- Email: [email protected]
Vertically acquired human immunodeficiency virus infection
Vertically Acquired Human Immunodeficiency Virus Infection Mark W. Kline, MD Vertical transmission of human immunodeficiency virus (HIV) accounts for greater than 90 percent of the more than 8,000 children with acquired immunodeficiency syndrome who have been reported to the US Centers for Disease Control and Prevention. Transmission can occur in utero, intrapartum, and via breast milk. Zidovudine administered to the pregnant HIV-infected woman and her newborn infant substantially reduces the risk of vertical transmission of HIV. The clinical manifestations of HIV infection in infancy and childhood are varied and nonspecific. Diagnosis of infection in an infant usually is confirmed by the presence of two positive HIV polymerase chain reaction tests. Antiretroviral therapy, usually combining two nucleoside reverse transcriptase inhibitors with one HIV protease inhibitor, is indicated for all HIV-infected infants, regardless of clinical or immunologic status. Copyright 9 1999 by W.B. Saunders Company
mportant features distinguish human immunodeficieucy virus (H1V) infection and acquired immunodeficiency syndrome (AIDS) in infants from the disease observed in older children and adults. Vertical transmission of HIV and the effects of the virus on an immature and naive immune system undoubtedly influence disease expression in ways that as yet are poorly defined. Difficulties in confirming the diagnosis of HIV infection in early infancy and rapid disease progression in some infants with vertically acquired infection limit opportunities for early therapeutic intervention. In addition, HIV has important adverse effects on the developing central nervous system and on normal linear growth and weight gain. The purpose of this article is to discuss some of the distinguishing features of H1V infection in infancy, particularly as they pertain to epidemiology, clinical manifestations, and diagnosis; prevention of vertical transmission; and treatment and prognosis.
I
Epidemiology and Determinants of Vertical HIV Transmission Worldwide, approximately 1 million children are infected with HIV. An estimated 590,000 new H1V infections and 460,000 HIV-related deaths among children occurred in 1997 alone] Vertical transmission of H1V accounted for 91 percent of the more than 8,000 children (younger than 13 years) with AIDS
From the Baylor College of Medicine and Texas Children's Hospital, Houston, TX. Address correspondenceto Mark W. Kline, MD, Baylor Collegeof Medicine, 6221Fannin St, MC1-4000,Houston, TX 77030. Copyright9 1999by W.B. SaundersCompany 1045-1870/99/1003-0001510.00/0
who were reported to the US Centers for Disease Control and Prevention (CDC) through December 1997. 2 Vertical transmission of H1V can occur at three time points. Convincing evidence indicates that infection occurs in utero in some cases. The virus has been detected in fetal tissues as early as the first trimester of gestation 35 and from cord blood at delivery. Isolation of the virus from amniotic fluid also has been reported. 6 Several investigators have detected HIV in placental tissue] ,8 and placenta-derived cells can support HIV replication in vitro, 9 suggesting a pathogenetic role for in utero transmission of the virus. In one report in which serial blood samples were obtained from an HIV-infected pregnant woman, the HIV viral sequence obtained from her infant at birth was homogeneous and more closely resembled the sequence population present in the mother's blood during the first and second trimesters than the sequence population present in the mother at the time of delivery. 1~ In addition to intrauterine transmission, circumstantial evidence supports the hypothesis that intrapartum exposure to infected maternal blood or genital secretions can result in transmission of the virus. Several investigators have described a virologic pattern in infants similar to that observed in primary HIV infection in adults, with no virus detection at birth, peak virus titers between 1 and 3 months of age, and subsequent decline of virus titerJ 1,12Some HIV-infected infants develop new antibody responses to H1V-specific peptides 1~or anti-HIV IgM 13 or IgA 14 antibody responses in the first few weeks to several months of life, suggesting virus transmission late in pregnancy or around the time of delivery. The relative contributions of in utero and intrapartum HIV transmission to the total burden of HIV vertical transmission are unknown. In one proposed definition, 15 the virus is said to have been transmitted early or in utero i f H I V is detected within the first 48 hours of life (eg, by HIV culture or polymerase chain reaction [PCR]). Late or intrapartum transmission is said to
Seminars in PediatricInfectious Diseases, Vo110, No 3 (July), 1999:pp 147-153
147
148
Mark W. Kline
have occurred if virologic evaluations during the first week of life are negative, followed by HIV detection between 7 and 90 days of age. Applying these proposed definitions to published studies suggests that 50 to 70 percent of HIVvertical transmission may occur intrapartum. Postpartum transmission of H1V via breast milk also can occur. The virus has been detected in breast milk by culture, 16 and well-documented cases of transmission of H1V by mothers who acquired the virus postpartum and breast-fed their infants have been reported. 17 The magnitude of the risk of HIV transmission through breast-feeding has been difficult to determine; a review of published studies placed the risk of transmission by a mother infected postpartum at 29 percent. TM If the mother had established HIV infection at the time of delivery, the estimated risk to the infant through breast-feeding was 14 percent. Worldwide, reported rates of vertical transmission have ranged from approximately 14 percent in Europe 19to 40 percent or greater in parts of Africa9 Before the widespread use in the United States of zidovudine (ZDV) for prophylaxis of vertical transmission of H1V, approximately 20 to 30 percent of infants born to HIV-infected mothers acquired HIV infection. 21"23Currently, many US centers report HIV vertical transmission rates of 5 percent or less. The factors that determine whether vertical transmission of HIV occurs are not fully understood. Women with more advanced H1V disease or lower C D 4 + lynlphocyte counts appear to be more likely to transmit the virus to their infants. 9~ High maternal viral load also is associated with a high risk of vertical transmission, 26,27 but there is not a threshold of virus load below which transmission will not occur. Infants born prematurely may be at greater risk of acquiring infection, 2~ possibly because they have lower concentrations of maternally derived anti-H1V antibodies. A role for genetic susceptibility to HIV infection is suggested by the finding that monozygotic twins are more likely than are dizygotic twins to be concordant for HIV infection status. 28 Several obstetric thctors may influence the risk of vertical transmission of HIV. Both rupture of amniotic membranes for more than 4 hours before delivery25 and vaginal delivery29 have been identified as important risk factors for vertical transmission of H1V. Among women receiving ZDV prophylaxis, a recent meta-analysis of data collected prospectively from US and European centers suggests that delivery by elective cesarean section before both rupture of membranes and onset of labor can decrease the rate of vertical transmission of HIV by almost 50 percent. 3~
Clinical Manifestations Only limited information is available on the effects of HIV on the outcome of the pregnancy. HIV infection in the mother may be associated with a greater-than-expected risk of intrauterine fetal demise, and H1V can be found in a high percentage of the aborted fetuses/ Higher-than-expected rates of prenmturity and intrauterine growth retardation have been observed in studies of infants of H1Vqnfected women in developing countries, 2~ but not in most studies of H1V-exposed infants in the
United States and Europe. 21,~3Most studies that have compared weight, length, and head circumference at birth in HIV-infected versus H1V-exposed but uninfected inIhnts have not reported significant differences. 21,24,31,~4 Infants with vertically acquired HIV infection usually are clinically normal during the neonatal period. A congenital H1V syndrome, encompassing microcephaly, a prominent boxlike forehead, flattened nasal bridge, short nose with flattened coiumella, well-formed triangular philtrum, and patulous lips with prominent upper vermilion border, has been described, 35 but its specificity for HIV infection is poor. 36 The CDC AIDS case definitions for adults and children are similar with several exceptions. Lymphoid interstitial pneumonia/pulmonary lymphoid hyperplasia (LIP/PLH) and multiple or recurrent serious bacterial infections are AIDS-defining conditions only for children. Several other conditions, including certain types of cytomegalovirus and herpes simplex virus infections and toxoplasmosis of the brain, are AIDS-defining only for adults and for children older than 1 month. 37 The expanded definition for AIDS in adolescents and adults, which became effective in 1993, does not apply to children younger than 13 years. 38 The AIDS case definition is used for purposes of surveillance and reporting. The CDC has a separate classification system to describe the spectrum of H1V disease, including HlV-exposed infants with undetermined infection status. 39 The system uses two axes to indicate the severity of clinical signs and symptoms and the degree of immunosuppression. Clinical categories include N, for no signs or symptoms, and A, B, and C, for mild, moderate, and severe signs or symptoms, respectively. All AIDS-defining conditions, with the exception of LIP/PLH, are included in category C. Several studies indicate that the prognoses for children with L1P/PLH is better than those for children with other AIDS-defining conditions. As a consequence, LIP/ PLH was separated from the other AIDS-defining conditions and placed in category B along with many infectious complications and organ dysfunctions (eg, cardiomyopathy and nephropathy). Immunologic categories outlined in the classification system include the following: 1, no evidence of suppression; 2, moderate suppression; and 3, severe suppression. The degree ofimmunosuppression is defined on the basis of age-adjusted CD4+ 13anphocyte counts and percentages. These clinical and immunologic categories are mutually exclusive. Once classified, an infant or child may not be reclassified in a less severe category, even if improvement in clinical or immunologic status occurs in response to antiretroviral therapy or other factors. An infant with HIV vertical exposure and indeterminate (unconfirmed) infection status has "E" (for vertically exposed) placed as a prefix to the appropriate classification code (eg, EN1). The clinical manifestations of H1V infection in infants and children are varied and often nonspecific. Lymphadenopathy, often in association with hepatosplenomegaly, can be an early sign of infection. During the first year of life, oral candidiasis, failure to thrive, and developmental delay are other common presenting features of H1V infection. Table 1 lists the most common AIDS-defining conditions observed among US children with vertical HIV infection.Pneumo-
Vertical H I V I@ction Table 1. Common AIDS-Defining Conditions in Children Pneumoo~stis carinii pneumonia Lymphoid interstitial pneumonia/pulmonary lymphoid hyperplasia Recurrent bacterial infections HIV encephalopathy Wasting syndrome Candida esophagitis Cytomegalovirus disease Mycobactoiurn avium-intracellulare complex infection
~ystis carinii pneumonia accounts for more than one-half of all AIDS-defining conditions diagnosed during the first year of lifeJ~ Affected children usually have progressive respiratory distress and hypoxemia. Fever may be absent. In young infants in particular, the clinical course may be fulminant. The chest roentgenogxam may show bilateral interstitial infiltrates (Fig 1), but any pattern of findings, including a completely normal roentgenogram, can be observed early in the course of illness. Diagnosis of P carinii pneumonia is best accomplished by bronchoalveolar lavage or open lung biopsy. Lynphoid interstitial pneumonia/pulmonary lymphoid hyperplasia affects a somewhat older group of children than does P carinii pneumonia. The onset of LIP/PLH generally is insidious. Cough and tachypnea often are noted. Examination of the chest reveals few auscultatory abnormalities. Frequently, marked generalized l~anphadenopathy, hepatosplenomegaly, and salivary gland enlargement are present. Digital clubbing may be observed in advanced cases. Chest roentgenography typically shows symmetrical, bilateral, reticulonodular interstitial infiltrates, sometimes in association with hilar adenopathy. Confirmation of the diagnosis is made by open lung biopsy. The majority of children with HI~/infection have central nervous system abnormalities.41,42Progressive HIV encephalopathy, which may include developmental delay or regression,
Figure 1. Chest roentgenogram of a 2-year-old boy with HIV infection and P carinii pneumonia, showing interstitial infiltrates, pneumomediastinum, and subcutaneous emphysema.
