Maternal Toxicity With Continuous Nevirapine in.2

8/10/2019 Maternal Toxicity With Continuous Nevirapine in.2

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RAPIDCOMMUNICATION

Maternal Toxicity With Continuous Nevirapine in Pregnancy

Results From PACTG 1022

Jane Hitti, MD,* Lisa M. Frenkel, MD,* Alice M. Stek, MD, Sharon A. Nachman, MD,

David Baker, MD, Adolfo Gonzalez-Garcia, MD, Arthur Provisor, MD, Edwin M. Thorpe, MD,

Mary E. Paul, MD,# Marc Foca, MD,** Jorge Gandia, MD, Sharon Huang, MS,

Lee-Jen Wei, PhD, Laura M. Stevens, BS, D. Heather Watts, MD,, and James McNamara, MD

for the PACTG 1022 Study Team

Objective: To compare the safety of nelfinavir and nevirapine-

based antiretroviral treatment in HIV1-infected pregnant women.Methods:In Pediatric AIDS Clinical Trials Group Protocol 1022,38 antiretroviral-naive pregnant women at 1030 weeks gestation

were randomized to nelfinavir or nevirapine with zidovudine plus la-

mivudine. The study was suspended because of greater than expected

toxicity and changes in nevirapine prescribing information. The inci-

dence of treatment-limiting hepatic or cutaneous toxicity was com-

pared between groups for all subjects and for the subset with CD4 cell

counts greater than 250 cells/L at study entry.

Results:Toxicity was seen in 1 (5%) of 21 subjects randomizedto nelfinavir and 5 (29%) of 17 subjects randomized to nevirapine

(P= 0.07). Within the nevirapine group, 1 subject developed fulmi-

nant hepatic failure and died,and another developed Stevens-Johnson

syndrome. The one adverse event associated with nelfinavir occurredin a subject with a CD4 cell count less than 250 cells/L. All 5 events

among subjects with a CD4 cell count greater than 250 cells/L were

associated with nevirapine (P= 0.04).

Conclusions: Continuous nevirapine may be associated with in-

creased toxicity among HIV-1-infected pregnant women with CD4

cell counts greater than 250 cells/L, as has been observed in non-pregnant women.

Key Words:pregnancy, hepatic toxicity, cutaneous toxicity, nelfina-

vir, nevirapine

(J Acquir Immune Defic Syndr2004;36:772776)

Potent antiretroviral therapy is commonly prescribed forpregnant women to reduce maternal viral load and therebyminimize the risk of mother-to-child transmission of HIV-1, as

well as to treat maternal HIV-1 disease when indicated. How-

ever, the relative safety and efficacy of specific antiretroviralmedications have not been well defined in pregnancy. We ini-

tiated a prospective randomized trial, Pediatric AIDS Clinical

Trials Group (PACTG) 1022, to evaluate the safety and effi-

cacy of two frequently prescribed antiretroviral regimens for

HIV-1infected pregnant women. Enrollment into this trial

was suspended after greater than expected toxicity was ob-

served, and in response to changes in nevirapine prescribing

information. The objectives of this report are to compare the

protocol-defined treatment-limiting toxicities associated with

nelfinavir compared with nevirapine, and to explore the asso-

ciation of nevirapine toxicity with initiation of HAART among

women with higher CD4 cell counts.

METHODS

HIV1 infected antiretroviral-naive pregnant women

between 1030 weeks gestation were randomized to either

nelfinavir (1250 mg twice daily) or nevirapine (200 mg once

daily for two weeks and then 200 mg twice daily), which were

administered with zidovudine (300 mg twice daily) plus lam-

ivudine (150 mg twice daily) in an open-label trial design. Eli-

gibility criteriaincluded an HIV-1 viral load greater than 1,000

Received for publication March 31, 2004; accepted May 14, 2004.

From the *University of Washington, Seattle, WA; University of Southern

California, Los Angeles, CA; State University of New York, Stony

Brook, NY; University of Miami, FL; Columbus Regional Healthcare

System, Columbus, GA; University of Tennessee Health Science Center,

Memphis, TN; #Baylor College of Medicine, TX; **Columbia University,

New York, NY; City Hospital of San Juan, Puerto Rico; Harvard

School of Public Health, Boston, MA; FrontierScience and Technology

Research Foundation, Buffalo, NY; and National Institutes of Health,

Bethesda, MD.

This study was supported in part by the Pediatric AIDS Clinical Trials Group

of the National Institute for Allergy and Infectious Diseases, the

Pediatric/Perinatal HIV-1 Clinical TrialsNetwork of the National Institute

of ChildHealthand Development,and theGeneral Clinical Research Cen-

ter Units funded by the National Center for Research Resources. Agouron

Pharmaceuticals: A Pfizer Company, Boehringer-Ingelheim Pharmaceu-

ticals and GlaxoSmithKline Company donated the study medications.

