy (after 40
weeks on nevirapine). Her liver enzymes were normal and
the rash resolved spontaneously whilst she continued
nevirapine. The other patient was on nevirapine in her
previous pregnancy for 20 weeks without any side effects
and stopped nevirapine after the previous childbirth.
During the current pregnancy she again started nevirapine
at 16 weeks and developed generalized maculopapular rash
5 weeks later; her liver enzymes were not raised, and she
recovered after stopping nevirapine.
To examine the effect of CD4 count on the development
of nevirapine toxicity, patients in group 1 were analysed
using two separate CD4 count cut-offs, namely 200 and
250 cells/mL. In the analysis with 200 cells/mL as the cut-
off, five of 51 patients (9.8%) developed rash and nine of
102 (8.8%) had rash and/or raised liver enzymes with
counts lower than 200 cells/mL, and seven of 102 patients
(6.8%) had rash and nine of 102 (8.8%) had rash and/or
raised liver enzymes with counts higher than 200 cells/mL.
In the analysis with 250 cells/mL as the cut-off, six of 75
patients (8%) developed rash and seven of 75 (9.3%) had
rash and/or raised liver enzymes with counts below
250 cells/mL and six of 78 patients (7.6%) had rash and
seven of 78 (8.9%) had rash and/or raised liver enzymes
with counts above 250 cells/mL (Table 4). CD4 counts were
not available for three patients who experienced adverse
effects. Similarly, there was no significant difference in
CD4 count or log viral load between those who did and
those who did not develop a rash (CD4 count, P 5 0.14;
viral load, P 5 0.5) or between those who did and those
who did not develop hepatitis (CD4 count, P 5 0.8; viral
load, P 5 0.33).
Table 3 Characteristics of patients with hepatotoxicity
Patient
number
Gestation time
at which
nevirapine was
started (weeks)
CD4 count
at initiation
of nevirapine Rash LFTs
Stopped
nevirapine Clinical features
121 NA No4 3 ULN Yes HELLP abdominal pain, proteinuria, deranged LFTs at 30 weeks, IUGR, emergency LSCS
at 30 weeks
2 22 239 Yes 4 5 ULN Yes Eosinophilia 0.5, poor adherence, viral load 72 000 copies/mL at 30 weeks, switched to
Kaletra
322 209 No4 5 ULN Yes Pruritis, no rash
422 411 Yes4 5 ULN Yes Nevirapine hypersensitivity
5 22 158 Yes 4 5 ULN Yes Nevirapine hypersensitivity
628 332 No4 3 ULN No Developed deranged LFTs, but developed PROM at 34 weeks nevirapine was not stopped
until emergency LSCS at 35 weeks
732 NA No4 5 ULN Yes Intense pruritis and deranged LFTs, but no rash
8 22 288 Yes 4 5 ULN Yes LFTs normalized and rash resolved after stopping nevirapine
HELLP, haemolysis, elevated liver enzymes, low platelets; IUGR, intrauterine growth retardation; LFT, liver function test; LSCS, lower segment caesarean
section; NA, not available; PROM, premature rupture of membranes; ULN, upper limit of normal.
Table 4 Incidence of cutaneous or hepatic events in women
commencing nevirapine-containing antiretroviral therapy during
pregnancy. (a) All hepatic and cutaneous events; (b) events not
attributed to nevirapine
(a)
CD4 count
(cells/lL)
n
Rash
[
n
(%)] v
2
Hepatitis
[
n
(%)] v
2
Rash and/
or hepatitis
[
n
(%)] v
2
o 200 51 5 (9.8) 0.4 1 (1.9) 0.8 5 (9.8) 0.04
4200 102 7 (6.8) 5 (4.9) 9 (8.8)
NA 17 1 (5.9) 2 (11.8) 3 (17.6)
o 250 75 6 (8) 0.005 3 (4) 0.002 7 (9.3) 0.006
4250 78 6 (7.6) 3 (3.8) 7 (8.9)
NA 17 1 (5.9) 2 (11.8) 3 (17.6)
(b)
CD4 count
(cells/lL)
n
Rash
[
n
(%)] v
2
Hepatitis
[
n
(%)] v
2
Rash and/
or hepatitis
[
n
(%)] v
2
o 200 51 2 (3.9) 0 1 (1.9) 0.4 2 (3.9) 0.07
4200 102 4 (3.9) 4 (3.9) 5 (4.9)
NA 17 0 (0) 1 (5.9) 1 (5.9)
o 250 75 3 (4) 0.002 3 (4) 0.24 4 (5.3) 0.2
4250 78 3 (3.8) 2 (2.6) 3 (3.8)
NA 17 0 (0) 1 (5.9) 1 (5.9)
No significant differences were detected. A w
2
value of43.84 would be
required for significance at the 5% level.
