Escolar Documentos
Profissional Documentos
Cultura Documentos
Review Article
Drug Therapy
A L A S T A I R J . J . W O O D , M. D. , Editor
M ANAGEMENT OF H UMAN
I MMUNODEFICIENCY V IRUS
I NFECTION IN P REGNANCY
D. HEATHER WATTS, M.D.
Antepartum care
History: symptoms; duration of HIV infection; hospitalizations for therapy; immunizations
Physical examination: ophthalmologic examination if <50 CD4+ lymphocytes/mm3
Additional laboratory testing: TB skin testing; Toxoplasma gondii, cytomegalovirus, and hepatitis C antibody status if unknown; renal- and
liver-function testing; lymphocyte subgroups; plasma HIV RNA level
Counseling: effect of pregnancy on HIV; effect of HIV on pregnancy
perinatal transmission, therapy, mode of delivery
Intrapartum care
Therapy: intravenous zidovudine; continuation of other antiretroviral
agents
Obstetrical management: avoidance of invasive monitoring, use of instruments to assist delivery, and a prolonged interval between rupture
of membranes and delivery
Postpartum care
Woman: continuation or discontinuation of therapy; psychosocial support; no breast-feeding; contraception
Infant: zidovudine for 6 wk with or without other antiretroviral agents;
initiation of PCP prophylaxis at 46 wk; determination of HIV-infection status with testing at 12 days, 2 wk, 12 mo, and 36 mo of age
*TB denotes tuberculosis, and PCP Pneumocystis carinii pneumonia.
N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org 1879
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
MATERNAL REGIMEN
AND
OUTCOMES
BIRTH WEIGHT
<2500 g
GESTATIONAL
AGE
mean
16
12
39 wk
40 wk
OF
PREGNANCY.*
COMMENTS
14
230
232
<37 wk (%)
452
112
17
13
NA
NA
NA
NA
14
17
35
31
427
70
14
11
17
19
15
European Collaborative Study and Swiss Mother and Child HIV Cohort Study16
No therapy
2819
NA
16
OR for preterm birth, 1.8 (95% CI, 1.1
Monotherapy
555
NA
17
2.9) for combination without PI and 2.6
Combination without PI
188
NA
22
(95% CI, 1.44.8) for combination with
Combination with PI
101
NA
29
PI, as compared with no therapy
Women and Infants Transmission Study17
Zidovudine only
685
Combination without PI
184
Combination with PI
247
19
15
17
17
19
17
*Combination therapy without a protease inhibitor (PI) included two or more nucleoside reverse-transcriptase inhibitors with or without a nonnucleoside reverse-transcriptase inhibitor. Combination therapy with protease inhibitor included two or more nucleoside reverse-transcriptase inhibitors with one or more protease inhibitors. PACTG denotes
Pediatric AIDS Clinical Trials Group, OR odds ratio, and CI confidence interval.
Regimen included oral zidovudine during pregnancy, intravenous zidovudine during labor, and a six-week regimen
of oral zidovudine for the infant.
Odds ratios were adjusted for use or nonuse of opiates, clinical stage of HIV disease, and use or nonuse of cesarean
section.
Odds ratios were adjusted for the CD4+ count and use or nonuse of illicit drugs.
1880 N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
D R UG TH ER A PY
TABLE 3. USE
DRUG
FDA PREGNANCY
CATEGORY
OF
ANTIRETROVIRAL DRUGS
ISSUES OF CONCERN
HUMAN PREGNANCY
Nelfinavir
Amprenavir
Lopinavir
Other
Hydroxyurea
PREGNANCY.*
RECOMMENDED USE
DURING PREGNANCY
IN
DURING
*Information is from the Centers for Disease Control and Prevention,18,19 the Physicians Desk Reference,20 Bersoff-Matcha et al.,21 and the interim report
of the Antiretroviral Pregnancy Registry.22 The Food and Drug Administration (FDA) categories are as follows: A, adequate and well-controlled studies
involving pregnant women failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during the later
trimesters); B, reproduction studies in animals failed to demonstrate a risk to the fetus, and adequate and well-controlled studies involving pregnant women
have not been conducted; C, safety in human pregnancy has not been determined, studies in animals are either positive for fetal risk or have not been
conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus; D, there is positive evidence of human
fetal risk in the form of data regarding adverse reactions from investigational or marketing experiences, but the potential benefits from the use of the drug
in pregnant women may be acceptable despite its potential risks; X, studies in animals or reports of adverse reactions have indicated that the risk associated
with the use of the drug for pregnant women clearly outweighs any possible benefit. HAART denotes highly active antiretroviral therapy, NRTI nucleoside
reverse transcriptase inhibitor, and PI protease inhibitor.