149
spastic weakness of the extremities, microcephaly, seizures, and by computed tomography, cerebral atrophy and basal ganglia calcification, occurs less commonly. Inflammatory lesions, reactive gliosis, and white matter degenerative changes are some of the neuropathologic findings noted in the brains of H1Vinfected children.43 Various other clinical manifestations of pediatric HIV infection have been described. Hematologic findings, including thrombocytopenia, anemia, and leukopenia, are particularly common. 44 Common dermatologic manifestations include fungal, bacterial, and viral infections of the skin, as well as severe seborrheic dermatitis, vasculitis, and drug eruptions.45 Oral findings include infections, aphthous ulcers, and parotid gland swelling. 46 Cardiomyopathy, pericardial effusion, myocarditis, and cardiac dysrhythmias are potentially lethal conditions observed in some H1V-infected children.47 Finally, renal disease with proteinuria, nephrotic syndrome, and renal insufficiency has been reported.4s
Diagnosis Early diagnosis of vertically acquired HIV infection has important implications for decisions concerning initiation of prophylactic and therapeutic medications, medical follow-up, and management of intercurrent illnesses. Unfortunately, standard HIV serologic tests, including enzyme-linked immunosorbent assay (ELISA) and Western blot immunoassay, are not useful in the diagnosis of HIV infection during infancy because of the confounding presence in the infants' blood of transplacentally derived maternal antibody; detectable anti-HIV antibody may persist for 18 months or longer in some uninfected infants born to infected women. Diagnosis of HIV infection during infancy by physical examination alone is difficult. Generalized lymphadenopathy and hepatosplenomegaly occur commonly among HIV-infected infants, but these findings are neither sensitive (particularly during the first 3 months of life) nor specific for the diagnosis.22 Hyperimmunoglobulinemia is a sensitive but nonspecific indicator of HIV infection during the first 6 months of life. 2~However, because of transplacental passage of maternal IgG, hyperimmunoglobulinemia G alone is a finding of doubtful significance in the HIV-exposed infant. Virus culture is the standard assay to which most other direct tests for HIV in infancy have been compared. In one study of H1V-exposed infants 6 months of age or younger, H1V culture had a diagnostic sensitivity and specificityof 80 percent and 100 percent, respectively.49However, HIV cultures were negative in one-half of the HIV-infected infants studied at birth. Other investigators have reported false-negative cultures in up to 50 to 70 percent of HrV-infected infants tested during the immediate newborn period. This observation has.been speculated to reflect low viral burden attributable to acquiSition of infection late in pregnancy or at birth. Apparent false-positive HIV cultures also have been reported during infancy.5~ Most if not all reported cases of transient HIV culture positivity in HIV-exposed infants can be attributed to laboratory error.51 Although HIu culture has been a useful test in clinical research settings, its more general use has been limited by the
150
M a ~ W . Kline
labor-intensive nature of the assay, the need fbr a specialized laboratory and equipment, the fact that 2 or 3 weeks often are required for determination of a positive test result, and the expense. Use of p24 antigen detection for diagnosing of H1V infection during infancy has been limited by the generally poor sensitivity of the assay. 22,52Acid dissociation, a technique used to free p24 antigen from immune complexes, may improve the sensitivity of the assay for diagnosis of vertical HIV infection. 53,54 In the United States, the HIV DNA PCR assay is used most widely for diagnosing H1V infection during infancy. Generally, testing should be performed in the immediate newborn period, at 1 to 2 months of age, and at 3 to 6 months of age.As is the case with HIV culture, false-negative test results sometimes are observed in the newborn period, but the sensitivity ofH1V DNA PCR at or after 1 m o n t h of age is excellent. 49,55Because PCR is used to amplify minute amounts of specific DNA by many orders of magnitude, and even the slightest contamination can produce false-positive tests results, a single positive HIV DNA PCR test result should be inteq0reted with caution. Any infant with a positive test result should be retested immediately. For purposes of clinical decision-making, an infant younger than 18 months is considered HIV-infected if known to be H1V seropositive or born to an HIV-infected mother and direct tests for H1V (ie, HIV culture, PCR, or p24 antigen detection) performed on two separate blood specimens show positive r e s u l t s 9 Cord blood should not be used. An infant also is considered HIV infected if the CDC surveillance case definition for AIDS is met. 37 Infection can be reasonably excluded by the presence of at least two negative H1V PCR tests, both of which are performed at or after 1 month of age and one of which is performed at or after 4 months of age. Infection is excluded
definitively in such an infant by the disappearance of serum anti-H1V antibody (ie, seroreversion) by 18 months of age in the absence of hypogammaglobulinemia. The routine diagnostic evaluation and m a n a g e m e n t of the HIV-exposed infant are outlined in Table 2. 56
Prevention of HIV Vertical Transmission A randomized, placebo-controlled trial of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG 076) showed that ZDV given to HIV-infected pregnant women and their newborn infants can reduce the likelihood of HIV vertical transmission. 57 In the study, H1V-infected pregnant women with C D 4 + ly~nphocyte counts greater than 200//.tL were enrolled between 14 and 34 weeks of gestation. Almost all the women enrolled were antiretroviral treatmentnaive. The ZDV regimen included three component parts: antepartum ZDV (100 mg orally five times daily), intrapartum ZDV (2 mg/kg intravenously over 1 hour, followed by a 1 mg/kg per hour intravenous infusion until delivery), and ZDV administration to the newborn (2 mg/kg orally every 6 hours for 6 weeks). Study results indicate that vertical transmission of HIV occurred in 25.5 percent of the mother-infant pairs receiving placebo, but only 8.3 percent of those receiving ZDV. This difference represents a 67 percent reduction in vertical transmission of HIV. The drug was well tolerated by both pregnant women and infants. Among infants, the only toxic effect observed was mild anemia, which was reversible on discontinuation of ZDV. Because of the design of the ACTG 076 trial, the findings are directly applicable only to women who initiate antiretroviral
Table 2. Evaluation and M a n a g e m e n t of the HIV-Exposed Infant
Age Birth
Assess risk of other diseases* Continuation of oral zidovudinet CBC and differential leukocyte counts$ HIV DNA PCRw C D 4 + lymphocyte count 82 Quantitative immunoglobulins Initiate prophylaxis for P carinii pneumonia Immunizations Hepatitis B Diphtheria-tetanus-pertussis Haemophilus influenzae# IPV
x x x x
2 wk
4 wk
6 wk
X
X
X
X
2 mo
3 mo
X
X
X
4 mo
6 mo
X X
X
X X
X
x X
X
X
X
X
X
Abbreviations: CBC, complete blood cell count; IPV, inactivated polio vaccine. *Test mother or neonate if maternal status for other infections has not been assessed. "~Zidovudine therapy to decrease the risk of HIV infection in the infant is discontinued at 6 weeks of age. $CBC and differential leukocyte count should continue monthly beyond 4 months of age in the infected child and in the child whose infection status is unclear at 4 months. w positive, repeat PCR or viral culture immediately to confirm infection. If initial test is negative, repeat test at 4 weeks to 2 months. If clinical status or other laborato~T parameters suggest H1V infection, repeat testing earlier than 4 months. If at 4 months the tests are still negative for infection, ongoing serologic follow-up is indicated. 82 lymphocyte count should be repeated at 6 months in infected children and in those whose infection status is unclear at 6 months. #Haemophilus influenzae vaccine schedule may vary depending on which type of vaccine is used. Data from Committee on Pediatric AIDS, American Academy of Pediatrics: Evaluation and medical management of the HIV-exposed infant. Pediatrics 99:909-917, 1997.56
Vertical H I V [@ction
treatment during pregnancy (ie, those who have not had prior therapy with ZDV or another antiretroviral agent) and who have baseline CD4+ lymphocyte counts greater than 200//zL. However, another multicenter study of the ACTG 185 shows that ZDV reduces the risk of H1V vertical transmission, even when the mother previously has received ZDV or has more advanced HIV disease. 5~ ACTG 185 was designed to test the efficacy of HIV imnmne globulin (HMG) in combination with ZDV fbr prevention of HIV vertical transmission. No effect could he attributed to H M G , but vertical transmission occurred in approximately 5 percent of the mother-infant pairs in both the H M G and control study arms, both of which received ZDV. Large observational studies also suggest a marked reduction in the rate of vertical transmission of HIV when the ACTG 076 or similar ZDV regimens are used. 59,6~ On the basis of the ACTG 076 study results, the ZDV regimen it examined has become the standard of care in the United States for all HlV-infected pregnant women and their infants. Other strategies for prevention of HIV vertical transmission, includingshort-course maternal or maternal-infantantiretroviral therapy, are under investigation. One of these strategies, the use of antepartum ZDV (300 nag orally twice daily) beginning at 36 weeks of gestation and intrapartum ZDV (300 mg orally every 3 hours), without treatment of the infant, reduced the rate of vertical transmission of H1V by approximately 50 percent (fiom 18.9% in the control group to 9.4% in the ZDV-treated group) in a study conducted in Thailand.61
