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Anti-hepatitis A virus seroprevalence and seroconversion in a cohort of patients with chronic viral hepatitis.

BACKGROUND: Patients with chronic hepatitis C infected by hepatitis A virus have a substantial risk of fulminant hepatitis or death, while the course of hepatitis A virus is uncomplicated in most subjects with chronic hepatitis B. AIM: To evaluate the prevalence of anti-hepatitis A virus antibodies and the incidence of hepatitis A virus seroconversion in a nationwide sample of 530 patients with chronic hepatitis B and/or hepatitis C infection initially susceptible to this infection after a follow-up of some years. RESULTS: The overall anti-hepatitis A virus prevalence was 85.7%, with no difference between males and females. By the age of 50 years, almost all patients were found to have been exposed to hepatitis A virus. After a mean follow-up period of 76 months the overall anti-hepatitis A virus seroconversion rate in the 76 initially susceptible individuals was 1.2 per 100 person/years. However, it was 0.3 per 100 person/years in those hepatitis B surface antigen positive but 3.36 per 100 person/years in those anti-hepatitis C virus positive. None of the seroconverters was affected by a clinically evident disease or showed deterioration of underlying chronic liver disease. CONCLUSIONS: The present study shows that Italian patients >50 years of age with chronic liver disease have already been exposed to hepatitis A virus suggesting that anti-hepatitis A virus screening is not advisable in these subjects.

Adolescent↗

Statistical models for predicting response to interferon-alpha and spontaneous seroconversion in children with chronic hepatitis B.

To develop prognostic models for identifying children with hepatitis B who are likely to respond to interferon-alpha (IFN-alpha) or to spontaneously seroconvert, we evaluated results of a multinational controlled trial comprising 70 children with chronic hepatitis B who received IFN-alpha and 74 children who did not receive therapy. Prognostic models were developed using SMILES (similarity of least squares), which is a data analysis network that incorporates multidimensional relationships in the clinical data of complex diseases. Commonly collected clinical data included age, gender, serum aminotransferase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and hepatitis B virus (HBV) DNA levels, and IFN-alpha dose. Additional data included pretreatment directional information (e.g. increases or decreases in serum aminotransferase and HBV DNA levels), liver biopsy results, race and transmission mode. Using data available prior to initiation of treatment, the SMILES models achieved prospective predictions of 89% for responders, 96% for non-responders, 100% for seroconverters and 93% for non-seroconverters. Although not predictive by themselves, the variables that had the greatest impact on predictions for IFN-alpha response were HBV DNA pretreatment direction, baseline HBV DNA, IFN-alpha dose and gender. The variables that had the greatest impact on predictions for spontaneous seroconversion were ALT pretreatment direction, baseline HBV DNA level, age and AST pretreatment direction. Therefore, these models may be useful in determining, in children with hepatitis B, the likelihood of response to IFN-alpha and spontaneous seroconversion.

Adolescent↗

Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy.

Hepatitis flares or acute exacerbations, defined as an abrupt elevation of serum alanine aminotransferase (ALT) over fivefold the upper limit of normal (ULN), of chronic hepatitis B virus (HBV) infection are the results of HLA-I restricted, cytotoxic T lymphocyte (CTL)-mediated immune response against HBV and its downstream mechanisms. Higher ALT levels reflect a more vigorous immune response and a more extensive hepatolysis that, in the extreme situation, may lead to decompensation and failure. In contrast, higher ALT also reflects a more robust immune clearance of HBV and, therefore, a higher chance of HBV-DNA loss and hepatitis B e antigen (HBeAg) seroconversion, both in the setting of natural course and drug therapy. Alanine aminotransferase of fivefold the ULN appears to be a significant cut-off level to categorize the patients in terms of endogenous immune response against HBV. Patients with ALT levels less than fivefold the ULN or those with a less vigorous immune response require immunomodulation to induce robust immune response to enhance HBV clearance. In contrast, those with a more vigorous immune response or those with ALT flare over fivefold the ULN should be monitored closely for spontaneous HBV clearance/HBeAg seroconversion or to start direct antiviral therapy in time to prevent the occurrence or deterioration of hepatic decompensation. In conclusion, a better understanding of the pathogenetic mechanisms and natural course of hepatitis flares, wiser selection of patients and the timing of drug therapy are crucial to achieve better treatment results.