N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org 1881
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
A number of studies have examined the use of antiretroviral drugs during the perinatal period. These
studies are described in the Appendix, and their designs and results are summarized in Table 4.5,14-17,23-26
The results of additional trials of short courses of antiretroviral drugs for the prevention of perinatal transmission of HIV-1 are summarized in Figure 1.
Nucleoside Reverse-Transcriptase Inhibitors
PACTG 076
14
PACTG 185
13
OF
PERINATAL TRANSMISSION
OF
HIV
AND
ANTIRETROVIRAL USE
DESIGN
STUDY QUESTION
Randomized, double-blind,
placebo-controlled
Randomized, double-blind,
placebo-controlled
PACTG 31624
Randomized, double-blind,
placebo-controlled
Observational cohort
Observational cohort
Observational cohort
Observational cohort
What clinical and virologic factors are associated with a reduced or increased risk of
perinatal transmission of HIV-1?
PETRA26
Four-group, randomized,
double-blind, placebocontrolled
DURING
PREGNANCY.*
OUTCOME
*PACTG denotes Pediatric AIDS Clinical Trials Group, HIV-1 human immunodeficiency virus type 1, HAART highly active antiretroviral therapy, and
PETRA Perinatal Transmission trial.
1882 N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
D RUG TH ER A PY
Duration of
Antiretroviral Therapy
PACTG 076
Thai Short
Thai 4-Group
PACTG 316
Ivory Coast
Before delivery
During labor
After delivery
PETRA
HIVNET 012
SAINT
N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org 1883
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Data on use of nonnucleoside reverse-transcriptase inhibitors during pregnancy are limited, but nevirapine and efavirenz readily cross the placenta in
primates.18 Use of efavirenz in the early stages of
pregnancy is not recommended because birth defects
(anencephaly, anophthalmia, or cleft palate) occurred
in 3 of 20 monkeys (15 percent) born after exposure
during the first trimester of pregnancy.18 However,
use during the later stages of pregnancy may be considered for women in whom other regimens have
failed. Delavirdine at high doses has been associated
with heart defects in rodents and should therefore,
like efavirenz, be used only during the later stages of
pregnancy. Nevirapine is the nonnucleoside reversetranscriptase inhibitor that has been used most commonly during pregnancy, primarily close to the time
of delivery.24,31
The most common toxic effect of nonnucleoside
reverse-transcriptase inhibitors is rash. Nevirapine-
Protease inhibitors are increasingly being used during pregnancy.17,47 There appears to be minimal transplacental passage in humans.48 No specific teratogenic
effects have been noted in animals. Optimal dosing of
protease inhibitors during pregnancy remains under
study. Lower serum concentrations of protease inhibitors have been observed in pregnant patients than
in nonpregnant patients, although in most cases, the
HIV RNA levels in pregnant women have been suppressed.49,50 The toxic effects among pregnant women appear to be similar to those among nonpregnant
women. There are insufficient data to support the recommendation of a specific protease inhibitor during
pregnancy, although nelfinavir has been used most
commonly.22
INDICATIONS FOR ANTIRETROVIRAL
THERAPY DURING PREGNANCY
Guidelines for the treatment of HIV infection during pregnancy have increasingly diverged from the
general guidelines for HIV treatment: a less aggressive
strategy has evolved for the management of HIV infection in pregnant women, although it is important to
reduce maternal HIV RNA levels in order to decrease
the risk of perinatal transmission. Although therapy is
recommended for nonpregnant persons with a CD4+
lymphocyte count below 350 per cubic millimeter or
an HIV RNA level above 55,000 copies per millimeter,51 antiretroviral therapy should be offered to all
HIV-infected pregnant women in order to reduce
the risk of perinatal transmission.18 This recommendation is based on the consistent findings that the risk
of perinatal transmission increases with increasing maternal HIV RNA levels,52,53 that transmission rates
are below 2 percent among women receiving highly
active antiretroviral therapy,17,54 and that the use of
multiple agents minimizes the potential for the development of resistance.51 Scheduled cesarean delivery is recommended for HIV-infected women with
HIV RNA levels above 1000 copies per milliliter,55
but highly active antiretroviral therapy may decrease
the need for cesarean delivery.