Treatment Antiretroviral Therapy As a practical nlatter, except in the clinical research setting or as prophylaxis against vertical transmission, antiretroviral therapy rarely is initiated in the immediate newborn period. Confirmation of the diagnosis of HIV infection in infancy requires time, and symptoms and signs rarely are present at birth or in the first few weeks of life. Nevertheless, with more widespread use of rapid diagnostic assays (eg, H1V PCR), initiation of therapy at earlier time points will be possible. Although no controlled studies have been performed, strong theoretical arguments favor initiation of treatment as early as possible in the newborn period to suppress early viral replication. Combination antiretroviral therapy is recommended for all HIV-infected infants younger than 12 months, regardless of clinical, immunologic, or virologic status. 62Monotherapy of any kind, with the exception of ZDV for prevention of vertical transmission of H1V, is not recommended. Clinical trials of combination therapy in early infancy are ongoing. In one preliminary study, six infants aged 2 to 4 months received combination therapy with ZDV, didanosine (ddl), and nevirapine (a nonnucleoside reverse transcriptase inhibitor).6s Five of the six infants had an initial virologic response to treatment (plasma H1V RNA concentration of less than 10,000 copies/ mL), and two infants maintained undetectable plasma HIV RNA concentrations after 168 days of treatment. Triple-combination therapy is recommended for most HIVinfected infants because of its potential to produce long-term suppression of viral replication, preservation of immune func-
15 1
tion, and delay of disease progression. Based on clinical trials of H1V-infected adults, the preferred regimens combine two nucleoside reverse transcriptase inhibitors (eg, stavudine [d4T] or ZDV, plus ddl or lamivudine [3TC]) with one protease inhibitor. Protease inhibitors with formulations suitable for infants indude nelfinavir (a powder) and ritonavir (a syTup). Little published information exists on the use of protease inhibitor-containingantiretroviral therapy in children.64-67Preliminary data suggest that children have the same virologic, immunologic, and clinical benefits observed among treated adults, but that the degree and durability of suppression of viral replication may be less. Very little is known about the appropriate dosing of most antiretroviral agents in the immediate newborn period. 62 The long-term effects of antiretroviral agents are almost entirely unknown. The potential exists for more pronounced adverse effects on young children who are growing and developing than on adults who have ceased growth. An important multicenter study is examining late outcomes and effects in children who have been enrolled in antiretroviral therapy protocols.
P carinii
Pneumonia Prophylaxis
Difficulties of diagnosing H1V infection during early infancy, as well as difficulties determinating significant immunosuppression and the risk for P carinii pneumonia, largely have been circumvented by the pediatric P carinii pneumonia prophylaxis guidelines published by the CDC. 68The guidelines state that all infants born to HIV-infected women should receive prophylaxis beginning at 4 to 6 weeks of age, regardless of CD4+ lymphocyte count. Prophylaxis is continued until HIV infection has been reasonably excluded, usually on the basis of two or more negative viral diagnostic tests (see Diagnosis). All HlV-infected infants and infants whose infection status is indeterminate should continue prophylaxis until 12 months of age. Thereafter, the need forPcarinii pneumonia prophylaxis in an HIV-infected child is based on a CD4+ lymphocyte count or percentage indicating severe immunosuppression (CDC immunologic category3). Intermittent (3 days per week) or daily trimethoprimsulfamethoxazole generally is recommended for P carinii pneumonia prophylaxis in HIV-infected children. 68 Daily oral dapsone and monthly intravenous pentamidine are useful alternatives for infants who are intolerant of trimethoprimsulfamethoxazole.
Prognosis Bimodal expression of HIV disease in children has been noted, with some vertically infected infants having onset of symptoms during the first few months of life with rapid disease progression and early death, whereas others remain symptom fi'ee or only mildly symptomatic for years. High maternal plasma H1V RNA concentrations and advanced maternal disease are associated independently with rapid disease progression in HIV-infected infants.69 In the infant, both clinical presentation and age at diagnosis of an AIDS-defining condition are important determinants of prognosis. P carinii pneumonia, especially when it occurs
152
Mark W. Kline
during the first year of life, candidal esophagitis, or severe encephalopathy p o r t e n d a particularly poor prognosis for longt e r m survival. 53,70-72 Correlations exist b e t w e e n rapid disease progression and certain laboratory markers of H1V disease, including low CD4 + lymphocyte counts, poor lymphocyte proliferative responses to mitogens and antigens, and lack of antiH1V neutralizing antibodies. 73,74 Infants with high plasma H I V RNA concentrations at birth and in the first 2 m o n t h s of life are especially likely to have rapid disease progression. 75,76
References 1. UNAIDS report, Available at: http: www.unaids.org. Accessed May 12, 1999 2. Centers for Disease Control and Prevention: HIV/AIDS surveillance report. 9:1-93, 1997 3. Lapointe N, MichaudJ, Pekovic D, et al: Transplacental transmission of HTLV-III virus. N EnglJ Med 312:1325-1326, 1985 4. Courgnaud V, Laure F, Brossard A, et al: Frequent and early in utero HIV-1 infection. AIDS Res Hum Retroviruses 7:337-341, 1991 5. Soeiro R, Rubenstein A, Rashbaun WF, et al: Materno-fetal transmission of AIDS: Frequency of human H1V-1 nucleic acid sequences in human fetal DNA.J Infect Dis 166:699-703, 1992 6. Mundy DC, Schinazi RF, Gerver AR, et al: Human immunodefieiencyvirus isolated from amniotic fluid. Lancet 2:459-460, 1987 7. Lewis SH, Reynolds-Kohler C, Fox HE, et al: HIV-1 in trophoblastic and villous Hofbauer cells and haematological precursors in eightweek fetuses. Lancet 335:565-568, 1990 8. Langston C, Lewis DE, Hammill HA, et al: Excess intrauterine fetal demise associated with maternal HIV infection.J Infect Dis 172:14511460, 1995 9. Phillips DM, Tan X: HIV-1 infection of the trophoblast cell line BeWo: A study of virus uptake. AIDS Res Hum Retroviruses 8:1683-1691, 1992 10. Mulder-Kampinga GA, Kuiken C, DekkerJ, et al: Genomic human imnmnodefidency virus type 1 RNA variation in mother and child following intrauterine virus transmission.J Gen Viro174:1747-1756, 1993 11. De Rossi A, Ometto L, Mammano F, et al: Time course of antigenemia and seroconversion in infants with vertically acquired HIV-1 infection. AIDS 7:1528-1529, 1993 12. Luzuriaga K, McQuilken P, Alimenti A, et al: Early viremia and immune responses in vertical human immunodeficiencyvirus type 1 infection.J Infect Dis 167:1008-1013, 1993 13. Pyun KH, Ochs HD, Dufford MTW, et al: Perinatal infection with human immunodeficiency virus: Specific antibody responses by the neonate. N EnglJ Med 317:611-614, I987 14. Parekh BS, Shaffer N, Coughlin R, et al: Human immunodeficiency virus 1-specific IgA capture enzyme immunoassay for early diagnosis of human immunodeficiency virus 1 infection in infants. Pediatr Infect DisJ 12:908-913, 1993 15. Bryson YJ, Luzuriaga K, SullivanJL, et al: Proposed definition for in utero versus intrapartum transmission of H1V-1. N Engl J Med 327:1246-1247, 1992 16. Thiry L, Sprecher-Goldberger J, Jonckheer T, et al: Isolation of AIDS virus from cell-free breast milk of three healthy virus carriers. Lancet 2:891-892, 1985 17. Stiehm ER, Vink P: Transmission of human immunodeficiency virus infection by breast-feeding.J Pediatr 118:410-412, 1991 18. Dunn DT, Newell ML, Ades AE, et al: Risk of human immunodeficiency virus ty-pe 1 transmission through breast feeding. Lancet 340:585-588, 1992
19. European Collaborative Study: Mother-to-child transmission of HIVinfection. Lancet 2:1039-1042, 1988 20. Ryder RW, Nsa W, Hassing S, et al: Perinatal transmission of HIV-1 to infants of seropositive women in Zaire. N Engl J Med 320:16371642, 1989 21. Hutto C, Parks WP, Lai S, et al: A hospital-based prospective study of perinatal infection with human immunodeficiency virus type 1.J Pediatr 118:347-353, 1991 22. Kline MW, Hollinger FB, Rosenblatt HM, et al: Sensitivity, specificity and predictive value of physical examination, culture and other laboratory studies in the diagnosis during early infancy of vertically acquired human immunodeficiency virus infection. Pediatr Infect DisJ 12:33-36, 1993 23. Goedert JJ, Mendez H, Drummond JE, et al: Mother-to-infant transmission of human immunodeficiency virus type 1: Association wit h prematurity or low anti-gp 120. Lancet 2:1351 - 1354, 1989 24. European Collaborative Study: Risk factors for mother-to-child transmission of H1V-1. Lancet 339:100%1012, 1992 25. Simonds RJ, Steketee T, Nesheim S, et al: Impact of zidovudine use on risk and risk factors for perinatal transmission of H1V. Perinatal AIDS collaborative transmission studies. AIDS 12:301-308, 1998 26. AleLxoLF, Goodenow MM, SleasmanJW: Zidovudine administered to women infected with human immunodeficiency virus type 1 and to their neonates reduces pediatric infection independent of an effect on levels of maternal virus.J Pediatr 130:906-914, 1998 27. Thea DM, Steketee RW, Pliner V, et al: The effect of maternal viral load on the risk of perinatal transmission of human immunodeficiencyvirus type 1. AIDS 11:437-444, 1997 28. Goedert JJ, Duliege AM, Amos CI, et al: High risk of HIV-1 infection