Alanine Transaminase↗

Fluctuation of HCV viral load before seroconversion in a healthy volunteer blood donor.

BACKGROUND: Newly implemented NAT has been shown to be able to effectively identify HCV-positive blood donated during the preseroconversion period. STUDY DESIGN AND METHODS: EDTA-plasma pools of 24 donations were tested using an HIV-1/HCV multiplex NAT under an FDA-approved IND application. Samples in a positive pool were retested individually. Positive samples were further tested by two discriminatory assays to determine specific viral reactivity. Upon obtaining informed consent, seronegative donors with positive NAT results were enrolled into a follow-up study for risk factor analysis and laboratory testing. RESULTS: A donation by a 29 year old female was identified as HCV NAT-positive with negative serology and an elevated ALT. Her two previous donations, 5 and 12 months earlier, were both seronegative and with normal ALT. Her husband tested positive for HCV RNA. The donor remained seronegative for at least 36 days. The index donation had a viral RNA concentration of >500,000 copies per mL while the first seropositive sample was NAT-negative. Laboratory data on serial follow-up samples showed 100- to 1,000-fold fluctuations in viral load during a period of 48 days prior to seroconversion. CONCLUSIONS: This case suggests that, at least in some newly infected individuals, the HCV viral load can fluctuate dramatically prior to seroconversion, and that NAT, even on individual samples, will not totally prevent HCV transmission.

Adult↗

Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.

The long-term effect of interferon alfa (IFN-alpha) in Chinese patients with chronic hepatitis B infection is unknown. A total of 411 chronic hepatitis B patients (208 treated with IFN-alpha and 203 as control) were followed up for hepatitis B serology and the development of hepatoma and other cirrhosis-related complications. The hepatitis B e antigen (HBeAg) seroconversion rate in the IFN-alpha-treated group, though significantly greater at 6 and 24 months, was comparable with the control group on subsequent follow-up, irrespective of pretreatment alanine transaminase (ALT) levels. HBeAg seroreversion rate was higher in the IFN-alpha group compared with the control group (21.1% vs. 2.2%; P =.001). Loss of hepatitis B surface antigen (HBsAg) occurred in 2.4% of the IFN-alpha-treated patients and 0.49% of the control patients (P = NS). Around 90% of the anti-HBe-positive patients in both groups were still hepatitis B virus (HBV)-DNA-positive by polymerase chain reaction (PCR) assay. Two patients suffered from hepatic reactivation during the course of treatment. Nine (4.3%) patients in the IFN-alpha group and 2 (1.0%) in the control group developed complications of cirrhosis and hepatoma (P =.062). In Chinese HBsAg carriers, IFN-alpha was of no long-term benefit in inducing HBeAg seroconversion or in the prevention of hepatoma and other cirrhosis-related complications.

Adolescent↗

Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma.

