Biomedical subjects
Publications and source records attributed to A Hatzakis.
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Phylogenetic analysis of partial env sequences of HIV-1 isolates from Cyprus and Greece suggested the existence of a distinct subtype of the virus, designated as I. We examined whether this subtype represents a distinct group, or a mosaic consisting of previously characterized subtypes. The full-length sequences under consideration were recovered from serum samples of "subtype I" obtained from two nonepidemiologically linked HIV-1-infected subjects in Greece. The first subject was an intravenous drug user (IDU), while the second was a vertically infected child born in 1984 whose parents were both IDUs. A variety of methods, such as diversity plots as well as phylogenetic and informative site analyses, were used to classify the DNA sequences. Subsequent detailed analysis revealed a unique genomic organization composed of alternating portions of subtypes A, G, and I. The two Greek isolates formed a distinct group in most of the pol, gp120, and gp41 regions, and in the vif/vpr, vpu, LTR, and 5' terminus of nef. In contrast, different parts of env and gag as well as the 3' pol region, and the first exons of tat and rev, appeared to have arisen from subtypes A and G. Our results indicate that subtype I, which was probably circulating in Greece in the early 1980s, is a triple mosaic consisting of A, G, and I sequences.
BACKGROUND: Cryoglobulins are associated with chronic infections. OBJECTIVE: To investigate the prevalence of mixed cryoglobulinemia in patients with HIV-1 infection, the clinical spectrum of cryoglobulinemia in these patients, and the possible role of HIV-1 in cryoglobulin formation. DESIGN: Prospective cohort study. SETTING: Laiko Hospital, Athens, Greece. PATIENTS: 89 patients with HIV-1 infection. MEASUREMENTS: Serum and cryoglobulins were evaluated for antibodies to HIV and hepatitis C virus (HCV), HIV-1, and HCV viral load. RESULTS: Mixed cryoglobulins were detected in 24 patients with HIV-1 infection (27% [95% CI, 18% to 36%]). The HIV-1 viral load was higher in cryoglobulin-positive patients (median, 38.25 x 10(3) copies/mL [25th, 75th percentiles: 13.8 x 10(3) copies/mL, 78.55 x 10(3) copies/mL]) than in cryoglobulin-negative patients (median, 5.3 x 10(3) copies/mL [25th, 75th percentiles: 0.7 x 10(3) copies/mL, 27.2 x 10(3) copies/mL]) (P = 0.001). Antibodies to HIV were detected in all cryoprecipitates, and HIV-1 RNA sequences were identified in 22 of the 23 cryoprecipitates examined. Nine cryoglobulin-positive patients (38% [CI, 19% to 54%]) had clinical manifestations compatible with cryoglobulinemia. CONCLUSIONS: Mixed cryoglobulinemia is common in patients with HIV-1 infection.
Fibrosing cholestatic hepatitis (FCH) has been described as a specific manifestation of hepatitis B virus (HBV) infection in liver allograft recipients characterized by a rapid progression to liver failure. Only sporadic cases have been reported in other immunocompromised groups infected with HBV and in a few transplant recipients with hepatitis C virus (HCV) infection. We present the occurrence of FCH in 4 HCV-infected renal transplant recipients within a series of 73 renal transplant recipients with HCV infection followed up closely serologically and with consecutive liver biopsies. All 4 patients received the triple-immunosuppressive regimen (azathioprine, cyclosporine A, methylprednisolone). The interval from transplantation to the appearance of liver dysfunction was 1 to 4 months and to histological diagnosis, 3 to 11 months. The biochemical profile was analogous to a progressive cholestatic syndrome in 3 patients, whereas the fourth patient had only slightly increased alanine aminotransferase and gamma-glutamyl transferase (gammaGT) levels. Liver histological examination showed the characteristic pattern of FCH in 2 patients, whereas the other 2 patients had changes compatible with an early stage. All patients were anti-HCV negative at the time of transplantation, whereas 2 patients, 1 with incomplete and 1with complete histological FCH features, seroconverted after 3 and 31 months, respectively. The patients were HCV RNA positive at the time of the first liver biopsy and showed high serum HCV RNA levels (14 to 58 x 10(6) Eq/mL, branched DNA). HCV genotype was 1b in 3 patients and 3a in 1 patient. After histological diagnosis, immunosuppression was drastically reduced. Two patients died of sepsis and liver failure 16 and 18 months posttransplantation, whereas the seroconverted patients showed marked improvement of their liver disease, which was histologically verified in 1 patient. In conclusion, FCH can occur in HCV-infected renal transplant recipients. It seems to develop as a complication of a recent HCV infection during the period of maximal immunosuppression and is associated with high HCV viremia levels. There are indications that drastic reduction of immunosuppression may have a beneficial effect on the outcome of the disease.
