The presence of hepatitis C virus (HCV) antibody in human immunodeficiency virus-positive hemophilic men undergoing HCV "seroreversion".

Hepatitis C virus (HCV) is a major cause of transfusion-induced chronic liver disease in hemophiliacs, with 70% to 90% being anti-HCV positive. Seroreversion or loss of antibody response to HCV has been observed in a small proportion of human immunodeficiency virus-positive [HIV(+)] anti-HCV(+) hemophilic men. Despite the seroreversion to an anti-HCV-negative state, such patients continue to show serum alanine aminotransferase (ALT) elevations and biopsy evidence of cirrhosis and/or chronic active hepatitis. To determine the cause for the loss of anti-HCV antibody, we compared first- and second-generation anti-HCV enzyme immunosorbent assay (EIA 1.0 and 2.0), second-generation recombinant immunoblot (RIBA 2.0), and HCV-RNA amplification using polymerase chain reaction (PCR) in 19 "seroreverters" before and after seroreversion. There was no difference between 19 seroreverters and 59 persistently anti-HCV-positive hemophiliacs in mean ALT (1.1 +/- 0.1 XUL v 2.0 +/- 0.2 XUL; chi 2 = 1.80, P > .05), in mean CD4 (188 +/- 36/microL v 232 +/- 28/microL; t = 0.965, P > .05), or in the rate of progression to acquired immunodeficiency syndrome (13 of 19 [68.4%] v 30 of 59 [50.9%]; chi 2 = .987, P > .05, respectively). Before seroreversion, all 19 seroreverters (100%) were positive for EIA 1.0 and 2.0 and PCR, and all but 2 of 19 (89.5%) were RIBA 2.0 positive, whereas, after seroreversion, none were positive for EIA 1.0, 15 of 19 (78.9%) were positive for EIA 2.0, 8 of 18 (44.4%) were positive for RIBA 2.0, and 18 of 19 (94.7%) were positive for PCR. There was a lower CD4 lymphocyte number after seroreversion in those who were RIBA 2.0 negative as compared with those who were RIBA 2.0 positive (32 +/- 10/microL v 171 +/- 52/microL; t = 2.638, P > .05). These results indicate that HIV(+) anti-HCV(+) hemophilic men who undergo "HCV seroreversion" are truly infectious and anti-HCV positive by second-generation tests. Anti-HCV detection in immunosuppressed hosts is significantly improved by second-generation EIA and RIBA assays.

When do gut flora in the newborn produce 3-phenylpropionic acid? Implications for early diagnosis of medium-chain acyl-CoA dehydrogenase deficiency.

Urinary excretion of 3-phenylpropionylglycine (PPG) is a diagnostic marker for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. PPG is derived from 3-phenylpropionic acid (PPA), a product of anaerobic bacterial metabolism in the gut. To determine when the infant gut was colonized with PPA-producing bacteria, we cultured stool in prereduced thioglycollate broth from 93 apparently healthy infants. We analyzed the products of bacterial metabolism by gas chromatography/mass spectrometry for the presence of PPA. Trend analysis demonstrated a significant difference (P less than 0.001) in PPA production between early and later infancy. PPA was not detected in 84% of media isolated from stool collected from infants younger than four months. For older infants, 67% of the samples were PPA-positive. Thus, because the normal gut is not sufficiently colonized with PPA-producing bacteria before three to four months of age, PPG analysis alone is not a sensitive marker for the early detection of MCAD deficiency. Using stable isotope dilution mass spectrometry, we measured PPG and n-hexanoylglycine (HG) excretion in two well newborns with MCAD deficiency. HG, believed to be an endogenous metabolite associated with MCAD deficiency, was consistently above normal in all urine samples.

Hemorrhagic sequelae of immune thrombocytopenic purpura in human immunodeficiency virus-infected hemophiliacs.

Clinical bleeding tendency and tests of immune function were studied prospectively in 11 human immunodeficiency virus (HIV)-infected hemophiliacs with immune thrombocytopenic purpura (ITP) and a platelet count less than 50,000/microL. These 11 patients represented 13% of a well-characterized cohort of 87 HIV + hemophiliacs. ITP developed a mean 3.5 years after seroconversion, mean platelet count at presentation was 36,000/microL (range 15,000 to 49,000/microL), and the mean age at seroconversion was 37.1 years. Nine patients (82%) suffered bleeding complications, including four with intracranial hemorrhage, which was fatal in three. At the onset of ITP, five had AIDS and six were asymptomatic. Mean T4 lymphocyte count at onset of ITP was 126 +/- 32/microL (range 5 to 267/microL). Sustained treatment responses occurred with intravenous gammaglobulin (2 of 2), one of whom spontaneously remitted, and with zidovudine (1 of 2), but not with steroids (0 of 6) or danazol (0 of 3). In conclusion, 13% of a cohort of HIV + hemophiliacs has developed ITP with platelets less than 50,000/microL, a significant proportion of whom (82%) have experienced bleeding complications. It is recommended that treatment for ITP in HIV + hemophiliacs be instituted once the platelet count falls below 50,000/microL in order to avoid serious hemorrhagic sequelae.

Cumulative risk for AIDS and other HIV outcomes in a cohort of hemophiliacs in western Pennsylvania.