Reprints: Jane Hitti, MD, MPH Department of Obstetrics/Gynecology Uni-

versity of Washington Medical Center, Box 356460 Seattle, WA 98195

(e-mail: jhitt [email protected]).

772 J Acquir Immune Defic Syndr Volume 36, Number 3, July 1 2004


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copies/mL and the intention to continue antiretroviral therapy

after delivery. Prior zidovudine monotherapy, limited to 10 times

the upper limit of normal. Study treatment was stopped for a

confirmed Grade 3 or 4 ALT or AST, any symptoms possibly

consistent with clinical hepatitis at any grade ALT, or rash

accompanied by urticaria, mucous membrane involvement or

constitutional symptoms. Study personnel at each site were

responsible for deciding whether non-specific symptoms were

possibly consistent with clinical hepatitis and merited treat-

ment discontinuation.Enrollment was suspended in August 2003 because of

greater than expected toxicity and changes in nevirapine pre-

scribing information that recommended caution for women

with CD4 cell counts greater than 250 cells/L. These events

led to a previously unscheduled intent-to-treat interim analysis

comparing the incidence of treatment-limiting toxicity by arm,

for all subjects and also for the subset of women with an entry

CD4 cell count greater than 250 cells/L. A 2-tailed Fisher

exact test was used to determine statistical significance.

RESULTS

Twenty-one subjects were randomized to the nelfinavir

arm and 18 subjects to the nevirapine arm for a total of 39subjects. One subject in the nevirapine arm withdrew before

treatment was dispensed. This report includes follow-up data

on the remaining 38 subjects through January 1, 2004. Table 1

summarizes the baseline demographic and clinical character-

istics, which were similar for each treatment group. Of note,

74% of subjects had an entry CD4 cell count greater than

250 cells/L, and all subjects were asymptomatic with respect

to HIV-1. The median length of follow-up as of January 1,

2004 was 38 weeks and was similar between treatment arms.

TABLE 1. Demographic and Clinical Characteristics of the Treatment Groups

Nelfinavir(n = 21)

n (%)

Nevirapine(n = 17)

n (%)

Age (median) 25 28

Race/ethnicity

White 0 (0) 1 (6)

African American 8 (38) 9 (53)

Hispanic 12 (57) 7 (41)

Asian/Pacific Islander 1 (5) 0 (0)

Weeksgestation at entry (median, range) 22 (1530) 20 (1428)

Weeks of follow-up* (median, range) 37 (2079) 41 (672)

Entry viral load (median and range, copies/mL) 7,762 (1,73885,114) 9,772 (3,38867,608)

Entry CD4 count (median and range, cells/L) 324 (30912) 359 (99371)

Entry CD4 > 250 cells/L 14 (67) 14 (82)

Entry CDC** Category A 21 (100) 17 (100)

Entry ALT*** 1.252.5 upper limit of normal 0 (0) 3 (18)

History of Hepatitis B or C 0 (0) 0 (0)

*As of January 1, 2004.**Centers for Disease Control and Prevention.***Alanine aminotransferase.

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2004 Lippincott Williams & Wilkins 773


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Table 2 summarizes the observed toxicity leading to

treatment discontinuation by arm. Treatment-limiting toxicity

was seen in 1 subject on nelfinavir and 5 on nevirapine. The

incidence of treatment-limiting toxicity was 5% (1 of 21) in

the nelfinavir and 29% (5 of 17) in the nevirapine groups

(P= 0.07). Among the subset of participantswithan entryCD4cell count greater than 250 cells/L, 0 of 14 in the nelfinavir

group and 5 (36%) of 14 in the nelfinavir arm had toxicity

leading to treatment discontinuation (P= 0.04). These adverse

events occurred at 6 weeks on nelfinavir and at 226 (median

5) weeks on nevirapine.

