(HCV) Infection to Human Immunodeficiency Virus ...

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Increased Transmission of Vertical Hepatitis C Virus (HCV) Infection to Human Immunodeficiency Virus (HIV)–Infected Infants of HIV- and HCV-Coinfected Women Vassiliki Papaevangelou,* Henry Pollack, Gemma Rochford, Robert Kokka, Zhiying Hou, David Chernoff, Bruce Hanna, Keith Krasinski, and William Borkowsky

Departments of Pediatrics and Pathology, New York University Medical Center-Bellevue Hospital Center, New York, New York; Chiron Corp., Emeryville, California

The transmission of perinatal hepatitis C virus (HCV) infection was studied retrospectively in 62 infants born to 54 HCV- and human immunodeficiency virus (HIV) – coinfected women enrolled in a prospective natural history study of HIV transmission. Infant HCV infection was assessed by nested RNA polymerase chain reaction. The overall rate of vertical HCV transmission was 16.4% (9/62). Most HCV-infected children did not develop antibodies to HCV. The rate of HCV infection was higher among HIV-infected infants (40%) than among HIV-uninfected infants (7.5%; odds ratio, 8.2; P Å .009). This difference in transmission was not related to differences in maternal HCV load, as measured by branched DNA assay, or mode of delivery. Why HIV-infected infants of HCVand HIV-coinfected women have significantly higher rates of perinatal HCV transmission remains to be elucidated. The rate of HCV transmission in HIV-uninfected infants of HCV- and HIVcoinfected women is similar to that reported for infants born to HIV-seronegative mothers.

Received 15 January 1998; revised 28 May 1998. Presented in part: 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 1995; IX Triennial International Symposium on Viral Hepatitis and Liver Disease, Rome, April 1996. Informed consent was obtained from all participants or their parents or guardians in this study. Guidelines for human experimentation of the US Department of Health and Human Services and the Institutional Review Board of NYU Medical Center were followed. Financial support: NYU Center for AIDS Research (P30A127742), NIH (DA/MH1064), Chiron Corp., and Shubert Foundation. Z.H. is a postdoctoral fellow of NYU-NIH AIDS Institution Training Grant (AI-07382). Reprints or correspondence: Dr. Henry Pollack, Dept. of Pediatrics, NYU Medical Center, 550 First Ave., New York, NY 10016 (henry.pollack@ ccmail.med.nyu.edu). * Present affiliation: 1st Department of Pediatrics, University of Athens Medical School, ‘‘St. Sophia’’ Children’s Hospital, Goudi, Athens, Greece. The Journal of Infectious Diseases 1998;178:1047–52 q 1998 by the Infectious Diseases Society of America. All rights reserved. 0022–1899/98/7804–0017$02.00

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vertical infection; it will overestimate infection during the first year of life, because of passively acquired maternal antibody, and will underestimate infection in older children [17 – 19]. The true rate of transmission, therefore, continues to remain controversial. While it has been hypothesized that the increased vertical transmission of HCV in HIV-infected women is simply a reflection of a higher plasma HCV load in HIV-coinfected women, this has not been supported by clinical data [6]. Several studies of heterosexual HCV transmission, on the other hand, suggest that HCV transmission is increased when there is also cotransmission of HIV [21] or when the subject is also HIVinfected [22]. Whether this is true for vertical HCV transmission has not been examined. In the following study, an extant cohort of HCV- and HIVcoinfected women in New York City and their children followed prospectively from birth was examined to determine the rate of vertical HCV infection among HCV- and HIV-coinfected women as assessed by nested RNA polymerase chain reaction (PCR). We compared the proportion of HIV-infected and HIV-uninfected infants who were vertically infected with HCV.