Zidovudine monotherapy was the first regimen
shown to reduce the rate of perinatal transmission of
HIV type 1 (HIV-1).14 Subsequent trials have documented reductions in transmission with shorter courses of zidovudine, intrapartum and neonatal treatment
with nevirapine, and treatment with zidovudine
lamivudine (Fig. 1).24,26,27-32,56-58 However, the lowest
transmission rates have been observed in cohorts re-
1884 N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
D RUG TH ER A PY
Drug Resistance
Whether pregnancy is a specific indication for resistance testing remains controversial. The guidelines
of the Public Health Service for perinatal treatment
recommend that resistance testing be performed for
the same indications in pregnant women as in nonpregnant adults specifically, acute infection, viral
rebound, or persistent viremia in a patient receiving
a highly active antiretroviral regimen.18 Other groups
recommend that resistance testing be performed in
all pregnant women with detectable HIV RNA levels,
even if they have not been treated, in order to maximize the response to antiretroviral drugs, although
there are no data available to demonstrate that resistance testing leads to improvement in outcomes for
mothers or infants.63,64
The prevalence of resistance mutations in pregnant women varies. No resistance to zidovudine was
detected at base line among women in PACTG 076,
all of whom had CD4+ lymphocyte counts above
200 per cubic millimeter and most of whom had not
received antiretroviral drugs.62 Conversely, a zidovudine-resistance mutation developed in 25 percent of
the women in the Women and Infants Transmission
Study who were receiving zidovudine for their own
health, and high-level resistance to zidovudine was
detected in 10 percent of 142 isolates.65 Mutations
in codon 215, which are associated with high-level
resistance to zidovudine, were detected in 9.6 percent
of 62 consecutive women in the Swiss Collaborative
HIV and Pregnancy Study.66 No such mutations developed in the 33 women in a New York cohort who
delivered before 1997, but such mutations did develop in 9.7 percent of the 31 women in the cohort
who delivered between 1997 and 1999; these mutations were detected only in women with previous
exposure to zidovudine.67
Of 220 pregnant women chosen because of previous exposure to zidovudine, 21.8 percent had a
mutation associated with resistance to nucleoside reverse-transcriptase inhibitors, and 17.7 percent had a
primary mutation associated with such resistance. A
total of 2.3 percent of the 220 had a mutation associated with resistance to nonnucleoside reverse-transcriptase inhibitors, but none had a primary mutation
associated with such resistance. A total of 0.5 percent had a primary mutation associated with protease-inhibitor resistance.25
In all of these studies, the women who were evaluated for resistance mutations represented a subgroup
with detectable HIV RNA and clinical characteristics suggesting an increased risk of resistance. Thus,
the rate of resistance mutations in the entire study
populations was probably lower.
The detection of mutations associated with resistance to zidovudine or other drugs was not associat-
N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org 1885
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Management of HIV infection in pregnant women who are already receiving antiretroviral therapy
depends on the gestational age of the fetus, clinical
findings, and the regimen being used. If the pregnancy is discovered after the first trimester, therapy
should be continued. A detailed ultrasonographic
examination should be performed at 18 to 20 weeks
of gestation to confirm the gestational age of the fetus and to screen for detectable anomalies. Options
during the first trimester include continuing the regimen; changing the regimen if it includes specific
drugs that carry an increased risk, such as efavirenz or
delavirdine; or discontinuing all antiretroviral drugs
and reinstituting them after the first trimester. This
last strategy has the potential to cause viral rebound
and might increase the risk of transmission. Decisions should depend on the clinical circumstances
and the treatment history. Hydroxyurea should be
discontinued during pregnancy, since it is teratogenic
in animals and its value in the treatment of HIV is unclear.18 If antiretroviral therapy must be interrupted
during the first trimester, all agents should be discontinued and reinstated simultaneously in order to
prevent the development of resistance.