BACKGROUND: If Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma, serologic evidence of infection should be present in patients before the disease develops. METHODS: Using an immunoblot assay for two latent nuclear antigens of KSHV, we tested serum samples from homosexual male patients with the acquired immunodeficiency syndrome (AIDS) with and without Kaposi's sarcoma (HIV-infected men with hemophilia), HIV-seronegative blood donors, and HIV-seronegative patients with high titers of antibodies against Epstein-Barr virus (EBV). Serial serum samples obtained from patients with Kaposi's sarcoma before the diagnosis of the disease were tested for evidence of seroconversion. RESULTS: Of 40 patients with Kaposi's sarcoma, 32 (80 percent) were positive for antibodies against KSHV antigens by the immunoblot assay, as compared with only 7 of 40 homosexual men (18 percent) without Kaposi's sarcoma immediately before the onset of AIDS. Of 122 blood donors, 22 EBV-infected patients, and 20 HIV-infected men with hemophilia, none were seropositive. When studied by the immunoblot assay over a period of 13 to 103 months, 21 of the 40 patients with Kaposi's sarcoma (52 percent) seroconverted 6 to 75 months before the clinical appearance of Kaposi's sarcoma. The median duration of antibody seropositivity for KSHV-related latent nuclear antigens before the diagnosis of Kaposi's sarcoma was 33 months. CONCLUSIONS: In most patients with kaposi's sarcoma and AIDS, seroconversion to positivity for antibodies against KSHV-related nuclear antigens occurs before the clinical appearance of Kaposi's sarcoma. This supports the hypothesis that Kaposi's sarcoma results from infection with KSHV.

Acquired Immunodeficiency Syndrome↗

Risk factors for HIV seroconversion in homosexual men in Australia.

BACKGROUND: Rates of newly acquired HIV infection are increasing in Australia, and sexual contact between men accounts for 85% of cases. OBJECTIVE: To investigate behavioural risk factors for HIV seroconversion among gay and bisexual men from Sydney and Melbourne, Australia. METHODS: 103 men with newly acquired HIV infection were recruited from clinics in Sydney and Melbourne and behavioural risk factor questionnaires were administered between January 2003 and October 2004. Results were compared with a cross sectional and a cohort study performed by our group that enrolled similar populations of men. RESULTS: The majority of seroconverters (73%) reported more than five sexual partners in the last six months. Ninety-five men (92%) were able to identify a high-risk event (HRE) that they thought had led to their HIV seroconversion. Most (70%) reported receptive unprotected anal intercourse (UAI), insertive UAI, or both at their HRE. Sixteen men (16%) reported no UAI in the preceding six months including the HRE. Men were more likely to report receptive UAI at their HRE when they perceived a partner to be HIV-negative as compared with when they perceived a partner to be HIV-positive (P = 0.05). Injection drug use was reported by 22% of the men in the previous six months, and 62% reported intoxication with alcohol (> or =5 drinks) or mood altering recreational drug use at the HRE. CONCLUSIONS: Gay and bisexual men who have recently seroconverted are highly sexually active and report high rates of unprotected anal intercourse and recreational drug use at the HRE.

Australia↗

Decline in HIV-1 seroprevalence and low seroconversion rate among injecting drug users at a methadone maintenance program in New York City.

To monitor the trend of HIV-1 seroprevalence, 2,194 newly admitted injecting drug users (IDUs) in a methadone maintenance program in New York City were tested from June 1988 through June 1992. This was a blinded study and unlabeled blood specimens were collected during the required physical examination. There was a significant linear trend (p = .01) toward decline in HIV-1 seropositivity by year of admission as follows: 47.0% in 1988, 43.4% in 1989, 43.2% in 1990, 39.8% in 1991, and 39.1% in 1992. From January 1988 through December 1992, admissions data that included the newly admitted IDUs showed a significant decrease (p < .0002) in self-reported current needle sharing from 11.3% to 5.4%. These two data sources suggest that a continued decline in HIV-1 seroprevalence among new admissions may be related to decreased needle sharing. A volunteer cohort of 235 HIV-1 seronegative IDUs was also enrolled from April 1990 through June 1991 in a study of HIV-1 seroconversion. Follow-up data were available on 177 patients for up to 12 months. For a total observation time of 155 person-years, there were two conversions (1.3 conversions per 100 person-years). A continued decline in HIV-1 seroprevalence among new admissions and a low HIV-1 seroconversion rate among existing patients have contributed to a lower overall HIV-1 prevalence in clinic patients of about 40%. This stands in contrast to 1985-86 estimates of HIV-1 seroprevalence that plateaued at 60%.

Adult↗

Characterization of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte clones isolated during acute seroconversion: recognition of autologous virus sequences within a conserved immunodominant epitope.