NA, XXX.
Safety of nevirapine in pregnancy 67
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2007 British HIV Association HIV Medicine (2007) 8, 64–69
Discussion
In this study of 235 pregnant women, nevirapine was well
tolerated, with a lower rate of adverse events than has
previously been reported. The 6.4% frequency of nevir-
apine-related rash noted in this study is much lower than
the 12–22% usually reported. However, a proportion of
mothers had commenced nevirapine prior to pregnancy,
introducing a bias in this subset towards women who had
come through the early risk period without toxicity.
Exclusion of these women from the analysis did not
significantly change the result, with a rash frequency of
7.6%. Similarly, the rate of nevirapine-associated increase
in transaminases was lower than the previously reported 8–
10% [10]. This may be partly explained by the low rates of
hepatitis B and C virus infection in our cohort. The rates of
hepatitis B and C virus infection were four out of 235
(1.7%) and seven out of 235 (2.9%), respectively. None of
the patients with adverse effects was known to be infected
with either hepatitis B or C virus.
For comparison with other reports, we also analysed all
patients with transaminase levels higher than 1.25 times
the ULN but lower than our cut-off of 3 times the ULN. By
these criteria, a further 12 patients in group 1 (7%) and four
patients in group 2 (6.2%) would have been categorized as
having hepatotoxicity. However, all patients had continued
nevirapine therapy and, given the natural history of
nevirapine toxicity and the similar pattern seen in the
two groups, it seems unlikely that these cases represented
nevirapine hepatotoxicty.
Although the usually accepted cut-off is 250 cells/mL,
higher rates of nevirapine-associated toxicity have been
found in women in the 250–400 cells/mL and 4400 cells/mL
ranges. In view of the fact that physiological haemodilu-
tion occurs in pregnancy, which tends to decrease the CD4
count [16], we reanalysed the data with an arbitrary lower
cut-off of 200 cells/mL. This did not produce any significant
difference in the frequency of adverse events.
The Paediatric AIDS Clinical Trials Group (PACTG) 1022
team [5] has questioned whether pregnancy per se poses an
additional risk for nevirapine-associated hepatic toxicity
beyond the risk associated with female gender. In our
study, a lower than expected incidence of nevirapine-
related adverse events was observed, which suggests that
pregnancy does not predispose to nevirapine toxicity. This
has also been suggested by recent studies from Thailand
[17], Kenya [18] and Brazil [19], none of which found a
high rate of adverse events despite a high proportion of
patients with CD4 counts4250 cells/mL. These studies and
our own data contrast with the very high rate (29.4%)
reported by PACTG 1022. Although it is not possible to
determine the incidence of fulminant hepatic failure and
death associated with continuous nevirapine use in
pregnancy, as the number of pregnant women who have
received nevirapine-containing ART is unknown, certainly
there are more retrospective data to suggest that nevirapine
is safer than suggested by PACTG 1022.
These discrepant results raise the possibility that
ethnicity or other factors contribute significantly to the
risk of toxicity with nevirapine. Of the subjects in PACTG
1022, nine were African American (53%), seven were
Hispanic (41%) and one was white (6%). Only 5% of our
cohort is of Caucasian origin, with 93.5% being of black
African or black Caribbean origin.
Concomitant administration of nevirapine with other
therapies associated with a high incidence of rash was
noted in this study, and these other therapies were thought
to be the cause of the rash in at least five of the 15 patients
(33%). Further, not all cases of nevirapine-associated rash
necessitated discontinuation of therapy.
In summary, these data suggest the following.
Nevirapine, with careful management, remains a useful
component of antiretroviral combination therapy in
pregnancy.