for first-born twins. Lancet 338:1471-1475, 1991 29. Mandelbrot L, Le ChenadecJ, Berrebi A, et al: Perinatal HIV-1 transmission: Interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort.JAMA 280:55-60, 1998 30. Read J, for the International Perinatal HIV Group: Mode of delivery and vertical transmission of HIV-I: A meta-analysis from fifteen prospective cohort studies. Program and Abstracts of the 12th World AIDS Conference. Geneva, Switzerland, 1998 (abstr 23603) 31. Halsey NA, Boulos R, Holt E, et al: Transmission of H1V- 1 infections from mothers to infants in Haiti: Impact on childhood mortality and malnutrition.JAMA 264:1088-1092, 1990 32. Weng S, Bulterys M, Chao A, et al: Perinatal human immunodeficiency virus- 1 transmission and intrauterine growth: A cohort study in Butare, Rwanda. Pediatrics 102:1-9, 1998 33. Mayers MM, Davenny K, Schoenbaum EE, et al: A prospective study of infants of human immunodeficiency virus seropositive and seronegative women with a history of intravenous drug use or of intravenous drug-using partners, in the Bronx, New York City. Pediatrics 88:1248-1256, 1991 34. Italian Multicentre Study: Epidemiology, clinical features, and prognostic factors of pediatric H1V infection. Lancet 2:1043-1046, 1988 35. Marion RW, Wiznia AA, Hutcheon RG, et aI: Human T-cell lymphotropic virus type III (HTLV-III) embryopathy: A new dysmorphic syndrome associated with intrauterine HTLV-III infection. Am J Dis Child 140:638-640, i986 36. Qazi QH, Sheikh TM, Fikrig S, et al: Lack of evidence for craniofacial dysmorphism in perinatal human immunodeficiency virus infection.J Pediatr 112:7-11, 1988 37. Centers for Disease Control: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 36:115S, 1987, (suppl 1) 38. Centers for Disease Control and Prevention: 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 41:1-19, 1992
Vertical H I V Infection
39. Centers for Disease Control and Prevention: 1994 revised classificauon system for human imnmnodeficiency virus infection in children less than 13 years of age. MMWR 43:1-10. 1994 40. Simonds RJ, Oxtoby MJ, Caldwell MB. et ah PneumocA ~tis carinii pneumonia among U.S children with perinatally acquired HIV infection.JAMA 270:470-473. 1993 41. Belman AL, Diamond G. Dickson D, et ah Pediatric acquired immunodeficiency syndrome: Neurologic syndromes. Am J Dis Child 142:29-35. 1988 42. European Collaborative Study: Neurologic signs in children with human immunodeficiency virus infection. Pediatr Infect Dis J 9:402-406. 1990 43. Sharer L. Epstein LG, Cho ES. et al: Pathologic features of AIDS encephalopathy in children: Evidence for LAV HTLV-III infection of brain. Hum Pathol 17:271-284. 1986 44. McClain K: Hematologic manifestations and malignancies of children with HIV infection. Semin Pediatr Infect Dis 6:26-31.1995 45. Prose NS: Mucocutaneous disease in pediatric human immunodeficiency virus infection. Pediatr Clin North Am 38:977-990, 1991 46. Kline MW: Oral manifestations of pediatric HIV infection. Pediatrics 97:380-388, 1996 47. Lipshultz SE, Chanock S, Sanders SP, et ah Cardiovascular manifestations of human immunodeficiency virus infection in infants and children. AmJ Cardio163:1489-1497, 1989 48. Strauss J, Abitbol C, Zilleruelo G, et ah Renal disease in children with the acquired immunodeficiency s~hadrome. N Engl J Med 32 l:625-630, 1989 49. Kline MW, Lewis DE, Hollinger FB, et al: A comparative study of human immunodeficiency virus culture, polymerase chain reaction and anti-human immunodeficiency virus immunoglobulin A antibody detection in the diagnosis during early infancy of vertically acquired human immunodeficiency virus infection. Pediatr Infect DisJ 13:90-94, 1994 50. European Collaborative Study: Children born to women with HIV- 1 infection: Natural history and risk of transmission. Lancet 337:253260, 1991 51. Frenkel I2VI, Mullins JI, Learn GH, et al: Genetic evaluation of suspected cases of transient H1V-1 infection in infants. Science 289:1073-1077, 1998 52. Krivine A, Yakudima A, Le May M, et ah A comparative study of virus isolation, polymerase chain reaction, and antigen detection in children of mothers infected with human immunodeficiency virus.J Pediatr 116:372-376, 1990 53. Miles SA, Balden E, Magpantay L, et ah Rapid serologic testing with immune-complex-dissociated HIV p24 antigen for early detection of H1V infection in neonates. N EnglJ Med 328:297-302, 1993 54. Quinn TC, Kline R, Moss MW, et ah Acid dissociation of immune complexes improves diagnostic utility of p24 antigen detection in perinatally acquired human immunodeficiency virus infection. J Infect Dis 167:1193-1196, 1993 55. Dunn DT, Brandt CD, KrMne A, et al: The sensitMty of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission. AIDS 9:F7-! 1, 1995 56. Committee on Pediatric AIDS, American Academy of Pediatrics: Evaluation and medical management of the HIV-exposed infant. Pediatrics 99:909-917, 1997 57. Connor EM, Sperling RS, Gelber R, et al: Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N EnglJ Med 331:1173-1180, 1994 58. Lambert J, Mofenson L, Stiehm ER, et al: Risk factors for perinatal HIV transmission in women/infants receMng standard zidovudine (ZDV) prophylaxis. Program and Abstracts of the 12tb World AIDS Conference, Geneva, Switzerland, 1998 (abstr 23265) 59. Fiscus SA, Adimora AA, Sehoenbach VJ, et al: Perinatal H1V
1 53
infection and the effect of zidovudine therapy on transmission in rural and urban counties.JAMA 275:1483-1488, 1996 60. Mayaux MJ, Teglas JP, Mandelbrot L, et ah Acceptability and impact of zidovudine for prevention of mother-to-child human immunodeficiency virus- 1 transmission in France.J Pediatr 131:857862, 1997 6i. Shaffer N, Bhadrakom C, Siriwasin W, et al: Randomized placebocontrolled trial of short-course oral ZDV to reduce perinatal H1V transmission, Thailand. Program and Abstracts of the 12th World AIDS Conference. Geneva, Switzerland, 1998 (abstr 33163) 62. Centers for Disease Control and Prevention: Guidelines for the use of antiretroviral agents in pediatric HIV infection. M M W 47:1-43, 1998 63. Luzuriaga K, Bryson Y, Krogstad P, et al: Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N EnglJ Med 336:13431349, 1997 64. Krogstad P, Kerr B, Anderson R, et al: Phase I study of the HIV-protease inhibitor nelfinavir mesylate (NFu in HIV+ children. Program and Abstracts of the IV Conference on Retroviruses and Opportunistic Infections. Washington, DC, 1997 (abstr 721) 65. Mueller BG, Nelson RPJr, SleasmanJ, et al: A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiencyvirus. Pediatrics 101:335-343, 1998 66. Pelton S, Stanley K, McIntosh K, et ah First large US study of efficacy and tolerability of ritonavir in HIV-infected children. Program and Abstracts of the 12th World AIDS Conference. Geneva, Switzerland, 1998 (abstr 12246) 67. Kline MW, Fletcher CV, Harris AT, et al: A pilot study of combination therapy with indinavir, stavudine (d4T), and didanosine (ddl) in children infected with the human immunodeficiency virus.J Pediatr 132:543-546, 1998 68. Centers for Disease Control and Prevention: 1995 revised guidelines for prophylaxis against Pneumoqystis carinii pnemnonia for children infected with or perinatally exposed to human immunodeficiencyvirus. M M W 44:1-11, 1995 69. Lambert G, Thea DM, P/iner V, et al: Effect of maternal CD4+ cell count, acquired immunodeficiency syndrome, and viral load on disease progression in infants with perinatally acquired human immunodeficiency virus type 1 infection. New York City Perinatal HIV Transmission Collaborative Study Group. J Pediatr 130:890897, 1997 70. Krasinski K, Borkowsky W, Holzman RS: Prognosis of human immunodeficiency virus infection in children and adolescents. Pediatr Infect DisJ 8:216-220, 1989 71. Tovo PA, de Martino M, Gabiano C, et ah Prognostic factors and survival in children with perinatal HIV-1 infection. Lancet 339:12491253, 1992 72. Blanche S, Tardieu M, Duliege A-M, et ah Longitudinal study of 94 synlptomatic infants with perinatally acquired human immunodeficiency virus infection. Evidence tbr a bimodal expression of clinical and biological symptoms. AmJ Dis Child 144:1210-1215, 1990 73. de Martino M, Tovo PA, Galli L, et ah Prognostic significance of immunologic changes in 675 infants perinatally exposed to human immunodeficiencyvirus.J Pediatr 119:702-709, 1991 74. Italian Register for HIV Infection in Children: Features of children perinatally infected with HIV-I surviving longer than 5 years. Lancet 343:191-195, 1994 75. Shearer WT, Quinn TC, LaRussa P, et al: Viral load and disease progression in infants infected with human immunodeficiency virus type 1. N EnglJ Med 336:1337-1342, 1997 76. Dickover RE, Dillon M, Leung K-M, et ah Early prognostic indicators in primary perinatal human immunodeficiency virus type 1 infection: Importance of viral RNA and the timing of transmission on long-term outcome.J Infect Dis 178:375-387, 1998
mportant features distinguish human immunodeficieucy virus (H1V) infection and acquired immunodeficiency syndrome (AIDS) in infants from the disease observed in older children and adults. Vertical transmission of HIV and the effects of the virus on an immature and naive immune system undoubtedly influence disease expression in ways that as yet are poorly defined. Difficulties in confirming the diagnosis of HIV infection in early infancy and rapid disease progression in some infants with vertically acquired infection limit opportunities for early therapeutic intervention. In addition, HIV has important adverse effects on the developing central nervous system and on normal linear growth and weight gain. The purpose of this article is to discuss some of the distinguishing features of H1V infection in infancy, particularly as they pertain to epidemiology, clinical manifestations, and diagnosis; prevention of vertical transmission; and treatment and prognosis.