Methods Study Population

Plasma samples from 100 HIV-infected women enrolled in a prospective study of perinatal HIV transmission at New York University Medical Center-Bellevue Hospital Center, New York, between March 1987 and October 1994, were tested for anti-HCV antibodies to identify women coinfected with HIV and HCV. In cases in which peripartum maternal samples were not available, infant samples from the first months of life were screened for

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The overall risk of vertical perinatal transmission of hepatitis C virus (HCV) infection from HCV-infected mothers to their infants has been estimated to be Ç7% [1], ranging from 0 to 18% in European and Japanese studies [2 – 15]. Neither the precise mechanism nor the timing of HCV vertical transmission is known. Several factors have been associated with a higher risk of transmission, including elevated maternal HCV load [7 – 9, 16, 17], vaginal delivery [6, 18], and human immunodeficiency virus (HIV) infection of the mother [5 – 7, 17 – 19]. Although vertical HCV transmission occurs more frequently among HIV-coinfected mothers, reported rates of transmission have varied between 9% and 80% [6, 11, 17, 19, 20]. Some differences can be attributed to differing definitions of HCV infection, differences in sensitivity of detection systems, and small sample sizes. HCV serology is an unreliable indicator of

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Detection of Anti-HCV Antibody

Anti-HCV antibodies were measured by a second-generation EIA (Abbott HCV A. 2.0; Abbott Laboratories, Elkgrove Village, IL) according to manufacturer’s instructions.

ethidium bromide. Positive results were verified by liquid hybridization using a radiolabeled probe [11]. To decrease the risk of contamination, the preparation and amplification of the PCR were done in separate rooms. All samples were run in duplicate with low- and high-copy positive RNA and DNA controls. Negative controls were included in each experiment. The assay sensitivity, as determined by end-point dilution of quantitative positive controls (provided by Chiron Diagnostics, Emeryville, CA), was Ç800 virus copies/mL of plasma. The amount of HCV RNA in all positive children’s PCR samples was assessed, semiquantitatively, by serial end-point dilution. bDNA assay. HCV RNA in maternal plasma samples from the peripartum period was quantified by the bDNA signal amplification assay (HCV bDNA version 1.0; Chiron) [24]. The lower limit of sensitivity of the assay is 3.5 1 105 HCV copies/mL.

Statistical Analysis

Only infants for whom a definitive HCV status could be assigned were included in calculating the vertical transmission rate. Fisher’s exact and x2 tests were used to compare the proportion of HIVinfected and HIV-uninfected children who were HCV-infected and to evaluate the association between perinatal transmission of HCV and maternal HCV RNA status and mode of delivery. The nonparametric Mann-Whitney test was used to compare the HCV load between HCV-transmitting and -nontransmitting mothers and between HIV-infected and -uninfected infants.

Results Description of Population

Fifty-four of the 100 HIV-infected women tested had detectable antibodies to HCV. None of the HIV- and HCV-coinfected women were receiving interferon-a or antiretroviral therapy during pregnancy. One woman developed acute hepatitis during pregnancy. Sixty-three children, including two sets of twins and 7 sibling deliveries, were born to these 54 HCV-infected women during the study period. Children were followed for a mean of 2.3 years (range, 9 months to 7 years).

Detection and Quantification of HCV RNA

HCV-Infected Infants

HCV RNA PCR. RNA was extracted from stored frozen plasma samples (0.25 mL) with TRI REAGENT (Molecular Research Center, Cincinnati). The pellet obtained was dissolved in 20 mL of diethyl pyrocarbonate–treated water. Five microliters of RNA was reverse-transcribed with Moloney murine leukemia virus reverse transcriptase using either random hexamers or the outer antisense primer, which had comparable efficiency. A nested PCR was done on 5 mL of cDNA using published primers to the highly conserved 5* untranslated region of the HCV genome [11, 23]. Each PCR reaction was amplified with Taq DNA polymerase (Perkin-Elmer, Foster City, CA) for 30 cycles (947C for 1 min, 557C for 1 min, and 727C for 1 min) as described [23]. PCR products were analyzed by electrophoresis on 1.5% agarose gels containing

Ten children were plasma HCV RNA PCR – positive on at least two separate occasions. One of these HCV-infected children became positive 6 months after receiving blood transfusions at age 4 months and was excluded from further analysis. Qualitative and semiquantitative HCV RNA PCR results for the remaining 9 HCV-infected infants are shown in figure 1, along with the results of HCV antibody testing and clinical correlation (see below). The median age at the time of the first positive PCR result was 60 days (range, 0 – 1090). Viremia was usually intermittent; 38% – 100% (median, 57%) of plasma samples from HCV-infected infants were PCR-positive. Only 1 of 3 infants tested in the first week of life was HCV RNA