Clinicians need to consider all potential causes of rash
in pregnancy to avoid unnecessarily eliminating nevir-
apine from the patient’s therapeutic options.
Prescribers should try to avoid coinitiation of therapies
with overlapping toxicities.
A CD4 count cut-off of 250 cells/mL may not be
applicable in pregnant women, and, taken together with
similar data from Kenya and Thailand, our data suggest
that toxicity rates may vary with ethnicity and that a
blanket warning to avoid prescription to all women with
CD4 counts of 4250 cells/mL might have been pre-
mature and may have to be reconsidered. It may be
useful to look at more data and the collective
experiences of different workers before a final recom-
mendation is made.
Acknowledgements
The authors thank Jane Clatworthy PhD, Research Fellow,
Behavioural Medicine Research Unit, University of Bright-
on for her help with statistical analysis of the data.
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Safety of nevirapine in pregnancy 69
r
2007 British HIV Association HIV Medicine (2007) 8, 64–69
    • "Author Year ART-naive (N) Region Period Study design TTT Liver (n) Skin (n) Deaths (n) Aaron 30 2010 79 USA 1999 -2005 Retrospective 42 2 6 N/R Coffie 31 2010 125 Cote d'Ivoire 2003 -2006 Prospective 58 5 3 6 Gonzales 32 2004 170 USA 1997 -2003 Retrospective N/R 6 5 0 Hitti 27 2004 17 USA 2003 -2004 Randomised 63 3 1 1 Jamisse 33 2007 146 Mozambique 2004 -2005 Prospective 36 4 4 0 Joy 34 2005 22 USA 2001 -2005 Retrospective 42 3 0 0 Kilewo 35 2009 429 Tanzania 2004 -2006 Prospective N/R 2 7 0 Kondo 4 2007 133 Brazil 2003 -2006 Retrospective 27 2 21 0 Lyons 36 2006 85 Ireland 2000 -2003 Retrospective 32 8 1 2 Marazzi 5 2006 703 Mozambique 2002 -2004 Retrospective 74 46 25 5 Natarajan 28 2007 153 UK 1997 -2003 Retrospective 42 5 6 0 Peters 29 2011 310 Kenya 2003 -2006 Prospective 68 12 16 0 Phanuphak 37 2007 244 Thailand N/R Prospective 42 15 9 0 Van Schalkwyk 38 2008 47 Canada 2001 -2005 Prospective 33 3 1 0 Total 2 663 116 105 14 "
    [Show abstract] [Hide abstract] ABSTRACT: Background. The package insert for nevirapine (NVP) cautions use in HIV-infected women (including pregnant women) with CD4 counts ≥250 cells/µl. However, recent studies showed that the CD4 count of pregnant women receiving antiretroviral therapy (ART) was not predictive of NVP toxicity. Objectives. To determine whether ART-naive pregnant women initiating NVP-based ART at higher CD4 counts experience greater toxicity compared with pregnant women at lower CD4 counts. Methods. We reviewed studies comparing serious adverse NVP-related events among ART-naive pregnant women who commenced therapy at higher v. lower CD4 counts. Relevant studies were extracted from PubMed, SCOPUS and EMBASE, major journals and conference proceedings prior to December 2011. Authors were contacted for additional data. Data were independently extracted and entered into Review Manager. Results. Fourteen studies (2 663 participants) were included for analysis. The odds ratio (OR) for overall NVP toxicity among pregnant women with CD4 <250 cells/µl was 0.61 (95% confidence interval (CI) 0.43 - 0.85). When analysis was restricted to prospective studies only (7 studies, 1 318 participants), the results were consistent for overall NVP toxicity (OR 0.43; 95% CI 0.25 - 0.73) and severe hepatotoxicity (OR 0.45; 95% CI 0.22 - 0.90), but not for severe cutaneous reaction (OR 0.53; 95% CI 0.26 - 1.10). Conclusion. Initiating NVP-based ART during pregnancy at CD4 ≥250 cells/µl increases toxicity risk and should be avoided, necessitating urgent revision of current guidelines supporting this practice.