Virus-specific cytotoxic T lymphocytes (CTL) are involved in protective immunity to many virus infections. It has recently been shown that CTL are detectable early during primary infection with the primate lentiviruses, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus. To better characterize the CTL response during acute HIV-1 infection, HIV-1-specific CTL clones were generated from two patients during symptomatic HIV-1 seroconversion. These CTL clones demonstrated specificity for env of HIV-1 and recognized sequences within gp41. Two human histocompatibility leukocyte antigen (HLA) A31-restricted clones from the same individual were found to have differing virus strain specificities. Both clones recognized the 11-amino acid peptide RLRDLLLIVTR from position 770-780 of gp41. A change from T to V at position 779 in this epitope abrogated lysis by one clone but not the other. A CTL clone from the other patient, restricted by a different class I HLA allele, recognized the nine-amino acid peptide HRLRDLLLI from position 769-777 of gp41. Of note, the peptide RLRDLLLIVTR has been shown by others to be presented to CTL by HLA-A3.1. Autologous virus sequences from seroconversion and up to 15 wk after presentation in these two patients were recognized by the CTL clones isolated during acute infection. None of the CTL clones recognized the MN strain of HIV-1, indicating the problems inherent in relying on a single virus strain in the development of a vaccine. These studies have identified an immunodominant and promiscuous area for the generation of CTL responses within gp41. This recognition of autologous virus sequences by the initial CTL response is consistent with the hypothesis that a single virus strain is transmitted to the seroconverter and that the CTL response is involved in the initial control of that virus. These studies indicate the importance of the CTL response to HIV-1 infection and have implications in the design of vaccines.

Adult↗

Relationship between human immunodeficiency virus type 1 (HIV-1)-specific memory cytotoxic T lymphocytes and virus load after recent HIV-1 seroconversion.

Human immunodeficiency virus type 1 (HIV-1)-specific memory, or precursor, cytotoxic T lymphocytes (CTL) in 14 subjects who had recently experienced seroconversion were evaluated with respect to virus set point, defined as plasma HIV-1 RNA level 6 months after seroconversion. Env-, Gag-, Pol-, and Nef-specific precursor CTL were detected in (51)Cr-release assays, using antigen-stimulated peripheral blood mononuclear cells as effectors and B cell lines infected with HIV-1-vaccinia recombinants as targets. All subjects tested had precursor CTL specific to at least 2 HIV-1 antigens. Detection of Env-specific precursor CTL was associated with a high set point (P=.0221). The number of antigens recognized tended to be greater in subjects with higher set points (rho=.45621; P=.1171). Gag-specific precursor CTL frequency correlated inversely with set point (rho=-.8478; P=.0003). Two heterozygotes for a 32-bp deletion in CCR5 had the lowest set points (P=.0220) and highest Gag precursor CTL frequencies (P=.0128). These data suggest that host factors that restrict viral replication may be important determinants of the level of HIV-1-specific precursor CTL.

Acquired Immunodeficiency Syndrome↗

Relationship between the development of precore and core promoter mutations and hepatitis B e antigen seroconversion in patients with chronic hepatitis B virus.

Chinese patients with chronic hepatitis B virus (332 with and 44 without cirrhosis-related complications) were studied. Fifty percent of patients <30 years old had precore mutations. The prevalence of precore mutations among hepatitis B e antigen (HBeAg)-positive patients, although lower than that among anti-HBe-positive patients (P=.031), was already high (44.2%). Median HBV DNA level in anti-HBe-positive patients was 1.5 x 10(6)-1.55 x 10(6) copies/mL, irrespective of the presence or absence of precore mutations. There was no difference in the prevalence of precore mutations between patients with and without complications (P, not significant). However the prevalence of core promoter mutations was higher among patients with complications than among those without complications (90.5% vs. 69.3%, respectively; P=.003). In conclusion, precore mutations occurred in a large proportion of Chinese patients with chronic hepatitis B virus before HBeAg seroconversion. The development of complications was not related to precore mutations but was probably due to the persistence of significant viremia after HBeAg seroconversion.

