Erik Nordenfelt

Dane Particles, DNA Polymerase, and e-Antigen in Two Different Categories of Hepatitis B Antigen Carriers

Two different categories of hepatitis B antigen carriers have been investigated. One comprises patients treated with dialysis and known to be highly infectious. The other consists of blood donors found in routine screenings. Serum specimens have been studied with regard to Dane particles. Dane-core-associated DNA polymerase activity, and e-antigen. The two groups differed markedly in the aspects studied. The five healthy blood donors had no, or very few, detectable Dane particles and no detectable DNA polymerase activity; four of the five healthy donors had antibodies against e-antigen. The one xickk donor and all six dialysis patients had many Dane particles and polymerase activity; five of the sick dialysis patients had e-antigen. Thus, these results further underline the difference between the two groups, and e-antigen and DNA polymerase activity could represent possible useful parameters for judging infectivity.

Continued transmission of hepatitis B and C viruses, but no transmission of human immunodeficiency virus among intravenous drug users participating in a syringe/needle exchange program.

The virological efficacy of a syringe/needle exchange program was evaluated in a cohort incidence study. Of 698 intravenous drug users (IVDUs) initially recruited, 15 (2.1%) were HIV-positive at baseline. Adequate follow-up was possible in 515 (74%) and showed no new cases of HIV infection during a median of 31 months. Most IVDUs had been previously exposed to HBV (anti-HBc-positive 70.1%) and HCV (anti-HCV-positive 90.7%). Of those 159 IVDUs negative at baseline for anti-HBc and/or anti-HCV, 56 (35%) seroconverted to one or both viruses during follow-up, corresponding to 11.7 seroconversions/100 y at risk for HBV and 26.3 seroconversions/100 y for HCV. Multiple logistic regression analysis showed hepatitis seroconversion to correlate with imprisonment during the study (OR 2.2; 95% CI 1.04-4.74), absence of drug-free periods (OR 5.7; CI 1.44-22.3) and frequent syringe/needle exchanges (OR 1.31; CI 1.02-1.7). The absence of HIV spread was probably partly due to the low prevalence of HIV-infected IVDUs in the city. Despite free syringes and needles, both HBV and HCV continued to spread at high rates. Nevertheless, syringe/needle exchange programs, coupled with monitoring of serostatus provide good surveillance and are valuable for further assessment of remaining risks.The virological efficacy of a syringe/needle exchange program was evaluated in a cohort incidence study. Of 698 intravenous drug users (IVDUs) initially recruited, 15 (2.1%) were HIV-positive at baseline. Adequate follow-up was possible in 515 (74%) and showed no new cases of HIV infection during a median of 31 months. Most IVDUs had been previously exposed to HBV (anti-HBc-positive 70.1%) and HCV (anti-HCV-positive 90.7%). Of those 159 IVDUs negative at baseline for anti-HBc and/or anti-HCV, 56 (35%) seroconverted to one or both viruses during follow-up, corresponding to 11.7 seroconversions/100 y at risk for HBV and 26.3 seroconversions/100 y for HCV. Multiple logistic regression analysis showed hepatitis seroconversion to correlate with imprisonment during the study (OR 2.2; 95% CI 1.04-4.74), absence of drug-free periods (OR 5.7; CI 1.44-22.3) and frequent syringe/needle exchanges (OR 1.31; CI 1.02-1.7). The absence of HIV spread was probably partly due to the low prevalence of HIV-infected IVDUs in the city. Despite free syringes and needles, both HBV and HCV continued to spread at high rates. Nevertheless, syringe/needle exchange programs, coupled with monitoring of serostatus provide good surveillance and are valuable for further assessment of remaining risks.

Clinical aspects of delta infection.

The clinical features of delta infection were analysed retrospectively in 191 hepatitis B surface antigen (HBsAg) carriers and 592 cases of acute hepatitis B seen over 11 years in the Swedish town of Malmö (population 250 000). With a few exceptions delta infections occurred exclusively in drug addicts. In the chronic HBsAg-carriers the most common clinical manifestation was an episode of acute hepatitis, which in some individuals became severe with a pronounced rise in serum alanine aminotransferase activity for many months. During the period of delta infection the HBsAg titre was lowered and in three out of 26 cases the patient lost HBsAg altogether and developed hepatitis B surface antibodies (anti-HBs). In one patient the acute hepatitis due to delta infection was fulminant and fatal. In patients with acute hepatitis B the clinical picture did not distinguish between those with and without simultaneous delta infection. The frequency with which acute hepatitis B was succeeded by a chronic carrier state was the same whether or not the patient was infected simultaneously with the delta agent. The discovery of the delta agent has improved understanding of the natural history of chronic hepatitis B infection in drug addicts. Thus, instances of acute hepatitis in a chronic carrier, previously termed hepatitis non-A, non-B, may actually be episodes of delta infection.