The purpose of this study was to determine hepatitis C virus (HCV) genotypes and their relationship to HCV RNA levels over time in a cohort of multitransfused hemophiliacs. Following reverse transcription and polymerase chain reaction amplification of HCV RNA, the product DNAs were genotyped by using the line probe assay. HCV RNA was quantified by the branched-chain DNA assay. Genotyping was done on 109 serum samples from 32 subjects. Genotype 3a had the highest prevalence (41%), followed by genotypes 1a (31%) and 1b (13%). Changes in genotypes were observed in 18 (58%) of the subjects >3-15 years of age. Changes were more common in human immunodeficiency virus (HIV)-positive subjects (13/17) than in HIV-negative subjects (5/15) (P=.014). HCV RNA increased 30-fold in HIV-positive subjects whose genotypes changed. Consensus nucleotide sequencing confirmed genotype changes in 2 patients. We conclude that genotype changes are common in hemophiliacs with chronic HCV, particularly in those who are coinfected with HIV.
BACKGROUND: Haemodialysis patients are at high risk of infection by hepatitis C virus. The aim of this study was to investigate a hepatitis C virus outbreak which occurred in a haemodialysis unit, using epidemiological and molecular methods. METHODS: Five seroconversions to hepatitis C virus antibody (anti-HCV) were observed over a 6 month period and these were added to the four previously recorded anti-HCV-positive patients. All nine patients involved in the outbreak were tested for HCV RNA by reverse transcription-polymerase chain reaction and hepatitis C genotype determination was accomplished by a reverse hybridization assay. Furthermore, part of the NS5 region of hepatitis C genome (nucleotide positions 7904-8304) was amplified and sequenced in all HCV RNA-positive patients. Then, phylogenetic analysis of the nucleotide sequences obtained was carried out in order to investigate any possible epidemiological linkage among patients. Detailed epidemiological records were also available for all haemodialysis patients. RESULTS: Samples from all five incident cases and three out of four prevalent HCV infections were found positive for HCV RNA. HCV genotyping studies revealed that all incident cases were classified as 4c/d, whereas one and two prevalent cases were 1a and 4c/d respectively. Sequence comparisons and phylogenetic tree analysis revealed that six of the patients harboured very similar strains and clustered together, including all incident and one prevalent case, which was implicated as index case. Further epidemiological analysis was consistent with patient to patient transmission. CONCLUSIONS: Molecular and epidemiological analysis suggested that horizontal nosocomial patient to patient transmission was the most likely explanation for the virus spread within the haemodialysis unit under study.