Several options are available for treatment during
labor in HIV-infected women who have had no previous antiretroviral therapy. Observational studies
found that the use of intravenous zidovudine during
labor plus a six-week regimen of oral zidovudine in
the infant reduced the rate of transmission: 27 to 31
percent of infants in the untreated group became infected, as compared with 10 percent of those in the
treated group.70,71 Other studies demonstrated re-
Among women who have not received antiretroviral therapy, more than half the cases of perinatal
transmission occur late in pregnancy or during delivery; focused efforts are needed to interrupt transmission in such cases.73 Early studies suggested that
cesarean delivery before labor began or the membranes ruptured was effective in reducing the rate of
transmission.74-76 Two large studies have confirmed
that such a reduction occurred among women who
were receiving either zidovudine monotherapy or no
antiretroviral drugs. In a meta-analysis of 15 cohorts,
the adjusted odds ratio for HIV infection was 0.43 (95
percent confidence interval, 0.33 to 0.56) among
infants delivered by cesarean section without labor
or membrane rupture, as compared with those born
by other modes of delivery, with a similar benefit in
the subgroup receiving zidovudine.77 HIV was transmitted to 1.8 percent of the infants of 178 women
who were randomly assigned to cesarean delivery
but to 10.5 percent of 200 infants who were delivered vaginally (P<0.001).78 These studies antedated
the use of highly active antiretroviral therapy and the
measurement of maternal HIV RNA levels in pregnancy. It would be difficult to assess the benefit of
1886 N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
D RUG TH ER A PY
N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org 1887
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Pneumocystis carinii
Toxoplasma gondii
Mycobacterium avium
complex
Mycobacterium
tuberculosis
Candida species
Cryptococcus neoformans
Histoplasma capsulatum
Coccidioides immitis
Cytomegalovirus
Herpes simplex virus
COMMENTS
Prophylaxis and therapy same as for nonpregnant patients; notify neonates health care
provider of maternal sulfa therapy
Therapy and secondary prophylaxis (maintenance therapy) same as for nonpregnant patients; primary prophylaxis with trimethoprimsulfamethoxazole only
Azithromycin first choice for primary prophylaxis during pregnancy; clarithromycin teratogenic in animals; for maintenance therapy,
azithromycin plus ethambutol
Isoniazid preferred for prophylaxis during pregnancy; for multidrug-resistant tuberculosis
during pregnancy, consult an expert
Prophylaxis not indicated during pregnancy;
craniofacial and skeletal abnormalities reported in 4 infants after prolonged exposure to
fluconazole in utero
Primary prophylaxis not recommended; anomalies as noted above after prolonged fluconazole exposure; consider switching to amphotericin B during first trimester for long-term
suppression
Primary prophylaxis not recommended; because
of concern about anomalies with fluconazole
exposure and uncertain safety of chronic itraconazole during pregnancy, consider switching to amphotericin B during first trimester if
continued long-term suppression indicated
Primary prophylaxis not recommended; anomalies as noted above after prolonged fluconazole exposure; consider switching to amphotericin B during first trimester if continued
long-term suppression indicated
Primary prophylaxis not recommended; manage
long-term suppression or therapy during
pregnancy in consultation with experts
Prophylaxis and therapy same as for nonpregnant patients
diagnosis is required for HIV-infected pregnant women. Although screening for serum markers or ultrasonographic examination may enhance the risk assessment, only invasive testing with fetal karyotyping can
rule out chromosomal abnormalities.92 It is unclear
whether invasive procedures for prenatal diagnosis
carry a risk of HIV transmission. An increase by a
factor of two to four in the risk of HIV transmission
related to amniocentesis or other invasive procedures
has been reported among untreated women.93,94 Invasive testing has not been identified as a specific risk
factor for transmission in cohort studies performed
since antiretroviral therapy has become standard, but
the use of amniocentesis among HIV-infected women is uncommon, and the use of chorionic-villus
sampling is rare. If a pregnant woman would not undergo amniocentesis after a positive result on serum
or nuchal translucency screening, then such screening
may be more anxiety-provoking than helpful. If an
invasive prenatal procedure is planned for an HIVinfected woman, she should be receiving optimal antiretroviral therapy and have undetectable HIV RNA
before the procedure.
Intrapartum Care
The potential mode of delivery should be discussed throughout the pregnancy, and the final decision should be based on the HIV RNA level at 34 to
36 weeks of gestation. Infusion of zidovudine should
be begun as soon as possible after the onset of labor
or the rupture of the membranes (or at least three
hours before a scheduled cesarean delivery), at a dose
of 2 mg per kilogram of body weight given over the
course of one hour, followed by a continuous infusion of 1 mg per kilogram per hour until delivery.14
The use of other antiretroviral medications should
be continued on schedule during labor or preoperatively. Stavudine may antagonize the effects of zidovudine and should therefore be given orally without zidovudine or discontinued before intravenous
zidovudine is administered.
Artificially induced rupture of the membranes
should be avoided, and the interval between rupture
and delivery should be minimized by augmenting labor as needed after spontaneous rupture has occurred.
Fetal-scalp electrodes, scalp blood sampling, the use of
instruments to assist delivery, and other procedures
that might be traumatic to the infant should be avoided. Avoidance of episiotomy may decrease the exposure of the infant to maternal blood. Midazolam and
ergot preparations should not be used in women receiving protease inhibitors, efavirenz, or delavirdine,
because their metabolism may be delayed by such
antiretroviral drugs.51 The infant should be washed
before any blood is drawn or any injections or other
invasive procedures are performed.
