Katherine Davenny

Perinatal Transmission of Hepatitis C Virus from Human Immunodeficiency Virus Type 1-Infected Mothers

Antepartum plasma hepatitis C virus (HCV) RNA was quantified in 155 mothers coinfected with HCV and human immunodeficiency virus type 1 (HIV-1), and HCV RNA was serially assessed in their infants. Of 155 singleton infants born to HCV antibody-positive mothers, 13 (8.4%) were HCV infected. The risk of HCV infection was 3.2-fold greater in HIV-1-infected infants compared with HIV-1-uninfected infants (17.1% of 41 vs. 5.4% of 112, P = .04). The median concentration of plasma HCV RNA was higher among the 13 mothers with HCV-infected infants (2.0 x 10(6) copies/mL) than among the 142 mothers with HCV-negative infants (3.5 x 10(5) copies/mL; P < .001), and there were no instances of HCV transmission from 40 mothers with HCV RNA concentrations of < 10(5) copies/mL. Women dually infected with HIV-1 and HCV but with little or no detectable HCV RNA should be reassured that the risk of perinatal transmission of HCV is exceedingly low.

Increased Vertical Transmission of Human Immunodeficiency Virus from Hepatitis C Virus-Coinfected Mothers

To determine if hepatitis C virus (HCV) infection affects vertical transmission of human immunodeficiency virus (HIV), 487 HIV-infected pregnant women in the prospective, multicenter, Women and Infants Transmission Study had HCV antibody (anti-HCV by second-generation ELISA) and HCV RNA (by quantitative polymerase chain reaction) measured in peripartum maternal plasma; 161 (33%) were anti-HCV-positive. HIV vertical transmission occurred from 42 HCV-infected mothers (26.1%) versus 53 HCV-uninfected mothers (16.3%; odds radio [OR], 1.82; P = .01). In a logistic regression model that included maternal drug use, a potential confounder, HCV infection was marginally associated with perinatal HIV transmission (OR, 1.64; P = .05), whereas drug use was not. Women who transmitted HIV had higher levels of HCV RNA (median, 721,254 copies/mL) than those who did not (337,561 copies/mL; P = .01). Maternal HCV infection is associated with increased HIV vertical transmission. Further studies are needed to ascertain if HCV directly affects perinatal HIV transmission or is a marker for another factor, such as maternal drug use.

Effects of HIV Infection on the Serologic Manifestations and Response to Treatment of Syphilis in Intravenous Drug Users