Adolescent↗

Seroconversion against Lutzomyia longipalpis saliva concurrent with the development of anti-Leishmania chagasi delayed-type hypersensitivity.

Antibody responses to salivary gland sonicate (SGS) from Lutzomyia longipalpis were investigated using serum samples from individuals living in an area where visceral leishmaniasis is endemic. Individuals were classified into 2 groups, according to the alteration of their responses to Leishmania chagasi antigen over the course of 6 months. Group 1 included children who experienced anti-L. chagasi seroconversion from negative to positive; group 2 included children who experienced delayed-type hypersensitivity (DTH) response to L. chagasi antigen conversion from negative to positive. Individuals who experienced seroconversion against L. chagasi antigens did not have increased anti-saliva antibody response, whereas those who developed a positive anti-L. chagasi DTH response had increased immunoglobulin (Ig) G, IgG1 and IgE anti-SGS antibody levels. Despite wide variation, serum samples from individuals in group 2 recognized more bands in SGS than did those from individuals in group 1. This simultaneous appearance of anti-saliva humoral response and anti-L. chagasi cell-mediated immunity supports the hypothesis that induction of immune response against SGS can facilitate induction of a protective response against leishmaniasis.

Animals↗

Undetectable viremia without antiretroviral therapy in patients with HIV seroconversion: an uncommon phenomenon?

BACKGROUND: The objective of this study was to identify the frequency and characteristics of patients with human immunodeficiency virus (HIV) infection who had spontaneously achieved viremia below the detection limit of either 400 or 500 copies/mL (depending on the test used) and to describe the duration of undetectable viremia without antiretroviral therapy (ART). METHODS: In the French Agence Nationale de Recherches sur le SIDA SEROCO cohort, 426 patients with HIV seroconversion (i.e., seroconverters) enrolled between 1988 and 1995 had serial measurement of HIV RNA levels during follow-up (with a cutoff date of 31 December 2002). Factors that distinguished those patients who had spontaneously achieved undetectable viremia (> or =2 consecutive viral loads <400 or <500 copies/mL while not receiving ART) were identified by logistic regression. A Cox model was used to estimate the predictive value of factors related to the duration of undetectable viremia. RESULTS: Undetectable viremia had been spontaneously achieved in 36 of 426 seroconverters. Women (adjusted odds ratio [aOR], 2.44; 95% confidence interval [CI], 1.03-5.80) and subjects with baseline HIV RNA level < or =3.76 log10 copies/mL (aOR, 0.31; 95% CI, 0.11-0.82), baseline HIV DNA level < or =2.61 log10 copies/mL (aOR, 0.14; 95% CI, 0.04-0.44), and high baseline CD4+ cell count (aOR, 1.18 for each 100 cells/mm3; 95% CI, 1.03-1.35]) were more likely to have achieved undetectable viremia. The sustainability of this phenomenon (median duration, 11.9 months; range, 4.6-62.8 months) was associated with low baseline HIV DNA and RNA levels. CONCLUSIONS: Achieving undetectable viremia without ART was not rare, because 6.7% of seroconverters still had a viral load of <400 or <500 copies/mL 5 years after seroconversion. These data should be considered when assessing virologic outcome for patients who interrupt highly active ART initiated during primary infection.

Adolescent↗

Serum levels of human immunodeficiency virus type 1 (HIV-1) RNA after seroconversion: a predictor of long-term mortality in HIV infection.