Decline of Herpes Simplex Virus Type 2 and Chlamydia trachomatis Infections from 1970 to 1993 Indicated by a Similar Change in Antibody Pattern

Antibodies to herpes simplex virus type 2 (HSV-2) and Chlamydia trachomatis (Ct) were determined in sera from pregnant women from 1970 and at intervals up to 1993. The trends for HSV-2 and Ct infections were deduced from the observed antibody rates in different age groups during the observation period. Total antibody rates for HSV-2 tended to decline toward the end of the period when age-matched groups were compared, while the Ct antibody rates peaked in 1979 and then declined gradually. Age-specific antibody rates showed declining frequencies in women younger than 20 years for both HSV-2 and Ct over the study period. Women 35 years of age and older in the early 1990s had significantly higher antibody rates than younger women at that time or than women of similar age in the early 1970s. This group of slightly older women with high antibody rates in the 1990s were 15-20 years of age in 1970 when a high antibody frequency was noted in this age group. High antibody rates against both HSV-2 and Ct in older pregnant women in the early 1990s may thus reflect a high incidence of these infections around 1970. The declining rates of antibodies in the youngest women would suggest a declining incidence of primary infections in this group.

Mixed Infection with Two Types of Hepatitis C Virus Is Probably a Rare Event

SummaryA search for the simultaneous presence of two hepatitis C virus (HCV) types in sera of a group of chronically infected intravenous drug users, hemodialysis patients and hemophiliacs from Sweden and Russia was performed with two genotyping methods based on the use of type-specific primers from core and NS4 regions of the viral genome. An important feature of NS4 based assay is that type-specific primers are used in both rounds of nested PCR, thus providing the possibility of the identification not only of the abundant type, but also of the minor HCV type present in a particular serum. The experiments, however, did not reveal the simultaneous presence of two or more HCV types in any of the 40 samples. These results suggest that the frequency of mixed infections in serum with different HCV types is very low even in high-risk groups, at least in the geographic region studied.

Increased occurrence of hepatitis A with cyclic outbreaks among drug addicts in a Swedish community

SummaryTo determine the prevalence of antibodies toHepatitis A virus (anti-HAV) among drug addicts, sera collected in a Swedish city during a ten-year period from 234 drug addicts with acute hepatitis B were tested for anti-HAV. The results were compared with the normal population, where only 3.8% of those born after 1950 were anti-HAV-positive. In individuals born between 1941 and 1965, 8.2% in the normal population and 30.2% of the drug addicts were anti-HAV-positive (p<0.001). The level of immunity to hepatitis A among drug addicts ranged from 7.7% to 60% during the ten-year period. Low levels of immunity were seen in the years preceeding outbreaks of hepatitis A among drug addicts. These outbreaks occurred in a cyclic pattern. Higher levels of immunity were seen after each outbreak.ZusammenfassungZur Bestimmung der Prävalenz vonHepatitis A Virus-Antikörpern (anti-HAV) bei Drogenabhängigen wurden Seren von 234 Drogenabhängigen mit akuter Hepatitis B, die in einer schwedischen Stadt während zehn Jahren gesammelt worden waren, auf anti-HAV getestet. Zum Vergleich wurde eine normale Bevölkerungsgruppe herangezogen, bei der nur 3,8% der nach 1950 Geborenen und 8,2% der Jahrgänge 1941–1965 anti-HAV positiv waren. Hingegen war bei 30,2% der Drogenabhängigen anti-HAV nachzuweisen (p<0,001). Die Rate von Drogenabhängigen mit Immunschutz variierte innerhalb von zehn Jahren zwischen 7,7% und 60%. In den Jahren von Hepatitis A-Ausbrüchen waren die Immunitätsraten jeweils niedrig. Die Ausbrüche traten zyklisch auf. Nach jedem Ausbruch war jeweils eine höhere Rate von Drogensüchtigen mit Immunschutz festzustellen.To determine the prevalence of antibodies toHepatitis A virus (anti-HAV) among drug addicts, sera collected in a Swedish city during a ten-year period from 234 drug addicts with acute hepatitis B were tested for anti-HAV. The results were compared with the normal population, where only 3.8% of those born after 1950 were anti-HAV-positive. In individuals born between 1941 and 1965, 8.2% in the normal population and 30.2% of the drug addicts were anti-HAV-positive (p<0.001). The level of immunity to hepatitis A among drug addicts ranged from 7.7% to 60% during the ten-year period. Low levels of immunity were seen in the years preceeding outbreaks of hepatitis A among drug addicts. These outbreaks occurred in a cyclic pattern. Higher levels of immunity were seen after each outbreak. Zur Bestimmung der Prävalenz vonHepatitis A Virus-Antikörpern (anti-HAV) bei Drogenabhängigen wurden Seren von 234 Drogenabhängigen mit akuter Hepatitis B, die in einer schwedischen Stadt während zehn Jahren gesammelt worden waren, auf anti-HAV getestet. Zum Vergleich wurde eine normale Bevölkerungsgruppe herangezogen, bei der nur 3,8% der nach 1950 Geborenen und 8,2% der Jahrgänge 1941–1965 anti-HAV positiv waren. Hingegen war bei 30,2% der Drogenabhängigen anti-HAV nachzuweisen (p<0,001). Die Rate von Drogenabhängigen mit Immunschutz variierte innerhalb von zehn Jahren zwischen 7,7% und 60%. In den Jahren von Hepatitis A-Ausbrüchen waren die Immunitätsraten jeweils niedrig. Die Ausbrüche traten zyklisch auf. Nach jedem Ausbruch war jeweils eine höhere Rate von Drogensüchtigen mit Immunschutz festzustellen.