I
Epidemiology and Determinants of Vertical HIV Transmission Worldwide, approximately 1 million children are infected with HIV. An estimated 590,000 new H1V infections and 460,000 HIV-related deaths among children occurred in 1997 alone] Vertical transmission of H1V accounted for 91 percent of the more than 8,000 children (younger than 13 years) with AIDS
From the Baylor College of Medicine and Texas Children's Hospital, Houston, TX. Address correspondenceto Mark W. Kline, MD, Baylor Collegeof Medicine, 6221Fannin St, MC1-4000,Houston, TX 77030. Copyright9 1999by W.B. SaundersCompany 1045-1870/99/1003-0001510.00/0
who were reported to the US Centers for Disease Control and Prevention (CDC) through December 1997. 2 Vertical transmission of H1V can occur at three time points. Convincing evidence indicates that infection occurs in utero in some cases. The virus has been detected in fetal tissues as early as the first trimester of gestation 35 and from cord blood at delivery. Isolation of the virus from amniotic fluid also has been reported. 6 Several investigators have detected HIV in placental tissue] ,8 and placenta-derived cells can support HIV replication in vitro, 9 suggesting a pathogenetic role for in utero transmission of the virus. In one report in which serial blood samples were obtained from an HIV-infected pregnant woman, the HIV viral sequence obtained from her infant at birth was homogeneous and more closely resembled the sequence population present in the mother's blood during the first and second trimesters than the sequence population present in the mother at the time of delivery. 1~ In addition to intrauterine transmission, circumstantial evidence supports the hypothesis that intrapartum exposure to infected maternal blood or genital secretions can result in transmission of the virus. Several investigators have described a virologic pattern in infants similar to that observed in primary HIV infection in adults, with no virus detection at birth, peak virus titers between 1 and 3 months of age, and subsequent decline of virus titerJ 1,12Some HIV-infected infants develop new antibody responses to H1V-specific peptides 1~or anti-HIV IgM 13 or IgA 14 antibody responses in the first few weeks to several months of life, suggesting virus transmission late in pregnancy or around the time of delivery. The relative contributions of in utero and intrapartum HIV transmission to the total burden of HIV vertical transmission are unknown. In one proposed definition, 15 the virus is said to have been transmitted early or in utero i f H I V is detected within the first 48 hours of life (eg, by HIV culture or polymerase chain reaction [PCR]). Late or intrapartum transmission is said to
Seminars in PediatricInfectious Diseases, Vo110, No 3 (July), 1999:pp 147-153
147
148
Mark W. Kline
have occurred if virologic evaluations during the first week of life are negative, followed by HIV detection between 7 and 90 days of age. Applying these proposed definitions to published studies suggests that 50 to 70 percent of HIVvertical transmission may occur intrapartum. Postpartum transmission of H1V via breast milk also can occur. The virus has been detected in breast milk by culture, 16 and well-documented cases of transmission of H1V by mothers who acquired the virus postpartum and breast-fed their infants have been reported. 17 The magnitude of the risk of HIV transmission through breast-feeding has been difficult to determine; a review of published studies placed the risk of transmission by a mother infected postpartum at 29 percent. TM If the mother had established HIV infection at the time of delivery, the estimated risk to the infant through breast-feeding was 14 percent. Worldwide, reported rates of vertical transmission have ranged from approximately 14 percent in Europe 19to 40 percent or greater in parts of Africa9 Before the widespread use in the United States of zidovudine (ZDV) for prophylaxis of vertical transmission of H1V, approximately 20 to 30 percent of infants born to HIV-infected mothers acquired HIV infection. 21"23Currently, many US centers report HIV vertical transmission rates of 5 percent or less. The factors that determine whether vertical transmission of HIV occurs are not fully understood. Women with more advanced H1V disease or lower C D 4 + lynlphocyte counts appear to be more likely to transmit the virus to their infants. 9~ High maternal viral load also is associated with a high risk of vertical transmission, 26,27 but there is not a threshold of virus load below which transmission will not occur. Infants born prematurely may be at greater risk of acquiring infection, 2~ possibly because they have lower concentrations of maternally derived anti-H1V antibodies. A role for genetic susceptibility to HIV infection is suggested by the finding that monozygotic twins are more likely than are dizygotic twins to be concordant for HIV infection status. 28 Several obstetric thctors may influence the risk of vertical transmission of HIV. Both rupture of amniotic membranes for more than 4 hours before delivery25 and vaginal delivery29 have been identified as important risk factors for vertical transmission of H1V. Among women receiving ZDV prophylaxis, a recent meta-analysis of data collected prospectively from US and European centers suggests that delivery by elective cesarean section before both rupture of membranes and onset of labor can decrease the rate of vertical transmission of HIV by almost 50 percent. 3~
Clinical Manifestations Only limited information is available on the effects of HIV on the outcome of the pregnancy. HIV infection in the mother may be associated with a greater-than-expected risk of intrauterine fetal demise, and H1V can be found in a high percentage of the aborted fetuses/ Higher-than-expected rates of prenmturity and intrauterine growth retardation have been observed in studies of infants of H1Vqnfected women in developing countries, 2~ but not in most studies of H1V-exposed infants in the
United States and Europe. 21,~3Most studies that have compared weight, length, and head circumference at birth in HIV-infected versus H1V-exposed but uninfected inIhnts have not reported significant differences. 21,24,31,~4 Infants with vertically acquired HIV infection usually are clinically normal during the neonatal period. A congenital H1V syndrome, encompassing microcephaly, a prominent boxlike forehead, flattened nasal bridge, short nose with flattened coiumella, well-formed triangular philtrum, and patulous lips with prominent upper vermilion border, has been described, 35 but its specificity for HIV infection is poor. 36 The CDC AIDS case definitions for adults and children are similar with several exceptions. Lymphoid interstitial pneumonia/pulmonary lymphoid hyperplasia (LIP/PLH) and multiple or recurrent serious bacterial infections are AIDS-defining conditions only for children. Several other conditions, including certain types of cytomegalovirus and herpes simplex virus infections and toxoplasmosis of the brain, are AIDS-defining only for adults and for children older than 1 month. 37 The expanded definition for AIDS in adolescents and adults, which became effective in 1993, does not apply to children younger than 13 years. 38 The AIDS case definition is used for purposes of surveillance and reporting. The CDC has a separate classification system to describe the spectrum of H1V disease, including HlV-exposed infants with undetermined infection status. 39 The system uses two axes to indicate the severity of clinical signs and symptoms and the degree of immunosuppression. Clinical categories include N, for no signs or symptoms, and A, B, and C, for mild, moderate, and severe signs or symptoms, respectively. All AIDS-defining conditions, with the exception of LIP/PLH, are included in category C. Several studies indicate that the prognoses for children with L1P/PLH is better than those for children with other AIDS-defining conditions. As a consequence, LIP/ PLH was separated from the other AIDS-defining conditions and placed in category B along with many infectious complications and organ dysfunctions (eg, cardiomyopathy and nephropathy). Immunologic categories outlined in the classification system include the following: 1, no evidence of suppression; 2, moderate suppression; and 3, severe suppression. The degree ofimmunosuppression is defined on the basis of age-adjusted CD4+ 13anphocyte counts and percentages. These clinical and immunologic categories are mutually exclusive. Once classified, an infant or child may not be reclassified in a less severe category, even if improvement in clinical or immunologic status occurs in response to antiretroviral therapy or other factors. An infant with HIV vertical exposure and indeterminate (unconfirmed) infection status has "E" (for vertically exposed) placed as a prefix to the appropriate classification code (eg, EN1). The clinical manifestations of H1V infection in infants and children are varied and often nonspecific. Lymphadenopathy, often in association with hepatosplenomegaly, can be an early sign of infection. During the first year of life, oral candidiasis, failure to thrive, and developmental delay are other common presenting features of H1V infection. Table 1 lists the most common AIDS-defining conditions observed among US children with vertical HIV infection.Pneumo-
Vertical H I V I@ction Table 1. Common AIDS-Defining Conditions in Children Pneumoo~stis carinii pneumonia Lymphoid interstitial pneumonia/pulmonary lymphoid hyperplasia Recurrent bacterial infections HIV encephalopathy Wasting syndrome Candida esophagitis Cytomegalovirus disease Mycobactoiurn avium-intracellulare complex infection
~ystis carinii pneumonia accounts for more than one-half of all AIDS-defining conditions diagnosed during the first year of lifeJ~ Affected children usually have progressive respiratory distress and hypoxemia. Fever may be absent. In young infants in particular, the clinical course may be fulminant. The chest roentgenogxam may show bilateral interstitial infiltrates (Fig 1), but any pattern of findings, including a completely normal roentgenogram, can be observed early in the course of illness. Diagnosis of P carinii pneumonia is best accomplished by bronchoalveolar lavage or open lung biopsy. Lynphoid interstitial pneumonia/pulmonary lymphoid hyperplasia affects a somewhat older group of children than does P carinii pneumonia. The onset of LIP/PLH generally is insidious. Cough and tachypnea often are noted. Examination of the chest reveals few auscultatory abnormalities. Frequently, marked generalized l~anphadenopathy, hepatosplenomegaly, and salivary gland enlargement are present. Digital clubbing may be observed in advanced cases. Chest roentgenography typically shows symmetrical, bilateral, reticulonodular interstitial infiltrates, sometimes in association with hilar adenopathy. Confirmation of the diagnosis is made by open lung biopsy. The majority of children with HI~/infection have central nervous system abnormalities.41,42Progressive HIV encephalopathy, which may include developmental delay or regression,
Figure 1. Chest roentgenogram of a 2-year-old boy with HIV infection and P carinii pneumonia, showing interstitial infiltrates, pneumomediastinum, and subcutaneous emphysema.