1888 N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
D RUG TH ER A PY
Postpartum Care
HIV-infected women require additional counseling and support during the postpartum period. In industrialized countries, breast-feeding by HIV-infected
women is not recommended because it is associated
with an additional 15 to 20 percent risk of transmission of HIV.95,96 Among women in whom antiretroviral therapy is continued after delivery, measures to
enhance adherence to the regimen may be needed
because of the demands of newborn care, the loss of
the incentive of preventing transmission, and postpartum depression. Adherence may be improved by
simplifying the regimen, explaining again the consequences of nonadherence, using aids such as daily
pill boxes or pagers, recruiting family and friends for
support, and using support groups. Additional psychosocial support is needed while the infants HIV
status is being determined and afterward if the infant
is found to be infected with HIV.
Options for contraceptive methods should be discussed during pregnancy and the need for condom
use should be emphasized. If a woman elects to use
additional methods, interactions with other therapies
must be considered. Estradiol levels from oral contraceptives are reduced by nevirapine, ritonavir, nelfinavir, rifampin, rifabutin, and possibly amprenavir, which
may reduce the contraceptive efficacy.51 Interactions
between medroxyprogesterone acetate and antiretroviral drugs are under study, but this agent is a reasonable choice. Intrauterine contraceptive devices may
be offered to HIV-infected women who have a low
risk of sexually transmitted infections and do not
have severe immune suppression.97 The appropriate
care for infants born to HIV-infected women is described in Table 1.98 Although the provision of early
access to prenatal care for all women and universal
voluntary HIV testing during pregnancy would allow
for interventions that can improve maternal health
and reduce HIV transmission, the ultimate goal must
be primary prevention of HIV infection in women.
APPENDIX. STUDIES OF
ANTIRETROVIRAL THERAPY
DURING THE PERINATAL PERIOD
The Pediatric AIDS Clinical Trials Group (PACTG) Protocol
076 study, a randomized, double-blind, placebo-controlled trial,
demonstrated that antepartum, intrapartum, and neonatal treatment with zidovudine could prevent perinatal transmission of
HIV type 1 (HIV-1).14 PACTG 185 evaluated whether zidovudine combined with infusions of HIV-1 hyperimmune globulin
administered monthly during pregnancy and to the neonate at
birth would result in lower rates of perinatal HIV transmission
than treatment with zidovudine and intravenous immune globulin without antibodies against HIV-1.23 PACTG 316, a phase 3,
randomized, double-blind, placebo-controlled trial, evaluated the
safety and efficacy of intrapartum and neonatal treatment with
nevirapine in addition to established antiretroviral treatment for
the prevention of maternalfetal HIV transmission. 24 The Perina-
REFERENCES
1. UNAIDS/WHO-AIDS epidemic update December 2000. Geneva:
UNAIDS, 2000. (Accessed May 21, 2002, at http://www.unaids.org/
epidemic_update/index.html.)
2. DeCock KM, Fowler MG, Mercier E, et al. Prevention of mother-tochild HIV transmission in resource-poor countries: translating research
into policy and practice. JAMA 2000;283:1175-82.
3. Saada M, Le Chenadec J, Berrebi A, et al. Pregnancy and progression
to AIDS: results of the French prospective cohorts. AIDS 2000;14:235560.
4. Burns DN, Landesman S, Minkoff H, et al. The influence of pregnancy
on human immunodeficiency virus type 1 infection: antepartum and postpartum changes in human immunodeficiency virus type 1 viral load. Am J
Obstet Gynecol 1998;178:355-9.
5. Weisser M, Rudin C, Battegay M, et al. Does pregnancy influence the
course of HIV infection? Evidence from two large Swiss cohort studies.
J Acquir Immune Defic Syndr Hum Retrovirol 1998;15:404-10.
6. Deschamps MM, Pape JW, Desvarieux M, et al. A prospective study of
HIV-seropositive asymptomatic women of childbearing age in a developing
country. J Acquir Immune Defic Syndr 1993;6:446-551.
7. Kumar RM, Uduman SA, Khurrana AK. Impact of pregnancy on maternal AIDS. J Reprod Med 1997;42:429-34.
8. Brocklehurst P, French R. The association between maternal HIV infection and perinatal outcome: a systematic review of the literature and
meta-analysis. Br J Obstet Gynaecol 1998;105:836-48.
9. Bucceri A, Luchini L, Rancilio L, et al. Pregnancy outcome among
HIV positive and negative intravenous drug users. Eur J Obstet Gynecol
Reprod Biol 1997;72:169-74.