Nevirapine-associated treatment-limiting toxicity in-

cluded one subject with Stevens-Johnson syndrome (Table 2,

Subject 2), two subjects with an increase in ALT accompanied

by non-specific symptoms thought by the managing clinicians

to be possibly consistent with clinical hepatitis (Subjects 3 and

4), one subject with Grade 3 ALT without symptoms (Subject

5), and 1 subject withfulminant hepaticfailure and death (Sub-

ject 6). The woman who died was a 33-ye ar-old AfricanAmerican woman, gravida 2 para 1, who began study medica-

tions at 29 weeksgestation. At study entry she had no labora-

tory evidence of hepatitis B or C, a normal ALT (59 U/L), an

AST just above normal limits (49 U/L), and an entry CD4 cell

count of 330 cells/L (22%). Her other medications at study

entry included prenatal vitamins, iron and pseudoephedrine as

needed for sinus congestion. Two weeks later, her ALT and

AST were 34 and 20 U/L, respectively. Four weeks after entry,

shereported a transient facial rash that hadresolved by the time

of her study visit. Her ALT and AST had increased to 177 and

244 U/L. Six days later she presented with nausea, malaise,

and jaundice, and she had an ALT of 1851 U/L and AST of

3288 U/L. She stopped all antiretroviral medications, was ad-

mitted to the hospital and 3 days later had a cesarean delivery

of a viable 34-week male infant. She subsequently developed

multi-system organ failure and died 3 days after delivery. A

post-mortem liver biopsy showed diffuse hepatic necrosis

without steatosis or fibrosis. A full autopsy was not performed.

DISCUSSION

We observed greater than expected toxicity associated

with nevirapine during the first phase of this randomized trial.

All of the adverse events in the nevirapine group occurred

among women with an entry CD4 cell count greater than

250 cells/L. The hepatic necrosis seen on liver biopsy fromthe subject who died is consistent with drug-induced hepatic

toxicity, possibly direct hepatocellular injury or an immunoal-

lergic response.1 The absence of significant hepaticsteatosis at

the time of death, and the onset occurring early after initiation

of HAART makes nucleoside analogueassociated hepatic

steatosis unlikely.

The maternal death observed in this trial is similar to

three other case reports of maternal death on nevirapine/zido-

vudine/lamivudine.2,3 Two additional cases of maternal mor-

tality associated with nevirapine in pregnancy have been

noted, beyond those cited above (Jorge Pinto, Escola de Me-

dicina, Universidade Federal de Minas Gerais, personal com-

munication; Patrick Robinson, Boehringer-Ingelheim Phar-maceuticals, personal communication).

The common features of all 6 cases include fulminant

hepatic failure presenting 45 weeks after starting nevirapine-

based antiretroviral therapy, in antiretroviral-naive subjects

with previously normal ALT and no history of hepatitisB or C.

Four of these 6 cases occurred in women with a baseline CD4

cell count greater than 250 cells/L. Furthermore, in these

cases hepatitis progressed rapidly to hepatic failure and death

despite discontinuation of nevirapine and close clinical and

laboratory monitoring. There is one additional published case

report of severe but non-fatal hepatitis associated with nevi-

rapine in a pregnant woman with an initial CD4 cell count

greater than 600 cells/L.4 These cases are also similar to re-

ports of severe hepatic toxicity among HIV-1negative indi-

viduals receiving nevirapine for post-exposure prophylaxis.5

These observations of hepatic toxicity in pregnancy, in

our study and other published case reports,24 agree with a re-

cent meta-analysis suggesting that non-pregnant women with

TABLE 2.Adverse Events Leading to Treatment Discontinuation

Subject Agent

WeeksGestation

at Entry

Weeks onTreatment

at Onset

EntryCD4 Cell

Count

ALT* (Grade)

DescriptionEntry Onset

1 Nelfinavir 22 6 239 11 (0) 568 (4) Clinical hepatitis

2 Nevirapine 17 2 380 11 (0) 62 (1) Stevens-Johnson syndrome

3 Nevirapine 21 4 606 21 (0) 135 (2) Nausea and vomiting

4 Nevirapine 23 22 259 12 (0) 41 (0) Right upper quadrant pain

5 Nevirapine 19 26 510 60 (1) 311 (3) Asymptomatic

6 Nevirapine 29 5 330 59 (0) 1851 (4) Fulminant hepatic failure and death

*Alanine aminotransferase, U/L

Hitti et al J Acquir Immune Defic Syndr Volume 36, Number 3, July 1 2004

774 2004 Lippincott Williams & Wilkins


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CD4 cell counts greater than 250 cells/L who receive continu-

ous nevirapine are at increased risk for hepatic toxicity6 in-

cluding fulminant hepatic failure and death. Men with higher

CD4 cell counts are also at increased risk for hepatic toxicity,

but at a greater CD4 threshold (400 cells/L) compared with

women. Thus, there appears to be an interaction between gen-der and immunologic status as risk factors for rash-associated

hepatic toxicity with continuous nevirapine. While the exact

mechanism for nevirapine-associated hepatic toxicity is not

understood, an immune-mediated hypersensitivity component

is postulated.