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transplacentally transferred maternal HCV antibodies. Medical records of HIV- and HCV-coinfected women were reviewed, and the use of antiretroviral therapy during pregnancy was noted. The amount of HCV RNA in maternal plasma samples obtained near the time of delivery ({2 months) was measured by the branched DNA (bDNA) assay. Samples in which the amount of HCV RNA was below the cutoff for the bDNA assay were assessed for the presence of HCV RNA by nested PCR. Infants born to HCV- and HIV-coinfected mothers were followed prospectively from birth. None of the infants were breastfed. Physical examination was done, and blood samples were obtained at scheduled visits. Infants were considered HIV-infected if HIV antigen or DNA was detected on 2 separate blood samples tested for the presence of p24 antigen, by HIV culture or by PCR. Stored sequential plasma samples from these children were examined for the presence of HCV RNA by nested PCR. At least 2 plasma samples were examined for the presence of HCV RNA in each child. In infants in whom HCV infection was detected, additional samples, when available, were then examined to better define the course of HCV infection. Positive PCR samples were always verified by repeat PCR. The amount of HCV RNA in an HCVpositive sample was further quantified by serial end-point dilution. Finally, anti-HCV antibodies were measured in serum samples obtained beyond the first year of life to avoid confounding of passively acquired transplacental antibodies of maternal origin. Children were considered HCV-infected if HCV RNA was detected in at least 2 separate samples or if they were HCV antibody– positive after 12 months of life. Infants receiving blood transfusions were excluded from further analysis. Children who had repeatedly detectable HCV RNA in only 1 plasma sample and therefore did not meet our definition criteria for the diagnosis of HCV infection were defined as having an indeterminate HCV infection and were not included as HCV-infected. Children’s medical records were reviewed and their HIV status and clinical and laboratory evidence of hepatitis were recorded.

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Figure 1. Results of semi-quantitative plasma HCV RNA polymerase chain reaction (PCR), HCV antibody (HCVAb) determinations, and clinical outcome in HCVinfected children. Log HCV RNA titer, determined by end-point dilution PCR, is given for each child at age done. 0 indicates negative PCR result. Each dash on time line is equivalent to Ç20 days. Patients 1 – 6 are HIV-coinfected. Patients 7 – 9 are HIV-uninfected. HCV antibody was measured after 18 months. Hepatitis was defined as alanine aminotransferase more than twice upper limit of normal for §6 months.

Vertical HCV Transmission Rate

The crude HCV transmission rate in the entire cohort was 16.4% (9/55). There was no difference in the HCV transmission rate among the 22 infants in this cohort, in whom HCV RNA PCR had been done at least one time in the first 3 months of life (5/22; 22.7%), and the total cohort, indicating that potential confounding intrafamilial infection was probably unlikely.

Association of Vertical HIV Infection and Vertical HCV Transmission

Sixteen children were HIV-infected and 47 were HIV-uninfected. The crude HIV transmission rate was 24%. HIV-infected infants were significantly more likely to be infected with HCV than were HIV-uninfected infants: 6 (40%) of 15 versus 3 (7.5%) of 40 (odds ratio, 8.2; 95% confidence interval, 1.9 – 36.2; P Å .009). A difference in the maternal-infant transmission rate of HCV between HIV-infected and HIV-uninfected infants was also observed in the smaller cohort of infants who were assessed in the first 3 months of life. In the latter group, 4 (50%) of 8 HIV-infected infants were HCV-infected compared with 1 (7.1%) of 14 HIV-uninfected infants (odds ratio, 13; 95% confidence interval, 1.5 – 109.8; P Å .039). Two-thirds of the HCV-infected infants in the entire cohort were HIVcoinfected. None of the 7 infants with an indeterminate HCV designation were HIV-infected.