OBJECTIVE: To assess the impact of age at seroconversion and HIV RNA level in serum during early chronic infection on the initial values and subsequent trends (slopes) of CD4+ lymphocyte counts. DESIGN AND METHODS: In a cohort of 137 HIV-1-positive hemophiliacs with well-estimated dates of seroconversion, baseline HIV RNA level was measured by reverse transcription PCR in serum specimens collected 12-36 months after the estimated date of seroconversion. Baseline values, 24 months after seroconversion, and slopes of CD4+ lymphocyte counts by age and HIV RNA quartile were examined by fitting random effects models that allowed for intrasubject variability. RESULTS: Both age at seroconversion and HIV RNA level were associated with the CD4+ lymphocyte count at baseline and its subsequent slope. The baseline median CD4+ lymphocyte count was 620 x 10(6)/l. Within each HIV RNA quartile, the median CD4+ cell count of the oldest subjects (age 30-58 years) was about 200 x 10(6)/l lower and at least 350 x 10(6)/l lower than the median counts of the younger (age 11-29 years) and youngest (age 2-10 years) subjects, respectively. Within each age-group, the median CD4+ cell count differed by about 200 x 10(6)/l between subjects in the lowest compared with the highest HIV RNA quartiles. The mean slope of the CD4+ lymphocyte count after month 24 was linear on the square-root scale, steeper in children, and did not vary significantly by baseline HIV RNA quartile. There was large variation between subjects that was unexplained by differences in age and HIV RNA level. CONCLUSIONS: By 24 months after HIV seroconversion, the oldest subjects and those with the highest HIV RNA levels during early chronic infection had experienced the most severe depletion of CD4+ cells. Subsequent declines in CD4+ cells varied little by early chronic HIV RNA level or age.
Our objectives are to describe the progression of HIV disease and to assess the influence of hemophilia-related variables, age at infection, and antibodies to cytomegalovirus infection (anti-CMV) in a Greek cohort of 158 HIV-1-positive hemophilic men, who received prospective follow-up for up to 16 years after infection. A total of 79 patients had died, representing a cumulative progression rate of 72.4% (95% confidence interval [CI], 56.6-83.3). A significant proportion of the mortality (30%) resulted from conditions not formally related to AIDS, with liver failure and cerebral hemorrhage predominant. At 16 years after seroconversion, 66 patients had developed clinical AIDS, a cumulative progression rate of 58.2% (95% CI, 47.1%-86.3%) whereas 15 years after infection 81.5% (95% CI, 74.2%-87.9%) of the patients had AIDS or a CD4 cell count <200 cells/mm3. Hemophilia-related variables or presence of anti-CMV were not significantly associated with disease progression. Age at infection was a strong prognostic factor for all three endpoints. Appropriate modeling showed a nonlinear age effect, with a steeper increase of relative hazard for patients >40 years of age at seroconversion. The age effect remained significant even after controlling for current CD4 cell count. Further investigation is required to elucidate the mechanisms of the age effect and the contribution of HCV coinfection on the disease progression.
The HIV-1 subtype distribution in 83 HIV-1-seropositive individuals living in Greece was investigated by using the heteroduplex mobility assay (HMA), DNA sequencing, and phylogenetic analysis. The results revealed that partial HIV-1 gp120 sequences from 71 (86%) patients were subtype B, 5 (6%) were subtype A, 4 were subtype D (5%), 2 (2%) were subtype C, and 1 (1%) was subtype I. The subtype I isolate was documented in an intravenous drug user. A high prevalence (90-100%) of B isolates among intravenous drug users, hemophiliacs, and homosexual men was observed, in contrast to heterosexuals, among whom non-B subtypes seemed to be common (42.9%, p < 0.001). Among the Greek population subtype B is the most frequent (94%), in contrast to the high prevalence (57%) of non-B isolates found in emigrants living in Greece (p < 0.001). A heterosexual transmission case of subtype D in a Greek individual not traveling abroad was also documented. The broad HIV-1 diversity in Greece may be explained by population movements, such as migration and traveling.