    Full-text · Article · Nov 2012
    • "Our lower rates of both grade 1+ and grade 3+ LEE are more similar to results reported in studies from Thailand [18], Brazil [19], Mozambique [16] and London [20]. While ethnic differences have been suggested as a possible factor in these discordant findings [20], our study population was very similar to the ethnic composition of the PACTG 1022 study. We observed no maternal deaths in our study of 1229 pregnant women on ART. "
    [Show abstract] [Hide abstract] ABSTRACT: To estimate whether HIV-infected pregnant women were at an increased risk of hepatotoxicity when taking nevirapine (NVP)-containing regimens compared with HIV-infected pregnant women taking antiretroviral therapy (ART) not containing NVP. This analysis included HIV-infected pregnant women on ART from two multicenter, prospective cohorts: the Women and Infants Transmission Study and the International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1025. Multivariate Cox proportional hazards regression models were used to investigate the association between NVP use and hepatotoxicity. NVP use was dichotomized as use or no use and further categorized according to ART exposure history. We investigated two outcomes: any liver enzyme elevation (LEE) (grade 1-4) and severe LEE (grade 3-4). A total of 1229 women with ART use during pregnancy were studied, 218 (17.7%) of whom received NVP. Among the women receiving NVP, 137 (62.8%) were NVP naive. Twenty-nine women (13.3%) who received NVP developed any LEE and one (0.5%) developed severe LEE. Of the 1011 women on non-NVP regimens, 145 (14.3%) developed any LEE and 14 (1.4%) developed severe LEE. There were no maternal deaths. In univariate models, LEE was not significantly associated with CD4 cell count above 250 cells/mul or NVP use. In adjusted multivariate models, no significant increased risk of LEE (any or severe) in women taking NVP was detected as compared to those taking other ART regardless of prior exposure history. We did not observe an increased risk of hepatotoxicity among HIV-infected pregnant women on NVP versus other ART, including women who were ART naive.
    Full-text · Article · Nov 2009
    • "However, it is unclear whether lower concentrations induce virologic failure, increase MTCT, or cause more frequent treatment changes. Complications of pregnancy may resemble adverse effects of antiretrovirals (ARV); for instance, glucose intolerance (common to pregnancy and indinavir), vomiting (pregnancy and several ARV such as lopinavir, ritonavir, zidovudine, tenofovir or lamivudine) and mitochondrial toxicity [possibly increased by pregnancy, and a well recognized side effect of nucleoside reverse transcriptase inhibitors (NRTI), in particular of the combination of didanosine and stavudine]151617181920. In this study, we describe the frequency of virologic failures and treatment changes in pregnant and nonpregnant women and, within the same women, before, during and after pregnancy in the Swiss HIV Cohort Study (SHCS). "
    [Show abstract] [Hide abstract] ABSTRACT: Virologic failure of HIV-positive patients is of special concern during pregnancy. We compared virologic failure and the frequency of treatment changes in pregnant and non-pregnant women of the Swiss HIV Cohort Study. Using data on 372 pregnancies in 324 women we describe antiretroviral therapy during pregnancy. Pregnant women on HAART at conception (n = 131) were matched to 228 non-pregnant women (interindividual comparison) and to a time period of equal length before and after pregnancy (intraindividual comparison). Women starting HAART during pregnancy (n = 145) were compared with 578 non-pregnant women starting HAART. The median age at conception was 31 years, 16% (n = 50) were infected through injecting drug use and the median CD4 cell count was 489 cells/microl. In the majority of pregnancies (n = 220, 59%), women had started ART before conception. When ART was started during pregnancy (n = 145, 39%), it was mainly during the second trimester (n = 100, 69%). Two thirds (n = 26) of 35 women starting in the third trimester were diagnosed with HIV during pregnancy. The risk of virologic failure tended to be lower in pregnant than in non-pregnant women [adjusted odds ratio 0.52 (95% confidence interval 0.25-1.09, P = 0.08)], but was similar in the intraindividual comparison (adjusted odds ratio 1.04, 95% confidence interval 0.48-2.28). Women starting HAART during pregnancy changed the treatment less often than non-pregnant women. Despite the physiological changes occurring during pregnancy, HIV infected pregnant women are not at higher risk of virologic failure.
    Full-text · Article · Dec 2008
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