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Comparison of HIV-Infected Infants Infected or Not Infected with HCV

Immunologic data were available for 13 of the 15 HIVinfected infants. This included 5 of the 6 HCV-infected infants. There was no difference in CD4 cell percentage either at birth or at 6 months of life between HCV-positive and HCV-negative infants, nor was there any difference in the rate of progression of HIV disease in these groups. HIV RNA data were available for 12 of the infected infants. Peak HIV load during the first 6 months was similar in the 2 groups. By contrast, the median HIV load at 6 months of life (a relative set-point in children) was higher among HCV-infected infants than HCV-uninfected infants (1,686,800 vs. 317,000 copies/mL), although these differences were not statistically significant (P Å .167). No differences in antiretroviral or prophylaxis usage were observed among the 2 groups. Maternal Factors

Mode of delivery. Data on mode of delivery were available for 51 mother-infant pairs: Overall, HCV infection was transmitted to 6 (17.1%) of 35 and 3 (18.8%) of 16 children born by vaginal and cesarean section, respectively. Similar results were obtained when only infants who were HCV RNA – positive in the first 3 months of life were considered vertically infected: 4 (11.8%) of 34 infants who were delivered vaginally and 2 (12.5%) of 16 infants who were delivered by cesarean section were HCV-infected. Perinatal maternal HCV RNA load. Maternal perinatal HCV RNA data were available for 45 mothers. The median HCV load was õ3.5 1 105 copies/mL in 5 HCV-transmitting mothers and 4.1 1 105 copies/mL in 40 nontransmitting mothers (P Å .8). Similar results were found for the group of infants evaluated within the first 3 months of life. No threshold for transmission was evident: 2 (9.1%) of 22 women with ú3.5 1 105 copies/mL transmitted, compared with 3 (13.0%) of 23 women with õ3.5 1 105 copies/mL. Of 12 women with ú106 RNA copies/mL, only 1 (8.3%) transmitted HCV.

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PCR – positive. Only 2 (22.2%) of the 9 HCV-infected children had detectable anti-HCV antibodies beyond the first year of life. In both twin births, HCV transmission was discordant. Among 13 children born to 6 women with multiple pregnancies, 1 (7.7%) was HCV-infected. Seven children were HCV RNA PCR – positive on a single occasion and, because of their indeterminate HCV status, were excluded from further analysis.

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HCV-transmitting mothers were as likely as non – HCVtransmitting mothers to be viremic during the perinatal period (3/5 vs. 27/40, P Å .9). One of 2 HCV-transmitting mothers who did not have detectable HCV RNA in her perinatal plasma samples was HCV-viremic at 20 weeks’ gestation. Her child was HCV RNA – positive at birth.

Clinical and Laboratory Manifestations of HCV-Infected Infants

Discussion This study illustrates many of the difficulties encountered in determining transmission rates of perinatal HCV infection. Serology is not reliable and may grossly underestimate the rate of transmission [6, 18, 19]. Although PCR is a much more sensitive method of detecting HCV infection, it too can be quite variable [23], especially since viremia is often intermittent and the incubation period may be prolonged. It is also difficult to be absolutely certain that postnatal intrafamilial infection