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AIMS: To determine HIV and hepatitis infection prevalence and correlates with risk behaviour. DESIGN: Cross-sectional study: voluntary, anonymous HIV, hepatitis (HCV, HBV and HDV) surveillance and questionnaire on risk factors. SETTING: Korydallos Prison, Athens and Ag. Stefanos Prison, Patra, Greece. PARTICIPANTS: Of 544 drug users imprisoned for drug related offences, all completed the questionnaire and 533 blood samples were collected. MEASUREMENTS: HIV (by anti-HIV-1), HCV (by anti-HCV), HBV (by anti-HBc, HBsAg) and HDV (by anti-HDV) prevalence. Data on demography, legal status, drug use, sharing of injecting equipment. FINDINGS: Of the 544 drug users, 375 (68.9%) had injected drugs (IDUs) at some time, 35% of whom had injected whilst in that prison. Of the 533 blood samples tested, one was positive for anti-HIV-1 (0.19%), 310 for anti-HCV (58.2%), 306/531 (57.6%) for anti-HBc, 34/527 (6.5%) for HBsAg and 12/527 (2.3%) for anti-HDV. Prevalence rates for IDUs only were 0.27% for HIV-1, 80.6% for hepatitis C, 62.7% for hepatitis B and 3.3% for hepatitis D. Ninety-two per cent of IDUs injecting in prison shared needles, indicating that IDUs inject less but share more during incarceration. Multiple logistic regression revealed needle-sharing as the most important risk factor for HCV infection in IDUs. Prior knowledge of a positive hepatitis result did not appear to inhibit IDUs from practising risky behaviours in prison. CONCLUSIONS: The epidemic of hepatitis B and C among imprisoned IDUs identified by this study constitutes a major public health problem. Prevention programmes, such as counselling, HBV vaccination, community-based methadone maintenance treatment and syringe exchange schemes, are necessary in order to prevent a further spread.
OBJECTIVES: To estimate the hepatitis C virus (HCV) vertical transmission rate, the effect of potential risk factors, and the pattern of HCV antibody response and viremia in HCV-infected infants. STUDY DESIGN: The Mothers and Infants Cohort Study enrolled both human immunodeficiency virus (HIV)-seropositive and HIV-seronegative pregnant women at five obstetric clinics in New York City in a prospective cohort study between January 1986 and January 1991. HCV-infected mothers and their 122 offspring were followed-up for a minimum of 12 months for evidence of HCV infection as determined by persistent HCV antibodies or detection of HCV RNA by reverse transcription polymerase chain reaction. Comparisons among groups for categorical variables were performed using the Fisher's exact test. RESULTS: Seven (6%; 95% confidence interval, 2%-11%) of the 122 infants were HCV-infected. There was a tendency for increased risk of transmission with maternal viral and obstetrical factors, such as coinfection with HIV (7% vs 4%), high HIV viral load (13% vs 6%), HCV viremia (8% vs 3%), vaginal delivery (6% vs 0%), and female gender of offspring (8% vs 3%), although none of the associations reached statistical significance. After loss of maternal antibody, HCV antibody seroconversion occurred at a mean age of 26 months in 3 HIV-coinfected infants compared with 7 months of age in 4 HCV-infected HIV-uninfected infants. Serial samples showed that HCV RNA persisted in 6 infants for at least 18 to 54 months. CONCLUSIONS: Our study is in accordance with other studies that have shown low overall HCV vertical transmission risk and a trend toward higher risk with maternal risk factors such as HIV-coinfection or HCV viremia. A delay in infant HCV antibody response may be associated with HIV coinfection although larger studies are needed to confirm these findings.
An RT-PCR assay using primers from the 5'-UTR of the GBV-C/HGV genome was used to detect viremia, and a serological assay was used to detect past exposure to GBV-C/HGV, in sera from 106 imprisoned Greek intravenous drug users. High seroprevalence rates indicative of the parenteral route of transmission of the virus were found (32.1% for GBV-C RNA and 46.2% for anti-GBV-C E2). These rates were nonetheless lower in comparison to the corresponding rates of HCV infection markers (64.2% for HCV RNA and 77.4% for anti-HCV). Statistically significant univariate associations were observed between GBV-C-RNA positivity and younger age (P=0.006) and HCV-RNA positivity (P=0.024), as well as with higher serum alanine aminotransferase levels (P< 0.001); this latter association was shown to be independent of coinfection with HCV and of age by a multiple logistic regression model. Apparently, GBV-C/HGV had spread readily by needle-sharing in prison, while causing acute subclinical hepatitis in infected inmates. Phylogenetic analysis of the partial 5'-UTR of the GBV-C/HGV genome from 16 seropositive individuals, which delineated their grouping within genotype 2, also revealed a close genetic relationship between two sets of sequences from 4 drug addicts, 3 of whom admitted to sharing needles while imprisoned.