10. Leroy V, Ladner J, Nyiraziraje M, et al. Effect of HIV-1 infection on
pregnancy outcome in women in Kigali, Rwanda, 1992-1994. AIDS 1998;
12:643-50.
11. Embree JE, Braddick M, Datta P, et al. Lack of correlation of maternal
human immunodeficiency virus infection with neonatal malformations.
Pediatr Infect Dis J 1989;8:700-4.
12. Stratton P, Tuomala RE, Abboud R , et al. Obstetric and newborn outcomes in a cohort of HIV-infected pregnant women: a report of the Women and Infants Transmission Study. J Acquir Immune Defic Syndr 1999;
20:179-86.
13. Lambert JS, Watts DH, Mofenson L, et al. Risk factors for preterm
birth, low birth weight, and intrauterine growth retardation in infants born
to HIV-infected pregnant women receiving zidovudine. AIDS 2000;14:
1389-99.
14. Connor EM, Sperling RS, Gelber R , et al. Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173-80.
15. Lorenzi P, Spicher VM, Laubereau B, et al. Antiretroviral therapies in
pregnancy: maternal, fetal and neonatal effects: Swiss HIV Cohort Study,
the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal
HIV Study. AIDS 1998;12:F241-F247.
16. Combination antiretroviral therapy and duration of pregnancy: European Collaborative Study, Swiss Mother and Child HIV Cohort Study.
AIDS 2000;14:2913-20.
17. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and
prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr
2002;29:484-94.
N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org 1889
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
18. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal
health and for reducing perinatal HIV-1 transmission in the United States.
MMWR Morb Mortal Wkly Rep 1998;47(RR-2):1-30. [Errata, MMWR
Morb Mortal Wkly Rep 1998;47:287, 315.] (May 2001 update available at
http://www.hivatis.org.)
19. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR
Morb Mortal Wkly Rep 1999;48(RR-10):1-66. (Draft of 2001 update
available at http://www.hivatis.org.)
20. Physicians desk reference. 55th ed. Montvale, N.J.: Medical Economics, 2001.
21. Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin Infect Dis 2001;32:124-9.
22. Interim report: 1/1/89-1/31/01. Wilmington, N.C.: Antiretroviral
Pregnancy Registry, May 2001.
23. Stiehm ER , Lambert JS, Mofenson L, et al. Efficacy of zidovudine and
human immunodeficiency virus (HIV) hyperimmune immunoglobulin for
reducing perinatal HIV transmission from HIV-infected women with advanced disease. J Infect Dis 1999;179:567-75.
24. Dorenbaum A. Report of results of PACTG 316: an international
phase III trial of standard antiretroviral (ARV) prophylaxis plus nevirapine
(NVP) for prevention of perinatal HIV transmission. In: Proceedings of
the Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, February 48, 2001:277. abstract.
25. Palumbo P, Holland B, Dobbs T, et al. Antiretroviral resistance mutations among pregnant human immunodeficiency virus type 1-infected
women and their newborns in the United States: vertical transmission and
clades. J Infect Dis 2001;184:1120-6.
26. The Petra Study Team. Efficacy of three short-course regimens of
zidovudine and lamivudine in preventing early and late transmission of
HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra
study): a randomised double-blind placebo-controlled trial. Lancet 2002;
359:1178-86.
27. Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomized
controlled trial. Lancet 1999;353:773-80.
28. Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. N Engl J Med 2000;343:982-91.
29. Dabis F, Msellati P, Meda N, et al. 6-Month efficacy, tolerance, and
acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cte dIvoire and Burkina Faso:
a double-blind placebo-controlled multicentre trial. Lancet 1999;353:78692.
30. Wiktor SZ, Ekpini E, Karon J, et al. Short-course zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cote
dIvoire: a randomised trial. Lancet 1999;353:781-5.
31. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of motherto-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795-802.
32. Moodley D. The SAINT trial: nevirapine (NVP) versus zidovudine
(ZVD) + lamivudine (3TC) in prevention of peripartum HIV transmission. In: Programme supplement of the XIII International AIDS Conference, Durban, South Africa, July 914, 2000:16. abstract.
33. Brinkman K, Ter Hofstede HJM, Burger DM, et al. Adverse effects of
reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998;12:1735-44.
34. Fortgang IS, Belitsos PC, Chaisson RE, et al. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral
therapy. Am J Gastroenterol 1995;90:1433-6.
35. Gerard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy. AIDS 2000;14:
2723-30.
36. Important drug warning: retyped text of a letter from Bristol-Myers
Squibb: January 5, 2001. Rockville, Md.: Food and Drug Administration,
2001. (Accessed May 21, 2002, at http://www.fda.gov/medwatch/safety/
2001/zerit&videx_letter.htm.)