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has not occurred during the period of incubation, since most infants are not viremic at birth [20, 25]. By use of a stringent definition of infection (at least 2 positive PCR results), the overall HCV transmission rate in this study was 16.4%. When we used more stringent criteria to reduce the possibility of confounding postnatal intrafamilial HCV transmission by examining HCV transmission in only those infants who were first assessed within the first 3 months of life [4], the rate of vertical HCV transmission was very similar, 22.7%. In both instances, there was a clear association between the vertical transmission of HCV and the vertical transmission of HIV. Infants who were HIV-infected were at least eight times more likely than HIV-uninfected infants to be vertically infected with HCV. The vertical HCV transmission rate to HIVuninfected infants (7%) detected in this study is similar to the rates observed in most other studies in HIV-uninfected women [1]. The overall rate of transmission for all infants of HCVand HIV-coinfected mothers in this study is lower than was found in several Italian studies of HIV- and HCV-positive mothers [6, 7, 19], a difference that may relate to their less stringent definition of HCV infection. The differences in HCV transmission rates between HIV-infected and -uninfected infants were not explained by differences in the mode of delivery or maternal virus load, which have previously been implicated as possible transmission determinants. Moreover, we did not find any association between maternal HCV load or mode of delivery in the HCV-transmitting or -nontransmitting mothers. While previous studies have suggested that only women with detectable HCV RNA in plasma during the perinatal period transmit HCV to their children [7 – 9], particularly women with high HCV load [9, 16], in our cohort, HCV-transmitting mothers did not have a higher HCV load than did nontransmitting mothers nor were they always viremic at delivery. The absence of correlation with maternal virus load and transmission observed in the present study agrees with the findings of an Italian study [6] that within the group of HIV-positive HCV-infected women, HCV-transmitting women did not have higher titers of HCV RNA than did nontransmitting women. Maternal virus load could have a threshold effect on perinatal transmission and thus affect the transmission rate in HIV-negative mothers with low HCV loads but not in HIV-infected women who have higher virus load [6, 24]. However, we could not identify any virologic threshold above 3.5 1 105 copies/mL that was associated with transmission. Although a previous Italian study [19] found that the rate of vertical transmission of HCV was significantly higher in children born by vaginal delivery than in those delivered by cesarean section, we found no such association in the present cohort, whether analyzed by stringent or nonstringent criteria. We have no clear explanation for the cotransmission of HIV and HCV, a finding that has also been observed in heterosexual partners of HIV- and HCV-positive hemophiliacs [21]. Breeches in placental integrity could lead to vertical transmis-

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HCV plasma virus load. The mean plasma HCV RNA load during the first year of life for all HCV-infected infants was 408,825 { 1,044,705 copies/mL (mean { SD). Among the HIV-coinfected infants, the mean plasma HCV copy number was 572,217 { 1,281,550 copies/mL, compared with 82,041 { 139,395 copies/mL for HIV-uninfected infants. The medians for these 3 groups were 9300, 15,050, and 2125 copies/mL, respectively. The difference in HCV load between HIV-coinfected and HIV-uninfected infants was not statistically different (P Å .3). HCV antibody. Only 2 (22.2%) of the 9 HCV-infected children had detectable anti-HCV antibodies beyond the first year of life; 1 was HIV-infected (1 of 6 HIV-infected infants made antibody) and 1 was HIV-uninfected (1 of 3 HIV-uninfected infants made antibody). Both infants who made HCV antibodies had §5 1 105 HCV copies/mL in their plasma. By comparison, 0 of 5 infants with õ5 1 105 HCV copies/mL made antibody. None of the infants had hypogammaglobulinemia. None of the children with indeterminate HCV status developed anti-HCV antibodies. Hepatitis. Alanine aminotransferase was chronically elevated (more than two times the upper limit of normal, 50 U/ L, for ú6 months) in 3 of 6 HCV- and HIV-coinfected children. Two of the children had severe chronic liver disease with acute exacerbations. Chronic hepatitis was confirmed at autopsy in 1 child who died. There was no correlation between transaminase elevations and HCV RNA levels. Neither clinical nor laboratory evidence of liver disease developed in the 3 HIV-uninfected children with HCV infection, nor did any of the children with a single positive PCR result (indeterminate HCV status) have any evidence of liver disease during the period of observation.



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administration of potentially hepatotoxic medications (e.g., zidovudine, trimethoprim-sulfamethoxazole, fluconazole) or to the interaction of all three factors remains unclear. In conclusion, we found that the rate of vertical HCV transmission is no higher among HIV-uninfected infants born to HIV-positive mothers than among infants of HIV-seronegative women. By contrast, vertical HCV transmission was markedly increased in infants who were also vertically infected with HIV. The reasons for the cotransmission of the two viruses will require further elucidation. Acknowledgments

We thank Rachel Brody for providing us with positive RNA and DNA controls for the HCV RNA PCR assay and R. Holzman for assistance with the statistical analysis.