Much uncertainty exists concerning the serologic manifestations, clinical course, and treatment of syphilis in persons infected with the human immunodeficiency virus (HIV). Atypical manifestations have been described, including fulminant presentation [1-4], rapid progression [5-7], irregular serologic findings [8, 9], and failure of conventional doses of penicillin to eradicate infection [10, 11]. Many clinicians are therefore treating syphilis more aggressively in patients with HIV infection. Persistence of syphilis after conventional doses of penicillin, although rare, was well described before the acquired immunodeficiency syndrome (AIDS) epidemic [6, 12], and treatment failure may also be rare in HIV-infected patients. The incidence of syphilis has increased dramatically during the last decade [13], as has coinfection with HIV [14, 15]. Users of intravenous drugs and crack cocaine, already at high risk for HIV infection, are also at substantial risk for syphilis [16-20]. Diagnosis and treatment of syphilis in HIV-infected intravenous drug users may be further complicated by the atypical syphilis serologic profiles known to occur in narcotic addicts [21, 22]. To assess the role of HIV infection on stage at presentation, serologic profiles, and response to therapy of patients with syphilis, we studied a cohort of HIV-seropositive and HIV-seronegative intravenous drug users attending a methadone maintenance treatment program in New York City, the site of an ongoing longitudinal study of HIV infection [23, 24]. Methods Cohort Description Data for this study were pooled from two sources. A longitudinal study of HIV infection among current and former intravenous drug users, initiated in mid 1985 in a long-term methadone maintenance program in New York City, has been previously described [23, 24]. In addition, a primary care clinic on the same site as the methadone program provided mandatory annual syphilis screening to all program patients, as well as ongoing primary medical care that included syphilis diagnosis and treatment [25]. All patients attending the program at any time between July 1985 and April 1991 were eligible for inclusion in this study. Baseline Measurements Baseline historical data concerning syphilis were obtained at enrollment, at 6- to 12-month intervals thereafter for all patients, and as indicated clinically when a diagnosis of syphilis was suspected by on-site medical providers. All patients underwent mandatory annual screening for syphilis (Roche Laboratories, Raritan, New Jersey) with a nontreponemal test (automated reagin test [ART, 1985 to 1986] or rapid plasma reagin [RPR, 1986 to 1991]). Reactive specimens were tested with a treponemal test (fluorescence treponemal antibody absorption test [FTA-Abs, 1985 to 1990] or microhemagglutination assay for antibodies to Treponema pallidum [MHA-TP, 1990 to 1991]). Nontreponemal test sera were not titrated beyond a 1:256 dilution. Patients with reactive serologic tests were further evaluated, staged, and treated if clinically indicated. Serum was analyzed at baseline and at 6-month intervals for evidence of HIV infection by enzyme immunoassay (Abbott Laboratories, North Chicago, Illinois), with confirmation by Western blot. Additional serum was frozen for future assay, including serologic testing for syphilis. Chart Review We reviewed the methadone program medical records and research database since July 1985 of all patients who 1) reported a recent history of syphilis; 2) showed reactive nontreponemal and treponemal tests for syphilis; 3) received treatment for syphilis at the on-site primary care clinic; or 4) were identified as possible syphilis cases through a review of hospital records. Data abstracted from medical and research records of each patient included previous history and treatment of syphilis, physical findings, date of confirmed HIV serologic status, CD4+ T-lymphocyte counts, treatment regimen, and baseline and post-treatment serologic studies. All serologic data reported here were obtained from fresh sera; results from frozen sera were only used to prompt chart review. Case Definition All patients with known HIV serologic status having both reactive nontreponemal and treponemal test results on at least one specimen were considered to have syphilis. Patients with reactive nontreponemal tests and nonreactive treponemal test results were classified as having biologic false-positive results, regardless of the titer [26, 27]. Patients with syphilis who had nonreactive FTA-Abs or MHA-TP test results after treatment were classified as FTA-Abs or MHA-TP reverters. The first date on which a patient had reactive nontreponemal and treponemal test results prompting treatment was considered the date of diagnosis. Patients with positive HIV serologic test results before or within 6 months of the diagnosis of syphilis were considered to be HIV seropositive; those with negative HIV test results after syphilis diagnosis were considered to be HIV seronegative. When applicable, HIV seroconversion dates were calculated as the midpoint between last negative and first positive HIV test result. Seroconverters were considered to be HIV seropositive if the assigned seroconversion occurred closer to the date of syphilis diagnosis than to the previous negative HIV test result. Patients with unknown HIV serologic status within 6 months of syphilis diagnosis were excluded from this study. Staging, Treatment, and Response Criteria Centers for Disease Control (CDC) criteria were used to stage syphilis cases and to classify treatment regimens and response to therapy [28, 29]. Dark-field microscopy was not available. Patients with a history of previous treatment for syphilis without evidence of new infection were excluded. Serologic results for HIV among patients enrolled in the longitudinal study were not routinely available to clinicians who diagnosed and treated syphilis. Data on sexual contacts regarding syphilis were unreliable, and therefore we could not differentiate relapse from reinfection with syphilis. The rate of titer change was determined using the time from syphilis treatment to the date the nontreponemal titer decreased sufficiently or failed to decrease sufficiently to meet CDC criteria for an adequate response [29]. Indications for Lumbar Puncture The presence of uveitis, neurologic signs or symptoms, or treatment failure in patients with syphilis prompted referral for lumbar puncture. Neither serum nontreponemal titer of 1:32 or greater nor HIV-seropositive status routinely prompted such referral [29]. A diagnosis of neurosyphilis was made if the cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test was reactive. Statistical Analyses Proportions were compared using chi-square analysis or the Fisher exact test. The Student t-test was used for comparisons of means of normally distributed data. Comparisons between non-Gaussian distributions (for example, nontreponemal titers) were done using the Wilcoxon test. Odds ratios and 95% confidence intervals (CIs) were calculated using standard methods. Correlation between non-Gaussian distributions were done using the Spearman correlation coefficient. All P values were derived using two-tailed tests and were considered significant at P = 0.05. Power calculations were done by standard methods [30]. Results Fifty patients attending the methadone maintenance treatment program from mid 1985 to April 1991 met the case definition for syphilis (Table 1). Table 1. Comparison of Demographic Characteristics of Patients with Syphilis* No significant differences were seen in stage of syphilis at presentation by HIV serologic status (Table 2). Clinical findings in all cases were typical for the stage of syphilis, with no evidence of unusually fulminant manifestations of syphilis among HIV-seropositive patients. Table 2. Stage of Syphilis at Presentation among All Syphilis Cases by Human Immunodeficiency Virus Status* Four HIV-seropositive patients with late latent syphilis received lumbar puncture. All four had negative CSF VDRL results. A fifth HIV-seropositive patient with an uncertain history of syphilis but with reactive serologic tests was hospitalized for fever and found to have a reactive CSF VDRL, consistent with asymptomatic neurosyphilis. Two additional patients, one with HIV infection, were diagnosed with syphilitic uveitis. Each had a reactive CSF VDRL, consistent with symptomatic neurosyphilis. No patient receiving lumbar puncture for the evaluation of neurosyphilis had an elevated CSF leukocyte count with a nonreactive CSF VDRL. Nontreponemal Titers Maximum nontreponemal titers were higher among HIV-seropositive (median, 1:128) than among HIV-seronegative (median, 1:32) patients with syphilis (P = 0.05) (Figure 1). This association was seen only among the 18 patients reporting a previous history of syphilis, even when maximum nontreponemal titers were corrected for the level of serofast titer preceding the episode of syphilis under investigation. Figure 1. Distribution of maximum nontreponemal titers by human immunodeficiency virus (HIV) serologic status. P The Mantel-Haenszel summary odds ratio for the association between HIV seropositivity and nontreponemal titer of 1:256 or greater, across all stages of syphilis, was 2.6 (95% CI, 1.3 to 3.9). No correlation was seen between maximum nontreponemal titer and CD4+ T-lymphocyte count for HIV-seropositive patients (Spearmans rho = 0.07, P > 0.2). Follow-up Median length of follow-up from the date of first treatment for syphilis until the last serologic evaluation was 11.4 months (range, 1.6 to 55.6 months) for 47 patients, with no difference by HIV serologic status. One HIV-seronegative and one HIV-seropositive patient left the methadone program after treatment, and the exact date of treatment was unknown for one HIV-seronegative patient. Treatment and Response Response to treatment could be assessed adequately in 43 of the 50 pat