To determine the incidence rates and to describe the epidemiological patterns of non-AIDS Kaposi's sarcoma in the central southern area of Greece during the period 1974-1989, all 473 incidence cases reported to Pathology Departments were studied. The mean age (SD) was 67.6 (12.9) years among 297 males and 66.1 (15.9) years among 176 females. The mean age-standardized (Greek population 1981) incidence rate was 0.47 cases per 100,000 total population per year (males 0.62, females 0.32). The standardized incidence rates increased over time for males, with the incidence-rate ratios relative to the earliest period, 1974-1978, being 1.44 (95% CI, 1.02-2.04) for the 1979-1983 interval and 2.12 (95% CI, 1.55-2.90) for the 1984-1989 interval. However, the rates for females did not show a similar pattern. The age-adjusted male:female ratio was 1.6 in 1974-1983 and 2.6 in 1984-1989. Poisson-regression modelling suggested a shift in the age-specific incidence rate in men, towards younger ages during the last period, 1984-1989.
BACKGROUND/AIMS: We determined the diagnostic significance of IgM anti-HBc by a rapid, fully automated microparticle enzyme immunoassay (IMx CORE-M) in acute HBsAg positive hepatitis. METHODS: We studied prospectively for at least 6 months 100 patients with acute self-limited hepatitis B (group A) and 40 patients with acute hepatitis superimposed on histologically confirmed chronic hepatitis B (group B). On admission, all patients in group A were positive and those in group B were negative for IgM anti-HBc by a commercially available enzyme immunoassay. RESULTS: Based on the assay criteria, the rates of IMx CORE-M (> 1.2) positive serum samples on admission, 4, 12 and 24 weeks later were: in group A: 100%, 95%, 72%, 44% and in group B: 20%, 27.5%, 17.5%, and 15%, respectively. Misclassification was observed in 20-27.5% of the acute on chronic hepatitis B cases. However, the mean IMx CORE-M index value was found to be significantly higher in group A during the whole follow-up. In particular, on admission the mean IMx CORE-M index value was 2.504 +/- 0.435 (range: 1.508-3.482) in group A and 0.747 +/- 0.346 (range: 0.062-1.384) in group B (p < 0.001). Discriminant function analysis showed that the cutoff level between the two groups for IMxCORE-M index on admission was 1.5. Four to 12 weeks from admission, in the group with acute on chronic hepatitis B cases, 13 patients with HDV and/or HCV superinfection had significantly lower IMx-CORE M index values compared with 27 patients with acute hepatitis due to exacerbation of chronic hepatitis B. CONCLUSIONS: IMx CORE-M appears to be an accurate diagnostic test to differentiate acute from acute on chronic HBsAg positive hepatitis, but the cut-off level seems to be higher (1.5 instead of 1.2).
AIM: To investigate the significance of IgM antibody to hepatitis C virus (HCV) core antigen (IgM anti-HCV core) in chronic hepatitis C. METHODS: In a group of 112 patients with histologically proven chronic hepatitis C positive for HCV RNA, IgM anti-HCV core level was studied by a sensitive semi-quantitative enzyme immunoassay. Quantitation of serum HCV RNA was done by a second generation bDNA assay and determination of HCV genotype by RT-PCR and reverse hybridization. RESULTS: IgM anti-HCV core was detected in 72 (64.3%) of the 112 patients. ALT levels were significantly higher in IgM anti-HCV core positive than negative patients. No other significant difference was observed in any of the patients' characteristics between IgM anti-HCV core positive and negative groups. On the contrary, IgM anti-HCV core level was found to be significantly higher in females than in males, in patients with moderate or severe chronic hepatitis, in patients with high HCV RNA levels and in patients infected with HCV genotype 1b. Moreover, IgM anti-HCV core level was significantly correlated with age and ALT level. Multiple regression analysis showed that IgM anti-HCV core level was significantly related only to the HCV genotype (p=0.001), histological grade (p=0.017) and ALT level (p=0.038). CONCLUSIONS: Our data support the hypothesis that IgM anti-HCV core level is associated mainly with HCV genotype and secondly with liver disease necroinflammatory activity. These associations may have implications in the pathogenesis of chronic hepatitis C.