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sion of both HCV and HIV. The case of the infant who was HIV DNA – and HCV RNA – positive at birth is consistent with in utero transmission of both viruses. The mother of this child was HCV RNA – negative at birth but had been HCV RNA – positive during the second trimester of pregnancy, further supporting the hypothesis of in utero transmission of HCV, possibly as early as the second trimester, and clarifying how vertical transmission could occur in mothers who are HCV RNA – negative at delivery. It is not known what percentage of vertical HCV transmission occurs in utero. In the present study, only 1 of 3 infants tested at birth was HCV RNA – positive. An alternative explanation for the difference in HCV transmission rates between HIV-infected and -uninfected infants is that HIV-infected infants, who are known to have early deficits in cell-mediated and humoral immunity [26], may have more difficulty than HIV-uninfected infants in eradicating small amounts of HCV that they are exposed to perinatally. Their effective threshold for infection would be lower than that of HCV-exposed HIV-uninfected infants. Although we did not detect differences in clinical, immunologic, or virologic profiles between HIV-infected infants who were HCV-infected or HCV-uninfected during the first 6 months of life, there appeared to be a trend toward a lower HIV load after 6 months of life in the HCV-uninfected infants. This would suggest more effective control of HIV replication in the HCV-uninfected infants. Studies in adults have correlated HCV incidence rates among HIV-1 – infected adults with their level of immunosuppression [22], suggesting a role of host immunity as an important determinant of heterosexual HCV transmission [22]. Larger studies in children need to be done to confirm these findings with respect to vertical HCV transmission. In this study, fewer than one-quarter of the children repeatedly positive for HCV RNA made antibodies to HCV. In some studies, concordance rates between PCR and serology for non – HIV-infected infants have been higher [20]. However, other investigators have also found an impaired humoral response in children with perinatal HCV infection [6, 18, 19, 27 – 29] as well as in children who are infected early in life [29]. It is also known that adults with HIV and HCV coinfection can have a spontaneous loss of anti-HCV antibodies, possibly secondary to immune dysfunction, leading to seroreversion and RIBAindeterminate results [30 – 33]. RNA PCR is, therefore, the method of choice for identifying children with perinatal HCV infection. None of the 3 HIV-uninfected children with HCV infection had clinical evidence of hepatitis or elevation of liver function tests despite persistent HCV viremia. Perinatal HCV infection in immunocompetent children has been shown to be often silent [18, 19, 29]. By contrast, 50% of the HIV-coinfected children, including 2 who developed severe chronic hepatitis, had persistently abnormal liver function tests, in agreement with a prior report [34]. Whether the increased incidence of clinically significant hepatitis is secondary to higher HCV load, coinfection with other hepatotropic viruses (HIV, cytomegalovirus), or the

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18. Paccagnini S, Principi N, Massironi E, et al. Perinatal transmission and manifestation of hepatitis C virus infection in a high risk population. Pediatr Infect Dis J 1995; 14:195 – 9. 19. Thaler MM, Park CK, Landers DV, et al. Vertical transmission of hepatitis C Virus. Lancet 1991; 338:17 – 8. 20. Palomba E, Manzini P, Flammengo P, Maderni P, Saracco G, Tovo PA. Natural history of perinatal hepatitis C virus infection. Clin Infect Dis 1996; 23:47 – 50. 21. Eyster ME, Alter HJ, Aledort LM, Quan S, Hatzakis A, Goedert JJ. Heterosexual co-transmission of hepatitis C virus (HCV). Ann Intern Med 1991; 115:764 – 8. 22. Giuliani M, Caprilli F, Gentilli G, et al. Incidence and determinants of hepatitis C virus infection among individuals at risk of sexually transmitted diseases attending a human immunodeficiency virus type 1 testing program. Sex Transm Dis 1997; 24:533 – 7. 23. French Study Group for the Standardization of Hepatitis C virus PCR. Improvement of hepatitis C virus RNA polymerase chain reaction through a multicentre quality control study. J Virol Methods 1994; 49: 79 – 88. 24. Sherman KE, O’Brien J, Gutierrez AG, et al. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol 1993; 31:2679 – 82. 25. Wiener AJ, Thaler MM, Crawford K, et al. A unique, predominant hepatitis C virus variant found in an infant born to a mother with multiple variants. J Virol 1993; 67:4365 – 8. 26. Borkowsky W, Rigaud M, Krasinski K, Moore T, Lawrence R, Pollack H. Cell-mediated and humoral responses in children infected with human