149
spastic weakness of the extremities, microcephaly, seizures, and by computed tomography, cerebral atrophy and basal ganglia calcification, occurs less commonly. Inflammatory lesions, reactive gliosis, and white matter degenerative changes are some of the neuropathologic findings noted in the brains of H1Vinfected children.43 Various other clinical manifestations of pediatric HIV infection have been described. Hematologic findings, including thrombocytopenia, anemia, and leukopenia, are particularly common. 44 Common dermatologic manifestations include fungal, bacterial, and viral infections of the skin, as well as severe seborrheic dermatitis, vasculitis, and drug eruptions.45 Oral findings include infections, aphthous ulcers, and parotid gland swelling. 46 Cardiomyopathy, pericardial effusion, myocarditis, and cardiac dysrhythmias are potentially lethal conditions observed in some H1V-infected children.47 Finally, renal disease with proteinuria, nephrotic syndrome, and renal insufficiency has been reported.4s
Diagnosis Early diagnosis of vertically acquired HIV infection has important implications for decisions concerning initiation of prophylactic and therapeutic medications, medical follow-up, and management of intercurrent illnesses. Unfortunately, standard HIV serologic tests, including enzyme-linked immunosorbent assay (ELISA) and Western blot immunoassay, are not useful in the diagnosis of HIV infection during infancy because of the confounding presence in the infants' blood of transplacentally derived maternal antibody; detectable anti-HIV antibody may persist for 18 months or longer in some uninfected infants born to infected women. Diagnosis of HIV infection during infancy by physical examination alone is difficult. Generalized lymphadenopathy and hepatosplenomegaly occur commonly among HIV-infected infants, but these findings are neither sensitive (particularly during the first 3 months of life) nor specific for the diagnosis.22 Hyperimmunoglobulinemia is a sensitive but nonspecific indicator of HIV infection during the first 6 months of life. 2~However, because of transplacental passage of maternal IgG, hyperimmunoglobulinemia G alone is a finding of doubtful significance in the HIV-exposed infant. Virus culture is the standard assay to which most other direct tests for HIV in infancy have been compared. In one study of H1V-exposed infants 6 months of age or younger, H1V culture had a diagnostic sensitivity and specificityof 80 percent and 100 percent, respectively.49However, HIV cultures were negative in one-half of the HIV-infected infants studied at birth. Other investigators have reported false-negative cultures in up to 50 to 70 percent of HrV-infected infants tested during the immediate newborn period. This observation has.been speculated to reflect low viral burden attributable to acquiSition of infection late in pregnancy or at birth. Apparent false-positive HIV cultures also have been reported during infancy.5~ Most if not all reported cases of transient HIV culture positivity in HIV-exposed infants can be attributed to laboratory error.51 Although HIu culture has been a useful test in clinical research settings, its more general use has been limited by the
150
M a ~ W . Kline
labor-intensive nature of the assay, the need fbr a specialized laboratory and equipment, the fact that 2 or 3 weeks often are required for determination of a positive test result, and the expense. Use of p24 antigen detection for diagnosing of H1V infection during infancy has been limited by the generally poor sensitivity of the assay. 22,52Acid dissociation, a technique used to free p24 antigen from immune complexes, may improve the sensitivity of the assay for diagnosis of vertical HIV infection. 53,54 In the United States, the HIV DNA PCR assay is used most widely for diagnosing H1V infection during infancy. Generally, testing should be performed in the immediate newborn period, at 1 to 2 months of age, and at 3 to 6 months of age.As is the case with HIV culture, false-negative test results sometimes are observed in the newborn period, but the sensitivity ofH1V DNA PCR at or after 1 m o n t h of age is excellent. 49,55Because PCR is used to amplify minute amounts of specific DNA by many orders of magnitude, and even the slightest contamination can produce false-positive tests results, a single positive HIV DNA PCR test result should be inteq0reted with caution. Any infant with a positive test result should be retested immediately. For purposes of clinical decision-making, an infant younger than 18 months is considered HIV-infected if known to be H1V seropositive or born to an HIV-infected mother and direct tests for H1V (ie, HIV culture, PCR, or p24 antigen detection) performed on two separate blood specimens show positive r e s u l t s 9 Cord blood should not be used. An infant also is considered HIV infected if the CDC surveillance case definition for AIDS is met. 37 Infection can be reasonably excluded by the presence of at least two negative H1V PCR tests, both of which are performed at or after 1 month of age and one of which is performed at or after 4 months of age. Infection is excluded
definitively in such an infant by the disappearance of serum anti-H1V antibody (ie, seroreversion) by 18 months of age in the absence of hypogammaglobulinemia. The routine diagnostic evaluation and m a n a g e m e n t of the HIV-exposed infant are outlined in Table 2. 56
Prevention of HIV Vertical Transmission A randomized, placebo-controlled trial of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG 076) showed that ZDV given to HIV-infected pregnant women and their newborn infants can reduce the likelihood of HIV vertical transmission. 57 In the study, H1V-infected pregnant women with C D 4 + ly~nphocyte counts greater than 200//.tL were enrolled between 14 and 34 weeks of gestation. Almost all the women enrolled were antiretroviral treatmentnaive. The ZDV regimen included three component parts: antepartum ZDV (100 mg orally five times daily), intrapartum ZDV (2 mg/kg intravenously over 1 hour, followed by a 1 mg/kg per hour intravenous infusion until delivery), and ZDV administration to the newborn (2 mg/kg orally every 6 hours for 6 weeks). Study results indicate that vertical transmission of HIV occurred in 25.5 percent of the mother-infant pairs receiving placebo, but only 8.3 percent of those receiving ZDV. This difference represents a 67 percent reduction in vertical transmission of HIV. The drug was well tolerated by both pregnant women and infants. Among infants, the only toxic effect observed was mild anemia, which was reversible on discontinuation of ZDV. Because of the design of the ACTG 076 trial, the findings are directly applicable only to women who initiate antiretroviral
Table 2. Evaluation and M a n a g e m e n t of the HIV-Exposed Infant
Age Birth
Assess risk of other diseases* Continuation of oral zidovudinet CBC and differential leukocyte counts$ HIV DNA PCRw C D 4 + lymphocyte count 82 Quantitative immunoglobulins Initiate prophylaxis for P carinii pneumonia Immunizations Hepatitis B Diphtheria-tetanus-pertussis Haemophilus influenzae# IPV
x x x x
2 wk
4 wk
6 wk
X
X
X
X
2 mo
3 mo
X
X
X
4 mo
6 mo
X X
X
X X
X
x X
X
X
X
X
X
Abbreviations: CBC, complete blood cell count; IPV, inactivated polio vaccine. *Test mother or neonate if maternal status for other infections has not been assessed. "~Zidovudine therapy to decrease the risk of HIV infection in the infant is discontinued at 6 weeks of age. $CBC and differential leukocyte count should continue monthly beyond 4 months of age in the infected child and in the child whose infection status is unclear at 4 months. w positive, repeat PCR or viral culture immediately to confirm infection. If initial test is negative, repeat test at 4 weeks to 2 months. If clinical status or other laborato~T parameters suggest H1V infection, repeat testing earlier than 4 months. If at 4 months the tests are still negative for infection, ongoing serologic follow-up is indicated. 82 lymphocyte count should be repeated at 6 months in infected children and in those whose infection status is unclear at 6 months. #Haemophilus influenzae vaccine schedule may vary depending on which type of vaccine is used. Data from Committee on Pediatric AIDS, American Academy of Pediatrics: Evaluation and medical management of the HIV-exposed infant. Pediatrics 99:909-917, 1997.56
Vertical H I V [@ction
treatment during pregnancy (ie, those who have not had prior therapy with ZDV or another antiretroviral agent) and who have baseline CD4+ lymphocyte counts greater than 200//zL. However, another multicenter study of the ACTG 185 shows that ZDV reduces the risk of H1V vertical transmission, even when the mother previously has received ZDV or has more advanced HIV disease. 5~ ACTG 185 was designed to test the efficacy of HIV imnmne globulin (HMG) in combination with ZDV fbr prevention of HIV vertical transmission. No effect could he attributed to H M G , but vertical transmission occurred in approximately 5 percent of the mother-infant pairs in both the H M G and control study arms, both of which received ZDV. Large observational studies also suggest a marked reduction in the rate of vertical transmission of HIV when the ACTG 076 or similar ZDV regimens are used. 59,6~ On the basis of the ACTG 076 study results, the ZDV regimen it examined has become the standard of care in the United States for all HlV-infected pregnant women and their infants. Other strategies for prevention of HIV vertical transmission, includingshort-course maternal or maternal-infantantiretroviral therapy, are under investigation. One of these strategies, the use of antepartum ZDV (300 nag orally twice daily) beginning at 36 weeks of gestation and intrapartum ZDV (300 mg orally every 3 hours), without treatment of the infant, reduced the rate of vertical transmission of H1V by approximately 50 percent (fiom 18.9% in the control group to 9.4% in the ZDV-treated group) in a study conducted in Thailand.61
Treatment Antiretroviral Therapy As a practical nlatter, except in the clinical research setting or as prophylaxis against vertical transmission, antiretroviral therapy rarely is initiated in the immediate newborn period. Confirmation of the diagnosis of HIV infection in infancy requires time, and symptoms and signs rarely are present at birth or in the first few weeks of life. Nevertheless, with more widespread use of rapid diagnostic assays (eg, H1V PCR), initiation of therapy at earlier time points will be possible. Although no controlled studies have been performed, strong theoretical arguments favor initiation of treatment as early as possible in the newborn period to suppress early viral replication. Combination antiretroviral therapy is recommended for all HIV-infected infants younger than 12 months, regardless of clinical, immunologic, or virologic status. 62Monotherapy of any kind, with the exception of ZDV for prevention of vertical transmission of H1V, is not recommended. Clinical trials of combination therapy in early infancy are ongoing. In one preliminary study, six infants aged 2 to 4 months received combination therapy with ZDV, didanosine (ddl), and nevirapine (a nonnucleoside reverse transcriptase inhibitor).6s Five of the six infants had an initial virologic response to treatment (plasma H1V RNA concentration of less than 10,000 copies/ mL), and two infants maintained undetectable plasma HIV RNA concentrations after 168 days of treatment. Triple-combination therapy is recommended for most HIVinfected infants because of its potential to produce long-term suppression of viral replication, preservation of immune func-
15 1
tion, and delay of disease progression. Based on clinical trials of H1V-infected adults, the preferred regimens combine two nucleoside reverse transcriptase inhibitors (eg, stavudine [d4T] or ZDV, plus ddl or lamivudine [3TC]) with one protease inhibitor. Protease inhibitors with formulations suitable for infants indude nelfinavir (a powder) and ritonavir (a syTup). Little published information exists on the use of protease inhibitor-containingantiretroviral therapy in children.64-67Preliminary data suggest that children have the same virologic, immunologic, and clinical benefits observed among treated adults, but that the degree and durability of suppression of viral replication may be less. Very little is known about the appropriate dosing of most antiretroviral agents in the immediate newborn period. 62 The long-term effects of antiretroviral agents are almost entirely unknown. The potential exists for more pronounced adverse effects on young children who are growing and developing than on adults who have ceased growth. An important multicenter study is examining late outcomes and effects in children who have been enrolled in antiretroviral therapy protocols.