The role of age on the risk of developing AIDS and on survival once AIDS occurs was studied in a cohort of HIV(+) hemophiliacs (n = 84), on whom HIV seroconversion dates and clinical endpoints were known. The Kaplan-Meier estimates of the proportion developing AIDS were 12, 28, and 49% by 4, 6, and 7 1/2 years' duration of infection, respectively. The proportion developing AIDS by 6 years after infection was estimated to be 49, 24, and 5% for those greater than 30 years of age at seroconversion, between 18 and 30, and 18 and under, respectively (p less than 0.002). The proportion estimated to have a fatal outcome by 0.5, 1.0, and 1.5 years after AIDS diagnosis was 64, 76, and 88%, respectively, for those over 40 at seroconversion, which was significantly greater than 33, 48, and 81, respectively, for those less than or equal to 40 (p less than 0.01). In conclusion, (a) nearly half of this cohort is estimated to develop AIDS by 7 1/2 years' duration of infection, and (b) older age is associated with significantly shorter time to AIDS and shorter survival once AIDS occurs.

Human immunodeficiency virus transmission and hemophilia.

Heterosexual transmission of human immunodeficiency virus (HIV) accounts for only a small percentage of the cases of acquired immunodeficiency syndrome in the United States, but it is a major public health care issue. However, despite intensive education and counseling regarding HIV transmission and prevention of transmission, including safe sex practices and pregnancy prevention, fewer than half of the couples in which one member is a hemophiliac practice these preventive measures consistently. Because heterosexual HIV transmission is preventable, this poor compliance is puzzling. The implementation of safe sex practices may increase the HIV-associated stress that is experienced by these couples, and the female partner may not necessarily be well informed, fearing testing and confidentiality issues in her own community. By providing education and counseling for female partners of hemophiliacs about their HIV-associated risk or by seeking alternative resources to help accomplish this task, hemophilia care providers will be fulfilling their ethical and moral obligations to these women.

Prognostic importance of antibodies to human immunodeficiency virus by recombinant immunoassay and Western blot techniques in HIV antibody-positive hemophiliacs.

Antibodies to specific HIV viral antigens were measured by ELISA recombinant proteins representing gag and env amino acid sequences of human immunodeficiency virus (HIV) (E. I. du Pont de Nemours, Wilmington, DE) and by a Western blot system using biotinavidin detection (Biotech Research Labs, Rockville, MD) on 36 HIV antibody-positive hemophiliacs (HTLV-III ELISA, du Pont) on whom date of seroconversion was known and on whom serial samples where available between 1977 and 1986, representing 2-8 years following seroconversion. The 36 included 9 acquired immunodeficiency syndrome (AIDS) and 27 non-AIDS (7 AIDS-related complex (ARC); 4 other HIV class IV, 16 asymptomatic) patients. The development of AIDS was preceded 1-4 years by loss or lack of antibody to gag (p15, 24, or 55) and/or to pol (p31, 53, or 64), each p less than 0.001, compared with non-AIDS patients. Correlation between Western blot and recombinant assays was good except in one Western blot p24 (gag) only seroconverter who showed strong reactivity to env by recombinant assay. In conclusion, HIV antibody patterns appear to show prognostic significance in HIV-infected hemophiliacs.

HIV transmission to female sexual partners of HIV antibody-positive hemophiliacs.

To study heterosexual transmission of the human immunodeficiency virus (HIV), 21 HIV antibody-positive hemophiliacs and their 21 spouses-sexual partners were evaluated. None belonged to other AIDS risk groups. HIV antibody was detected in four (19 percent) of the female partners. HIV was isolated from peripheral blood lymphocytes of one hemophiliac (4.8 percent), and one female partner (4.8) was antibody-positive. None of the couples engaged in anal intercourse. Compared with HIV antibody-negative female partners, HIV antibody-positive female partners were younger (P less than .05), had younger hemophiliac partners (P less than .05), and were likely (although not significantly so) to engage in oral sex (P = .08) and to have had more than one sexual partner in the previous 5 years (P = .08). Condoms were used all the time by only eight couples (40 percent), and pregnancy occurred in two other couples (9.5 percent), despite prior counseling. These data confirm the low frequency of heterosexual transmission of HIV from HIV antibody-positive hemophiliacs to their female sexual partners and suggest, moreover, that this may be due to the low rate of HIV infectivity in HIV seropositive hemophiliacs exposed to HIV. Further, these data document the need to design more effective educational programs to prevent heterosexual transmission of HIV.

The disposition of indomethacin in preterm babies.

Limited pharmacokinetic data are available concerning the disposition of indomethacin in preterm infants. Since oral absorption of the drug may be poor or incomplete, the current report provides pharmacokinetic data on 37 premature infants who received indomethacin intravenously. Each of these infants had a hemodynamically significant patent ductus arteriosus. Findings included variable serum indomethacin concentrations from four to 12 hours after a single dose of 0.2 mg/kg. Female preterm infants generally had lower serum drug values at 12 hours and beyond when compared to males. An extrauterine age dependence was found of serum indomethacin levels. Total body clearance, serum half lives and volumes of distribution also bore a direct relationship to extrauterine age. Thus, when indomethacin is administered shortly after birth, one may anticipate a longer duration of action after a single dose and a relatively greater risk of accumulation of the drug when more than one dose is required for treating a duct al patency.