A cohort of 79 homosexual men with documented dates of human immunodeficiency virus type 1 (HIV-1) seroconversion and baseline CD4 cell counts of > or = 500/microL were followed for up to 11.5 years. HIV-1 RNA was measured from stored sera obtained a median of 7 months after the estimated seroconversion date. AIDS progression and mortality among the men were studied, stratified by median baseline levels of HIV-1 RNA. AIDS progression rates at 11.5 years were 69% and 34%, respectively, among those with higher versus lower than median baseline virus loads (> or = 3040 copies/mL; P = .002), and mortality rates were 61% and 27%, respectively (P = .003). Survival curves continued to diverge throughout the 11.5 years, suggesting that the future clinical course of HIV-1 infection may already be determined at the earliest phases of disease. Initiation of definitive treatment very early in HIV-1 infection may be essential.

Adult↗

Proposed antiretroviral therapy guidelines for prophylaxis of occupationally related HIV seroconversion: a practical approach.

Recent research indicates that antiretroviral prophylaxis significantly reduces occupationally related human immunodeficiency virus (HIV) seroconversion. This article outlines principles on which guidelines were based for treating aggressively those healthcare workers (HCWs) exposed to HIV occupationally at the Catholic Medical Center in Jamaica, New York. These recommendations attempt to provide HCWs with the best possible available antiretroviral therapy to treat occupational HIV seroconversion. New options must continue to be explored as new information becomes available.

Anti-HIV Agents↗

Antibodies to HIV-1 nef(p27): prevalence, significance, and relationship to seroconversion.

A sensitive and specific enzyme-linked immunoassay for antibodies to the human immunodeficiency virus type 1 (HIV-1) nef gene product, p27, has been developed using recombinant Escherichia coli-derived protein from the LAV-1-Bru sequence. Of 92 HIV-1 infected hemophiliacs, 72 (78%) produced anti-nef antibodies in this assay; the early appearance of anti-nef prior to full seroconversion was a rare event in this population, occurring in only one subject (approximately 1%). Anti-nef antibodies were not detected in any of 500 sera from 98 repeatedly HIV seronegative subjects who had been exposed to sexually transmitted modes of HIV infection (45 subjects) or through blood products (53 subjects). There was no significant association of titer or anti-nef antibody with protection from disease in HIV infection (p = 0.1). Although the nef protein is relatively immunogenic in natural infection, this study cannot confirm the previously reported high prevalence of anti-nef antibodies prior to seroconversion, nor the finding of anti-nef antibodies in HIV seronegative but exposed subjects.

Cohort Studies↗

Anti-CD4 antibodies are associated with HIV-1 seroconversion and may be detectable before anti-HIV-1 antibodies. The Multicenter AIDS Cohort Study.

We examined the sera from 14 HIV-1 seroconverters for the presence of autoantibodies against CD4. Anti-CD4 antibodies were detected in the serum of 11 of 13 HIV-1-infected persons at the time of HIV-1 seroconversion. In 6 of 14 persons from whom a serum was obtained prior to HIV-1 seroconversion, anti-CD4 antibodies were found 90 to 540 days before antibodies to HIV-1 were detectable. In comparison, anti-CD4 antibodies were present in only 7 serum samples from 62 HIV-1 seronegative individuals, including 50 from a seronegative homosexual male cohort. These results suggest that anti-CD4 antibodies are generated in response to early HIV-1 infection and possibly could be used as a marker for HIV-1 infection in some infected persons who are seronegative for HIV-1.

Autoantibodies↗

Alcoholism and rapid progression to AIDS after seroconversion.

Rapid progression of infection with human immunodeficiency virus type 1 (HIV-1) to AIDS after seroconversion is rare; it has been associated with coinfection by cytomegalovirus or human T lymphotrophic virus type I. We describe an alcoholic patient whose condition progressed to AIDS 3 months after HIV-1 seroconversion occurred. Culture of peripheral blood mononuclear cells yielded a syncytium-inducing variant of HIV-1. T lymphocytes showed no spontaneous cytotoxic activity against HIV-infected cells, nor could such activity be demonstrated following stimulation with HIV-1 antigen in the presence of recombinant interleukin-2. We hypothesize that our patient's accelerated course was due to alcohol abuse, which may have suppressed T cell function and stimulated HIV replication.

Acquired Immunodeficiency Syndrome↗