P carinii
Pneumonia Prophylaxis
Difficulties of diagnosing H1V infection during early infancy, as well as difficulties determinating significant immunosuppression and the risk for P carinii pneumonia, largely have been circumvented by the pediatric P carinii pneumonia prophylaxis guidelines published by the CDC. 68The guidelines state that all infants born to HIV-infected women should receive prophylaxis beginning at 4 to 6 weeks of age, regardless of CD4+ lymphocyte count. Prophylaxis is continued until HIV infection has been reasonably excluded, usually on the basis of two or more negative viral diagnostic tests (see Diagnosis). All HlV-infected infants and infants whose infection status is indeterminate should continue prophylaxis until 12 months of age. Thereafter, the need forPcarinii pneumonia prophylaxis in an HIV-infected child is based on a CD4+ lymphocyte count or percentage indicating severe immunosuppression (CDC immunologic category3). Intermittent (3 days per week) or daily trimethoprimsulfamethoxazole generally is recommended for P carinii pneumonia prophylaxis in HIV-infected children. 68 Daily oral dapsone and monthly intravenous pentamidine are useful alternatives for infants who are intolerant of trimethoprimsulfamethoxazole.
Prognosis Bimodal expression of HIV disease in children has been noted, with some vertically infected infants having onset of symptoms during the first few months of life with rapid disease progression and early death, whereas others remain symptom fi'ee or only mildly symptomatic for years. High maternal plasma H1V RNA concentrations and advanced maternal disease are associated independently with rapid disease progression in HIV-infected infants.69 In the infant, both clinical presentation and age at diagnosis of an AIDS-defining condition are important determinants of prognosis. P carinii pneumonia, especially when it occurs
152
Mark W. Kline
during the first year of life, candidal esophagitis, or severe encephalopathy p o r t e n d a particularly poor prognosis for longt e r m survival. 53,70-72 Correlations exist b e t w e e n rapid disease progression and certain laboratory markers of H1V disease, including low CD4 + lymphocyte counts, poor lymphocyte proliferative responses to mitogens and antigens, and lack of antiH1V neutralizing antibodies. 73,74 Infants with high plasma H I V RNA concentrations at birth and in the first 2 m o n t h s of life are especially likely to have rapid disease progression. 75,76
References 1. UNAIDS report, Available at: http: www.unaids.org. Accessed May 12, 1999 2. Centers for Disease Control and Prevention: HIV/AIDS surveillance report. 9:1-93, 1997 3. Lapointe N, MichaudJ, Pekovic D, et al: Transplacental transmission of HTLV-III virus. N EnglJ Med 312:1325-1326, 1985 4. Courgnaud V, Laure F, Brossard A, et al: Frequent and early in utero HIV-1 infection. AIDS Res Hum Retroviruses 7:337-341, 1991 5. Soeiro R, Rubenstein A, Rashbaun WF, et al: Materno-fetal transmission of AIDS: Frequency of human H1V-1 nucleic acid sequences in human fetal DNA.J Infect Dis 166:699-703, 1992 6. Mundy DC, Schinazi RF, Gerver AR, et al: Human immunodefieiencyvirus isolated from amniotic fluid. Lancet 2:459-460, 1987 7. Lewis SH, Reynolds-Kohler C, Fox HE, et al: HIV-1 in trophoblastic and villous Hofbauer cells and haematological precursors in eightweek fetuses. Lancet 335:565-568, 1990 8. Langston C, Lewis DE, Hammill HA, et al: Excess intrauterine fetal demise associated with maternal HIV infection.J Infect Dis 172:14511460, 1995 9. Phillips DM, Tan X: HIV-1 infection of the trophoblast cell line BeWo: A study of virus uptake. AIDS Res Hum Retroviruses 8:1683-1691, 1992 10. Mulder-Kampinga GA, Kuiken C, DekkerJ, et al: Genomic human imnmnodefidency virus type 1 RNA variation in mother and child following intrauterine virus transmission.J Gen Viro174:1747-1756, 1993 11. De Rossi A, Ometto L, Mammano F, et al: Time course of antigenemia and seroconversion in infants with vertically acquired HIV-1 infection. AIDS 7:1528-1529, 1993 12. Luzuriaga K, McQuilken P, Alimenti A, et al: Early viremia and immune responses in vertical human immunodeficiencyvirus type 1 infection.J Infect Dis 167:1008-1013, 1993 13. Pyun KH, Ochs HD, Dufford MTW, et al: Perinatal infection with human immunodeficiency virus: Specific antibody responses by the neonate. N EnglJ Med 317:611-614, I987 14. Parekh BS, Shaffer N, Coughlin R, et al: Human immunodeficiency virus 1-specific IgA capture enzyme immunoassay for early diagnosis of human immunodeficiency virus 1 infection in infants. Pediatr Infect DisJ 12:908-913, 1993 15. Bryson YJ, Luzuriaga K, SullivanJL, et al: Proposed definition for in utero versus intrapartum transmission of H1V-1. N Engl J Med 327:1246-1247, 1992 16. Thiry L, Sprecher-Goldberger J, Jonckheer T, et al: Isolation of AIDS virus from cell-free breast milk of three healthy virus carriers. Lancet 2:891-892, 1985 17. Stiehm ER, Vink P: Transmission of human immunodeficiency virus infection by breast-feeding.J Pediatr 118:410-412, 1991 18. Dunn DT, Newell ML, Ades AE, et al: Risk of human immunodeficiency virus ty-pe 1 transmission through breast feeding. Lancet 340:585-588, 1992
19. European Collaborative Study: Mother-to-child transmission of HIVinfection. Lancet 2:1039-1042, 1988 20. Ryder RW, Nsa W, Hassing S, et al: Perinatal transmission of HIV-1 to infants of seropositive women in Zaire. N Engl J Med 320:16371642, 1989 21. Hutto C, Parks WP, Lai S, et al: A hospital-based prospective study of perinatal infection with human immunodeficiency virus type 1.J Pediatr 118:347-353, 1991 22. Kline MW, Hollinger FB, Rosenblatt HM, et al: Sensitivity, specificity and predictive value of physical examination, culture and other laboratory studies in the diagnosis during early infancy of vertically acquired human immunodeficiency virus infection. Pediatr Infect DisJ 12:33-36, 1993 23. Goedert JJ, Mendez H, Drummond JE, et al: Mother-to-infant transmission of human immunodeficiency virus type 1: Association wit h prematurity or low anti-gp 120. Lancet 2:1351 - 1354, 1989 24. European Collaborative Study: Risk factors for mother-to-child transmission of H1V-1. Lancet 339:100%1012, 1992 25. Simonds RJ, Steketee T, Nesheim S, et al: Impact of zidovudine use on risk and risk factors for perinatal transmission of H1V. Perinatal AIDS collaborative transmission studies. AIDS 12:301-308, 1998 26. AleLxoLF, Goodenow MM, SleasmanJW: Zidovudine administered to women infected with human immunodeficiency virus type 1 and to their neonates reduces pediatric infection independent of an effect on levels of maternal virus.J Pediatr 130:906-914, 1998 27. Thea DM, Steketee RW, Pliner V, et al: The effect of maternal viral load on the risk of perinatal transmission of human immunodeficiencyvirus type 1. AIDS 11:437-444, 1997 28. Goedert JJ, Duliege AM, Amos CI, et al: High risk of HIV-1 infection for first-born twins. Lancet 338:1471-1475, 1991 29. Mandelbrot L, Le ChenadecJ, Berrebi A, et al: Perinatal HIV-1 transmission: Interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort.JAMA 280:55-60, 1998 30. Read J, for the International Perinatal HIV Group: Mode of delivery and vertical transmission of HIV-I: A meta-analysis from fifteen prospective cohort studies. Program and Abstracts of the 12th World AIDS Conference. Geneva, Switzerland, 1998 (abstr 23603) 31. Halsey NA, Boulos R, Holt E, et al: Transmission of H1V- 1 infections from mothers to infants in Haiti: Impact on childhood mortality and malnutrition.JAMA 264:1088-1092, 1990 32. Weng S, Bulterys M, Chao A, et al: Perinatal human immunodeficiency virus- 1 transmission and intrauterine growth: A cohort study in Butare, Rwanda. Pediatrics 102:1-9, 1998 33. Mayers MM, Davenny K, Schoenbaum EE, et al: A prospective study of infants of human immunodeficiency virus seropositive and seronegative women with a history of intravenous drug use or of intravenous drug-using partners, in the Bronx, New York City. Pediatrics 88:1248-1256, 1991 34. Italian Multicentre Study: Epidemiology, clinical features, and prognostic factors of pediatric H1V infection. Lancet 2:1043-1046, 1988 35. Marion RW, Wiznia AA, Hutcheon RG, et aI: Human T-cell lymphotropic virus type III (HTLV-III) embryopathy: A new dysmorphic syndrome associated with intrauterine HTLV-III infection. Am J Dis Child 140:638-640, i986 36. Qazi QH, Sheikh TM, Fikrig S, et al: Lack of evidence for craniofacial dysmorphism in perinatal human immunodeficiency virus infection.J Pediatr 112:7-11, 1988 37. Centers for Disease Control: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 36:115S, 1987, (suppl 1) 38. Centers for Disease Control and Prevention: 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 41:1-19, 1992