Hepatitis C Virus Coinfection and HIV Load, CD4+ Cell Percentage, and Clinical Progression to AIDS or Death among HIV-Infected Women: Women and Infants Transmission Study

BACKGROUNDnDespite previous study, it remains unclear whether hepatitis C virus (HCV) coinfection affects the progression of human immunodeficiency virus (HIV) type 1 infection. The Women and Infants Transmission Study provided an opportunity to assess this issue.nnnMETHODSnLongitudinal data on 652 HIV-1-infected women enrolled in the study before the availability of highly active antiretroviral therapy (HAART; 1989-1995) were analyzed. Random effects models were used to determine whether HCV coinfection was associated with different CD4+ cell percentages and HIV-1 RNA levels over time, and Cox proportional hazards models were used to compare the rates of clinical progression to acquired immunodeficiency syndrome (AIDS) or death.nnnRESULTSnOf 652 women, 190 (29%) were HCV infected. During follow-up, 19% of women were exposed to HAART. After controlling for indicators of disease progression (CD4+ cell percentages and HIV-1 RNA levels determined closest to the time of delivery in pregnant women), ongoing drug use, receipt of antiretroviral therapy, and other important covariates, no differences were detected in the HIV-1 RNA levels, but the CD4+ cell percentages were slightly higher in HCV-infected women than in HCV-uninfected women. During follow-up, 48 women had progression to a first clinical AIDS-defining illness (ADI), and 26 died with no documented antecedent ADI. In multivariable analyses, HCV-infected participants did not have faster progression to a first class C AIDS-defining event or death (relative hazard, 0.75; 95% confidence interval, 0.37-1.53).nnnCONCLUSIONSnIn this cohort, the rate of clinical progression of HIV-1 infection was not greater for HCV-infected women.