37. Ibdah JA, Yang Z, Bennett MJ. Liver disease in pregnancy and fetal
fatty acid oxidation defects. Mol Genet Metab 2000;71:182-9.
38. Grimbert S, Fromenty B, Fisch C, et al. Decreased mitochondrial oxidation of fatty acids in pregnant mice: possible relevance to development
of acute fatty liver of pregnancy. Hepatology 1993;17:628-37.
39. Grimbert S, Fisch C, Deschamps D, et al. Effects of female sex hormones on mitochondria: possible role in acute fatty liver of pregnancy. Am
J Physiol 1995;268:G107-G115.
40. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues.
Lancet 1999;354:1084-9.
41. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA 2001;285:2129-31.
42. Nucleoside exposure in the children of HIV-infected women receiving
antiretroviral drugs: absence of clear evidence for mitochondrial disease in
children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 2000;25:261-8.
43. Lange J, Stellato R, Brinkman K, et al. Review of neurological adverse
events in relation to mitochondrial dysfunction in the prevention of mother
to child transmission of HIV: PETRA study. In: Program and abstracts of
the Second Conference on Global Strategies for the Prevention of HIV
Transmission from Mothers to Infants, Montreal, September 16, 1999:87.
abstract.
44. Olivero OA, Anderson LM, Diwan BA, et al. Transplacental effects of
3'-azido-2'3'-dideoxythymidine (AZT): tumorigenicity in mice and genotoxicity in mice and monkeys. J Natl Cancer Inst 1997;89:1602-8.
45. Ayers KM, Torrey CE, Reynolds DJ. A transplacental carcinogenicity
bioassay in CD-1 mice with zidovudine. Fundam Appl Toxicol 1997;38:
195-8.
46. Hanson IC, Antonelli TA, Sperling RS, et al. Lack of tumors in infants
with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine.
J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:463-7.
47. Minkoff H, Ahdieh L, Watts DH, et al. The relationship of pregnancy
to the use of highly active antiretroviral therapy. Am J Obstet Gynecol
2001;184:1221-7.
48. Mirochnick M, Dorenbaum A, Holland D, et al. Cord blood protease
inhibitor (PI) concentrations following in utero exposure. Pediatr Infect
Dis J 2001;20:803-5.
49. Wara D, Tuomala R, Bryson Y, et al. PACTG 358 safety, pharmacokinetics and antiretroviral activity of indinavir, zidovudine (ZDV), and lamivudine (3TC) in HIV-1 seropositive pregnant women and infants. In:
Program and abstracts of the Second Conference on Global Strategies for
the Prevention of HIV Transmission from Mothers to Infants, Montreal,
September 16, 1999:191. abstract.
50. Hayashi S, Beckerman K, Homma M, et al. Pharmacokinetics of indinavir in HIV-positive pregnant women. AIDS 2000;14:1061-2.
51. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected
adults and adolescents. MMWR Morb Mortal Wkly Rep 1998;47(RR-5):
1-82. (August 2001 update available at http://www.hivatis.org.)
52. Mofenson LM, Lambert JS, Stiehm ER , et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated
with zidovudine. N Engl J Med 1999;341:385-93.
53. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human
immunodeficiency virus type 1 RNA and the risk of perinatal transmission.
N Engl J Med 1999;341:394-402.
54. HIV-infected pregnant women and vertical transmission in Europe
since 1986: European Collaborative Study. AIDS 2001;15:761-70.
55. Scheduled cesarean delivery and the prevention of vertical transmission
of HIV infection. Committee opinion. No. 234. Washington, D.C.: American College of Obstetricians and Gynecologists, May 2000.
56. DITRAME ANRS 049 Study Group. 15-Month efficacy of maternal
oral zidovudine to decrease vertical transmission of HIV-1 in breastfed African children. Lancet 1999;354:2050-1.
57. Dabis F, Elenga N, Meda N, et al. 18-Month mortality and perinatal
exposure to zidovudine in West Africa. AIDS 2001;15:771-9.
58. Owor M, Deseyve M, Duefield C, et al. The one year safety and efficacy data of the HIV NET 012 trial. In: Programme supplement of the
XIII International AIDS Conference, Durban, South Africa, July 914,
2000:16. abstract.
59. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med 1996;335:1621-9.
60. Ioannidis JPA, Abrams EJ, Ammann A, et al. Perinatal transmission of
human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis 2001;183:539-45.