Vertical H I V Infection
39. Centers for Disease Control and Prevention: 1994 revised classificauon system for human imnmnodeficiency virus infection in children less than 13 years of age. MMWR 43:1-10. 1994 40. Simonds RJ, Oxtoby MJ, Caldwell MB. et ah PneumocA ~tis carinii pneumonia among U.S children with perinatally acquired HIV infection.JAMA 270:470-473. 1993 41. Belman AL, Diamond G. Dickson D, et ah Pediatric acquired immunodeficiency syndrome: Neurologic syndromes. Am J Dis Child 142:29-35. 1988 42. European Collaborative Study: Neurologic signs in children with human immunodeficiency virus infection. Pediatr Infect Dis J 9:402-406. 1990 43. Sharer L. Epstein LG, Cho ES. et al: Pathologic features of AIDS encephalopathy in children: Evidence for LAV HTLV-III infection of brain. Hum Pathol 17:271-284. 1986 44. McClain K: Hematologic manifestations and malignancies of children with HIV infection. Semin Pediatr Infect Dis 6:26-31.1995 45. Prose NS: Mucocutaneous disease in pediatric human immunodeficiency virus infection. Pediatr Clin North Am 38:977-990, 1991 46. Kline MW: Oral manifestations of pediatric HIV infection. Pediatrics 97:380-388, 1996 47. Lipshultz SE, Chanock S, Sanders SP, et ah Cardiovascular manifestations of human immunodeficiency virus infection in infants and children. AmJ Cardio163:1489-1497, 1989 48. Strauss J, Abitbol C, Zilleruelo G, et ah Renal disease in children with the acquired immunodeficiency s~hadrome. N Engl J Med 32 l:625-630, 1989 49. Kline MW, Lewis DE, Hollinger FB, et al: A comparative study of human immunodeficiency virus culture, polymerase chain reaction and anti-human immunodeficiency virus immunoglobulin A antibody detection in the diagnosis during early infancy of vertically acquired human immunodeficiency virus infection. Pediatr Infect DisJ 13:90-94, 1994 50. European Collaborative Study: Children born to women with HIV- 1 infection: Natural history and risk of transmission. Lancet 337:253260, 1991 51. Frenkel I2VI, Mullins JI, Learn GH, et al: Genetic evaluation of suspected cases of transient H1V-1 infection in infants. Science 289:1073-1077, 1998 52. Krivine A, Yakudima A, Le May M, et ah A comparative study of virus isolation, polymerase chain reaction, and antigen detection in children of mothers infected with human immunodeficiency virus.J Pediatr 116:372-376, 1990 53. Miles SA, Balden E, Magpantay L, et ah Rapid serologic testing with immune-complex-dissociated HIV p24 antigen for early detection of H1V infection in neonates. N EnglJ Med 328:297-302, 1993 54. Quinn TC, Kline R, Moss MW, et ah Acid dissociation of immune complexes improves diagnostic utility of p24 antigen detection in perinatally acquired human immunodeficiency virus infection. J Infect Dis 167:1193-1196, 1993 55. Dunn DT, Brandt CD, KrMne A, et al: The sensitMty of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission. AIDS 9:F7-! 1, 1995 56. Committee on Pediatric AIDS, American Academy of Pediatrics: Evaluation and medical management of the HIV-exposed infant. Pediatrics 99:909-917, 1997 57. Connor EM, Sperling RS, Gelber R, et al: Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N EnglJ Med 331:1173-1180, 1994 58. Lambert J, Mofenson L, Stiehm ER, et al: Risk factors for perinatal HIV transmission in women/infants receMng standard zidovudine (ZDV) prophylaxis. Program and Abstracts of the 12tb World AIDS Conference, Geneva, Switzerland, 1998 (abstr 23265) 59. Fiscus SA, Adimora AA, Sehoenbach VJ, et al: Perinatal H1V
1 53
infection and the effect of zidovudine therapy on transmission in rural and urban counties.JAMA 275:1483-1488, 1996 60. Mayaux MJ, Teglas JP, Mandelbrot L, et ah Acceptability and impact of zidovudine for prevention of mother-to-child human immunodeficiency virus- 1 transmission in France.J Pediatr 131:857862, 1997 6i. Shaffer N, Bhadrakom C, Siriwasin W, et al: Randomized placebocontrolled trial of short-course oral ZDV to reduce perinatal H1V transmission, Thailand. Program and Abstracts of the 12th World AIDS Conference. Geneva, Switzerland, 1998 (abstr 33163) 62. Centers for Disease Control and Prevention: Guidelines for the use of antiretroviral agents in pediatric HIV infection. M M W 47:1-43, 1998 63. Luzuriaga K, Bryson Y, Krogstad P, et al: Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N EnglJ Med 336:13431349, 1997 64. Krogstad P, Kerr B, Anderson R, et al: Phase I study of the HIV-protease inhibitor nelfinavir mesylate (NFu in HIV+ children. Program and Abstracts of the IV Conference on Retroviruses and Opportunistic Infections. Washington, DC, 1997 (abstr 721) 65. Mueller BG, Nelson RPJr, SleasmanJ, et al: A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiencyvirus. Pediatrics 101:335-343, 1998 66. Pelton S, Stanley K, McIntosh K, et ah First large US study of efficacy and tolerability of ritonavir in HIV-infected children. Program and Abstracts of the 12th World AIDS Conference. Geneva, Switzerland, 1998 (abstr 12246) 67. Kline MW, Fletcher CV, Harris AT, et al: A pilot study of combination therapy with indinavir, stavudine (d4T), and didanosine (ddl) in children infected with the human immunodeficiency virus.J Pediatr 132:543-546, 1998 68. Centers for Disease Control and Prevention: 1995 revised guidelines for prophylaxis against Pneumoqystis carinii pnemnonia for children infected with or perinatally exposed to human immunodeficiencyvirus. M M W 44:1-11, 1995 69. Lambert G, Thea DM, P/iner V, et al: Effect of maternal CD4+ cell count, acquired immunodeficiency syndrome, and viral load on disease progression in infants with perinatally acquired human immunodeficiency virus type 1 infection. New York City Perinatal HIV Transmission Collaborative Study Group. J Pediatr 130:890897, 1997 70. Krasinski K, Borkowsky W, Holzman RS: Prognosis of human immunodeficiency virus infection in children and adolescents. Pediatr Infect DisJ 8:216-220, 1989 71. Tovo PA, de Martino M, Gabiano C, et ah Prognostic factors and survival in children with perinatal HIV-1 infection. Lancet 339:12491253, 1992 72. Blanche S, Tardieu M, Duliege A-M, et ah Longitudinal study of 94 synlptomatic infants with perinatally acquired human immunodeficiency virus infection. Evidence tbr a bimodal expression of clinical and biological symptoms. AmJ Dis Child 144:1210-1215, 1990 73. de Martino M, Tovo PA, Galli L, et ah Prognostic significance of immunologic changes in 675 infants perinatally exposed to human immunodeficiencyvirus.J Pediatr 119:702-709, 1991 74. Italian Register for HIV Infection in Children: Features of children perinatally infected with HIV-I surviving longer than 5 years. Lancet 343:191-195, 1994 75. Shearer WT, Quinn TC, LaRussa P, et al: Viral load and disease progression in infants infected with human immunodeficiency virus type 1. N EnglJ Med 336:1337-1342, 1997 76. Dickover RE, Dillon M, Leung K-M, et ah Early prognostic indicators in primary perinatal human immunodeficiency virus type 1 infection: Importance of viral RNA and the timing of transmission on long-term outcome.J Infect Dis 178:375-387, 1998