Antibody to a hepatitis C virus related protein among patients at high risk for hepatitis B

Anti-HCV prevalence in treated hemophiliacs, their heterosexual partners, intravenous drug addicts and homosexual men was studied. In hemophiliacs and many of the intravenous drug addicts, greater than or equal to 2 sera drawn 1-18 or 1-17 years apart were available. Anti-HCV testing was performed by ELISA (Ortho). Among patients with severe and moderate hemophilia A, 87% (98/112) were positive for anti-HCV at least once and among patients with severe and moderate hemophilia B, 83% (24/29) were positive for anti-HCV. Seroconversion to anti-HCV was observed in 21% of hemophilia patients. In hemophilia A, HCV infection generally occurred during the first years of life and in hemophilia B somewhat later. Loss of anti-HCV antibody was seen in 12% (17 patients). The rest, 54% (76 patients) were seropositive in first and last samples. All 12 tested spouses to anti-HCV positive men were anti-HCV negative. 80% of the drug addicts (137/172) were seropositive for anti-HCV. In those with greater than 1 serum tested, 8% were consistently negative and 68% consistently positive. 21% seroconverted to anti-HCV while 3% lost antibody. 10% (22/211) of homosexual men were anti-HCV positive. Intravenous transmission of HCV thus seemed highly efficient whereas sexual transmission was much less efficient.

Relation between donor transaminase and recipient hepatitis non-A, non-B in Sweden

Abstract. The relation between donor alanine aminotransferase (ALT) and recipient post‐transfusion hepatitis (PTH) non‐A, non‐B was studied in patients tested before and 6 and 12 weeks after transfusion. The minimum ALT criterion for PTH was 105 IU/1 (> 2.5 times the upper normal of 42 IU/1). In 8.8% of donors, ALT was > 42 IU/1, and in 2.3% ALT was > 63 IU/1, i.e., 1.5 times elevated. PTH non‐A, non‐B occurred in 14 of 742 recipients. The PTH incidence increased when donor ALT was above 63 IU/1 (1.5 vs. 5.6%; p < 0.05). However, if the confounding factor of volume variations was compensated for, elevated donor ALT and PTH were only statistically linked among recipients < 70 years (p < 0.02; Mantel‐Haenszel test).

Influence of twenty potentially antiviral substances on in vitro multiplication of hepatitis A virus

A multiwell tissue culture system was developed to study the influence of various substances on hepatitis A virus (HAV) propagation. A panel of 20 substances of different structure types, each with known effect against at least some viruses, was studied at a concentration of 100 microM. Three substances showed reproducible inhibition. The strongest inhibitor, arabinosylcytosine, also produced cytotoxic changes in cells down to a concentration of 1 microM, and its effect was considered as nonspecific. Amantadine and ribavirin showed a moderate effect at 100 microM. A stronger inhibition was seen at 250 and 500 microM, doses that are toxic and impractical for clinical use. Although no promising candidates for antiviral treatment of hepatitis A have emerged from the present study, the assay model described here would seem useful in the screening of substances with inhibitory effects on HAV.

Hepatitis C in chronic liver disease: an epidemiological study based on 566 consecutive patients undergoing liver biopsy during a 10-year period.

We analysed the presence of hepatitis C virus (HCV) antibodies in 566 patients undergoing liver biopsy. While over 20% of the patients were anti‐HCV positive according to elisa, only 13.8% had HCV antibodies when tested with a four‐antigen recombinant immunoblot assay (RIBA 2). At the time of inclusion in the study, most patients were asymptomatic, irrespective of whether they were HCV‐positive. Histological findings in anti‐HCV‐positive patients were chronic persistent hepatitis, chronic active hepatitis or cirrhosis in > 75% of cases. Only four of the patients who were anti‐HCV‐positive according to the RIBA 2 had autoimmune chronic active hepatitis. Risk behaviour could be identified in the majority of cases. Community‐acquired sporadic cases were rare (12%). Of the 153 patients who died during follow‐up, 23 subjects were anti‐HCV positive. Although age‐ and sex‐adjusted survival was not shorter in anti‐HCV‐positive patients than in anti‐HCV‐negatives, the risk of hepatocellular cancer was higher (P = 0.01). We conclude that HCV infection is associated with chronic liver disease, even when critical evidence of viral aetiology is slight. Truly sporadic cases are rare. Patients infected with HCV are at increased risk of developing hepatocellular cancer.