Evaluation of Human Immunodeficiency Virus (HIV) Type 1 Load, CD4 T Cell Level, and Clinical Class as Time-Fixed and Time-Varying Markers of Disease Progression in HIV-1—Infected Children

Human immunodeficiency virus (HIV) type 1 RNA load, CD4 T cell level, and Centers for Disease Control and Prevention (CDC) clinical class history were measured as potential correlates of a CDC class C diagnosis or death in 165 HIV-1-infected children followed from birth. These covariates were assessed at fixed landmark ages from 6 to 24 months and were also assessed as time-varying values. Virus load was associated with progression in all analyses, even after adjusting for immunologic and clinical status. This confirms its importance for monitoring pediatric disease progression. CD4 T cell level was associated with disease progression in time-varying but not in adjusted landmark analysis, suggesting that CD4 cells reflects immediate risk more than long-term risk. The distinction between clinical class B and lower classes is prognostic during the first 18 months of life; class C versus classes N/A/B becomes more important as the patient ages. Virologic, immunologic, and clinical status all provide information regarding disease progression risk.

Laboratory markers and the risk of developing HIV-1 disease among injecting drug users

ObjectiveTo characterize the progression to HIV-1 disease among injecting drug users (IDU) according to laboratory markers. DesignProspective study of cohort of HIV-1-seroprevalent IDU, with case-comparison component. MethodsDifferent laboratory markers were examined as predictors of progression to HIV-1-associated diseases including AIDS in a cohort of 318 HIV-1-infected IDU. The cohort was enrolled from a methadone treatment program in the Bronx, New York, USA. The independent utility of non-CD4 cell markers was evaluated after adjustment for the association of low CD4 lymphocyte count with AIDS risk. Clinical events in the natural history of HIV-1 were related to changes in levels of two variables related to duration of infection, CD4 lymphocyte count and serum β2-microglobulin (β2M) concentration. ResultsOn univariate analysis, AIDS incidence measured from baseline increased with declining CD4 lymphocyte number and percentage, increasing serum β2M level, low platelet count, low leukocyte count and p24 antigenemia. Among HIV-1-related outcomes prior to any AIDS diagnosis, the relative risk of pyogenic bacterial infections conferred by these markers was similar to the relative risk of AIDS. For all HIV-1 outcomes, the elevated risk encountered at CD4 lymphocyte number ≤ 200x106/l was entirely due to the high risk at ≤150x106/l. On multivariate analysis, control for CD4 lymphocyte count eliminated the association of any other marker with increased AIDS hazard. HIV-1-related outcomes tended to occur in this order: multiple constitutional symptoms, oral candidiasis, pyogenic bacterial infections and AIDS. ConclusionsIn HIV-1-infected IDU, several laboratory markers may predict AIDS when analyzed individually. These are not, however, independently related to increased AIDS risk after adjustment for low CD4 lymphocyte count. A CD4 count ≤150×106/l is more strongly related to immediate risk of adverse outcome than a count of 200×106/l. A progressive series of clinical events is associated with markers of duration, of HIV-1 infection, prior to and including AIDS diagnosis.

A Comparison of Peripheral Blood Coculture versus 18- or 24-Month Serology in the Diagnosis of Human Immunodeficiency Virus Infection in the Offspring of Infected Mothers

The Women and Infants Transmission Study (WITS) has established virologic definitions of human immunodeficiency virus (HIV)-infected and uninfected children that have been widely used but never formally compared with serologic definitions of infection. Data from the offspring of HIV-infected women in the WITS with frequent HIV cultures during the first year of life and with HIV serology at 18 and/or 24 months of age were analyzed. Seventy-seven infants were HIV-infected and 430 uninfected by both virologic and serologic criteria. Thirteen were virologically infected (> or = 2 positive cultures) but either seronegative or serologically indeterminate. All but 1 of these had clinical HIV disease at the time of analysis. In this pediatric cohort, children defined as infected by virologic criteria often (13/90) had negative or indeterminate serology despite symptoms of HIV disease. Results suggest that serology at 18-24 months has high specificity but poor sensitivity. It should not be considered the reference standard in identifying HIV infection in perinatally exposed children.