It is difficult to estimate the true incidences of treatment-

limiting toxicity and fulminant hepatic failure associated with

continuous nevirapine use in pregnancy. At present, there are

no reliable mechanisms to consistently identify and tabulate

severe but non-fatal toxicity associated with antiretroviral

therapy in pregnancy occurring outside of the context of a

clinical trial. Thus, it is unknown whether pregnancy poses an

additional risk for nevirapine-associated hepatic toxicity be-yond the risk associated with female gender. It is also not pos-

sible to determine the incidence of fulminant hepatic failure

and death associated with continuous nevirapine use in preg-

nancy, because the number of pregnant women who have re-

ceived nevirapine-containing antiretroviral therapy is unknown.

The data from this and other reports24,6 should not be

extrapolated to the use of single-dose intrapartum nevirapine

to prevent mother-to-child HIV-1 transmission. In three large

randomized trials, over 1,600 pregnant women received a

single intrapartum dose of nevirapine without any increase in

maternal toxicity.79 Similarly, this report does not imply that

women who initiate nevirapine and tolerate it well should then

discontinue nevirapine if they experience immune reconstitu-

tion. There is no evidence to suggest that immune reconstitu-

tion increases the risk of nevirapine-associated toxicity, re-

gardless of pregnancy status. It is also not known whether

antiretroviral-experienced women with immune reconstitution

who switch to a nevirapine-containing regimen would have an

increased risk of hepatic toxicity.

The major limitation of this study is its small sample

size, which could lead to an overestimate of the incidence of

hepatic toxicity associated with nevirapine during pregnancy.

It is possible that the increased incidence of nevirapine-

associated hepatic adverse events observed in this trial will not

be confirmed in larger data sets. In addition, since the majorityof subjects in both treatment arms were asymptomatic and had

CD4 cell counts greater than 250 cells/L, this study does not

prov ide information abou t nevirapine-associated toxicity

among pregnant women with more advanced HIV-1 disease

and lower CD4 cell counts. However, the toxicities observed

thus far in this small randomized trial may be clinically rel-

evant even though the sample size is small. The single case

of fulminant hepatic toxicity leading to death in our study,

together with similar published case reports involving other

pregnant women2,3 raise concern about the safety of continu-

ous nevirapine in pregnancy in women with CD4 cell counts

greater than 250 cells/L. Since these observations agree with

much larger data sets from non-pregnant women, it would

seem prudent to be cautious in the useof continuous nevirapine

in pregnant women with CD4 greater than 250 cells/L. Thesafety of nevirapine-containing antiretroviral regimens

for pregnant women with lower CD4 cell counts deserves

additional investigation, especially since continuous nevirap-

ine-containing antiretroviral treatment is rapidly becoming a

first-line regimen for pregnant women in resource-limited

countries.

ACKNOWLEDGMENTS

The following individuals assisted with conducting

PACTG 1022: Ana Melendrez, RN, Michael Neely, MD and

James Homans, MD, University of Southern California,

Los Angeles; Jennifer Griffin, RN, Deborah Hattenback, RNand Sylvia Muniz, State University of New York, Stony

Brook; Dawn Barnes, RN and Anita Whitten, RN, Columbus

Regional Healthcare System; Robert Pass, MD and Terry

Byars, MD, University of Alabama; Chivon D. Jackson, RN,

Christine M. Owen, RN and Valencia Y. Johnson, RN, Baylor

College of Medicine; Alice Higgins, RN and Philip LaRussa,

MD, Columbia University; Midnela Acevedo, MD, Elvia Prez-

Hernndez, MPH and Antonio Rodriguez-Mimoso, MD, City

Hospital at San Juan; Nina Sublette, RN, Pat Flynn, MD, Jill

Utech, RN and Mary Dillard, RN, University of Tennessee

Health Science Center; Deborah Goldman, ARNP, Michele

Acker, ARNP and Kathey Mohan, ARNP, University of Wash-

ington; Joseph Mrus, MD, Patricia Kohler, RN and MichelleSaemann, RN, University of Cincinnati; Margaret A. Keller,

MD, Marie Beall, MD and Judy Hayes, RN, University of

California, Los Angeles; Kathy Kabot, Paula Karnick, Gloria

Seals and Charles Lampley, Mount Sinai Hospital; Andrew D.

Hull, MD, Patricia Franklin, FNP, Mary Caffery, RN and Ste-

phen A. Spector, MD, University of California, San Diego;

Patricia Strock, PA, Jhoanna Roa, MD, Patricia Houston-Yu,

MS and Sohail Rana, MD, Howard University; Saroj Bakshi,

MD, Murli Purswani, MD, Marilyn Crane, CNM and Mavis

Dummitt, RN, Bronx-Lebanon Hospital.

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