BACKGROUND: Classic Kaposi's sarcoma (CKS) is not uncommon in Greece with a reported incidence of 0.20 per 100,000 per year. METHODS: Epidemiological, clinical and histological features of all CKS cases, diagnosed in 'A. Sygros' hospital, Athens, Greece during the years 1989-1994, have been recorded and studied prospectively. RESULTS: During the five-year period studied, 66 CKS patients have been diagnosed in our hospital. Incidence among dermatologic patients was 2.11 per 10,000 patients examined, representing 1.35% of total skin malignancies. Patients' age at diagnosis ranged from 53 to 94 years (mean 72 +/- 8.8). The male to female ratio was 2.47:1. A high proportion of the patients were born in Peloponnesos (42.42%) and were residing in Athens (51.51%) or in Peloponnesos (24.24%). Nodules and/or plaques were the most frequent type of lesion, most commonly located on the feet (43.93%) or the hands (28.78%). Accompanying edema was seen in 51.51% of the patients. There were 16 stage I patients (24.24%), 40 stage II (60.60%), 0 stage III and 10 stage IV (15.15%). Involvement of visceral organs was detected in seven patients (10.60%), while 10 had lymph node involvement (15.15%) and three, involvement of the underlying bones (4.54%). Second primary malignancy was diagnosed in 6 cases (9.09%), most often of the reticuloendothelial system (83.33%). CONCLUSIONS: CKS in Greece exhibits some special characteristics, including older age of onset; lower male to female ratio; endemic clustering; disseminated skin disease at diagnosis, often accompanied by lymphedema; not unusual visceral or lymph node involvement and association with second malignancies. We suggest that CKS in Greece possibly represents a distinct endemic subtype of CKS.
BACKGROUND: The study of the sensitivity of screening assays is greatly facilitated by testing the sequential changes in seroconverting individuals. The aim of this study was to investigate the early immunologic response after hepatitis C virus (HCV) infection and to evaluate whether HCV envelope (E2) recombinant antigen would provide a significant increase in sensitivity for detection of anti-HCV. STUDY DESIGN AND METHODS: Twenty hemodialysis patients who were seroconverting to anti-HCV were included in this study. They were followed up for a mean period (+/- SD) of 10.5 +/- 3.3 months, in which 13 to 46 serum samples per case were collected. Each sample was tested for anti-HCV by second- and third-generation enzyme immunoassay (EIA-2 and EIA-3) and recombinant immunoblot assay (RIBA-3). E2 antibodies were tested by a prototype EIA in which E2 was expressed as a recombinant antigen in Chinese hamster ovary cells. RESULTS: Alanine aminotransferase elevation was observed in 18 of 20 cases. Reactivity against c100, c33c, c22, NS5, and E2 was detected in 15 (75%), 19 (95%), 15 (75%), 2 (10%), and 17 (85%) patients, respectively; c33c was the most immunogenic antigen, followed in descending order by E2, c22, c100, and NS5. E2 antibody reactivity resolved the two RIBA-3-indeterminate cases. However, there was no case in which E2 reactivity preceded all other HCV antigens. Anti-E2 was found to react in all patients of genotypes 1a, 1b, and 3a but in only 2 of 4 patients of genotype 4a. CONCLUSION: In this group of seroconverting individuals, E2 antigen was shown to be highly immunoreactive and did resolve some RIBA-3-indeterminate samples as being positive, on the basis of reactivity to multiple antigens, but it did not improve early detection of seroconversion.