61. Bardeguez A, Mofenson LM, Fowler MG, et al. Lack of clinical or immunologic disease progression with transient use of zidovudine (ZDV) to
reduce perinatal HIV transmission in PACTG 076. In: Conference record
of the 12th World AIDS Conference, Geneva, June 28July 3, 1998:58.
abstract.
62. Eastman PS, Shapiro DE, Coombs RW, et al. Maternal viral genotypic
zidovudine resistance and infrequent failure of zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in Pe-
1890 N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.
D RUG TH ER A PY
diatric AIDS Clinical Trials Group Protocol 076. J Infect Dis 1998;177:
557-64.
63. Hirsch MS, Brun-Vezinet F, DAquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. JAMA 2000;283:2417-26.
64. The EuroGuidelines Group for HIV Resistance. Clinical and laboratory guidelines for the use of HIV-1 drug resistance testing as part of treatment management: recommendations for the European setting. AIDS
2001;15:309-20.
65. Welles SL, Pitt J, Colgrove R, et al. HIV-1 genotypic zidovudine drug
resistance and the risk of maternal-infant transmission in the Women and
Infants Transmission Study. AIDS 2000;14:263-71.
66. Kully C, Yerly S, Erb P, et al. Codon 215 mutations in human immunodeficiency virus-infected pregnant women. J Infect Dis 1999;179:705-8.
67. Sitnitskaya Y, Rochford G, Rigaud M, et al. Prevalence of the T215Y
mutation in human immunodeficiency virus type 1-infected pregnant
women in a New York cohort, 1995-1999. Clin Infect Dis 2001;33:e3-e7.
68. Mofenson L, Lambert J, Stiehm ER , et al. Association of zidovudine
(ZDV) genotypic resistance with perinatal HIV transmission in women receiving ZDV in Pediatric AIDS Clinical Trials Group (PACTG) protocol
185. In: Vol. 1 of the Programme supplement of the XIII International
AIDS Conference, Durban, South Africa, July 914, 2000:337. abstract.
69. Johnson VA, Petropoulos CJ, Woods CR , et al. Vertical transmission
of multidrug-resistant human immunodeficiency virus type 1 (HIV-1) and
continued evolution of drug resistance in an HIV-1-infected infant. J Infect
Dis 2001;183:1688-93.
70. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of
zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med 1998;339:1409-14.
71. Fiscus SA, Adimora AA, Schoenbach VJ, et al. Trends in human immunodeficiency virus (HIV) counseling, testing, and antiretroviral treatment of HIV-infected women and perinatal transmission in North Carolina. J Infect Dis 1999;180:99-105.
72. Cunningham CK, Chaix M-L, Rekacewicz C, et al. Development of
resistance mutations in women on standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal HIV-1 transmission: a
substudy of Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis
(in press).
73. Mock PA, Shaffer N, Bhadrakom C, et al. Maternal viral load and timing of mother-to-child HIV transmission, Bangkok, Thailand. AIDS 1999;
13:407-14.
74. Dunn DT, Newell ML, Mayaux MJ, et al. Mode of delivery and vertical transmission of HIV-1: a review of prospective studies. J Acquir Immune Defic Syndr 1994;7:1064-6.
75. Kuhn L, Bobat R , Coutsoudis A, et al. Cesarean deliveries and maternal-infant HIV transmission: results from a prospective study in South Africa. J Acquir Immune Defic Syndr Hum Retrovirol 1996;11:478-83.
76. Maguire A, Sanchez E, Fortuny C, Casabona J, Working Group on
HIV-1 Vertical Transmission in Catalonia. Potential risk factors for vertical
HIV-1 transmission in Catalonia, Spain: the protective role of cesarean section. AIDS 1997;11:1851-7.
77. The International Perinatal HIV Group. The mode of delivery and the
risk of vertical transmission of human immunodeficiency virus type 1: a metaanalysis of 15 prospective cohort studies. N Engl J Med 1999;340:977-87.
78. The European Mode of Delivery Collaboration. Elective cesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission:
a randomised clinical trial. Lancet 1999;353:1035-9.
79. Landesman SH, Kalish LA, Burns DN, et al. Obstetrical factors and
the transmission of human immunodeficiency virus type 1 from mother to
child. N Engl J Med 1996;334:1617-23.
80. International Perinatal HIV Group. Duration of ruptured membranes
and vertical transmission of HIV-1: a meta-analysis from 15 prospective cohort studies. AIDS 2001;15:357-68.
N Engl J Med, Vol. 346, No. 24 June 13, 2002 www.nejm.org 1891
Downloaded from www.nejm.org on September 24, 2008 . Copyright 2002 Massachusetts Medical Society. All rights reserved.