The effectiveness of anti-retroviral drug therapy for HIV-1 is associated with HIV-1 proviral DNA levels and viral selection.

The effect of combination anti-retroviral therapy regimens on HIV-1 proviral DNA levels in peripheral blood mononuclear cells was examined in 12 HIV-1-positive patients, using endpoint dilution polymerase chain reaction and serial cloning, and sequencing of the gag region of HIV-1. The major clone was defined as the most numerous of 10 analysed clones, and observation periods ranged from 8 months to 32 months (mean 19.7 +/- 10.2 months). In five patients (one with primary-stage HIV-1 infection) receiving three anti-retroviral drugs, HIV-1 RNA reduced to undetectable levels (i.e. < or = 100 copies/ml). HIV-1 proviral DNA and the number of major clones reduced in four of these patients. HIV-1 RNA levels reduced, but remained detectable, in five other patients. In the two remaining patients (both receiving two rather than three anti-retroviral drugs), HIV-1 RNA levels increased. These results suggest that the population of major clones may be affected when HIV-1 RNA levels reduce following combination regimens of anti-retroviral therapy.

Evidence of B cell clonal expansion in HIV type 1-infected patients.

HIV-1 infection results in a gradual decrease in CD4(+) T cell counts and progressive immune deficiency. Increased T cell turnover in HIV-1-infected patients, which can be interpreted as T cell clonal expansion, has been thought to be relevant to its pathogenesis. To investigate whether B cell clonal expansion also occurs in HIV-1-infected patients, we examined the expressed V(H)DJ(H) gene sequences of peripheral B cells in HIV-1-infected patients with hypergammaglobulinemia. Identical V(H)DJ(H) gene rearrangements with additional nucleotide differences in V(H) genes were analyzed as a marker of clonally related B cells. From healthy individuals and HIV-1-uninfected patients with hypergammaglobulinemia, clonally related B cells were detected in none of 10 (0%) and 2 of 10 (20%), respectively. No clonally related B cells were detected in any of the nine HIV-1-infected patients with detectable viral loads and normal Ig levels (0%). In contrast, from 9 of 14 HIV-1-infected patients with hypergammaglobulinemia (64%), clonally related B cells were detected. In addition, no HIV-1-infected patients who exhibited normal Ig levels after antiretroviral therapy had clonally related B cells. These findings suggest that B cell clonal expansion is present in HIV-1-infected patients with hypergammaglobulinemia.

[Effect of highly active antiretroviral therapy (HAART) on hypergammaglobulinemia in HIV infected patients].

To investigate the mechanism of hypergammaglobulinemia in HIV infected patients, the effect of highly active antiretroviral therapy (HAART) on the hypergammaglobulinemia was analyzed. Involved in this study were 34 untreated, 21 HAART-effective (complete response) and 14 HAART-non-effective (partial response) patients. Serum levels of HIV-RNA and gammaglobulin and immunoglobulin (Ig) isotypes were measured. Mean HIV-RNA levels of untreated and partial response patients were 1.6 x 10(4) copies/ml and 0.4 x 10(4) copies/ml, respectively. HIV-RNA levels of all complete response patients were below 4.0 x 10(2) copies/ml. Mean gammaglobulin percentages of untreated, partial response and complete response patients were 24.4%, 21.8% and 17.9%, respectively (p < 0.01 in untreated vs complete response patients). Mean IgG levels in the three groups were 2,489 mg/dl, 1,947 mg/dl and 1,618 mg/dl, respectively (p < 0.001 in untreated vs complete response patients). IgA levels were high in some untreated patients and lower in complete response patients. IgE levels were increased in some untreated and partial response patients, but there was no significant difference among the three groups. These results suggested that the hypergammaglobulinemia found in HIV infected patients was associated with HIV replication. The activation mechanism might differ by Ig isotypes.

Acute hepatitis C among Japanese hemodialysis patients: a prospective 9-year study.

OBJECTIVES: The aims of this prospective survey were to determine the incidence and clinical characteristics of newly acquired hepatitis C virus (HCV) infection in hemodialysis patients after the start of antibody to HCV (anti-HCV) screening for blood products in Japan in 1989. METHODS: In serial serum samples from 269 hemodialysis patients who were followed over a mean period of 6.6 yr (+/- 2.1 yr) from 1990 to 1998, HCV RNA and anti-HCV were detected by reverse transcription-polymerase chain reaction and second generation ELISA, respectively. RESULTS: During the observation period, newly acquired HCV infection was found in 26 (15.4%) of the 169 hemodialysis patients without anti-HCV or HCV RNA at entry, an annual incidence rate of 2.59%. Of these 26, only four had a history of blood transfusion, one of whom had received the blood transfusion after 1992, the year in which screening of blood products for anti-HCV by second-generation ELISA was introduced in Japan. Persistent HCV viremia was found in 17 (65.4%) of the 26 patients; the other nine (34.6%) had transient HCV infection. The mean period of continuous ALT abnormality was significantly longer in the former (12.4+/-13.6 months) than in the latter (1.9+/-3.5 months) (p = 0.0067). However, only three (17.6%) of 17 patients with chronic HCV viremia had continuous ALT abnormality for more than 24 months; in all of them, ALT eventually normalized. CONCLUSIONS: These findings indicate that newly acquired HCV infection has continued to occur in hemodialysis patients after the initiation of anti-HCV screening of blood products and that the abnormal ALT found in these patients is related to HCV chronicity.

Influenza in three patients with human immunodeficiency virus infection.

Three Japanese outpatients with human immunodeficiency virus (HIV) infection on anti-retroviral therapy showed evidence of influenza in January 1999. CD4+ T cell counts of these patients prior to the diagnosis of influenza were 72, 248, and 152/mm3, and HIV RNA levels were 19,953, 1,259, and 1,585 copies/ml, respectively. Fever continued 4 to 5 days with no severe complications. One patient showed post-influenzal bronchitis which was effectively treated by antibiotics. None of these patients showed increased serum HIV RNA levels during and after influenza, however, in one patient, a transient reduction of CD4+ and CD8+ cells was seen during the active phase of influenza. Although symptoms of influenza in HIV carriers are generally mild and similar to those in healthy adults, careful follow-up is needed as symptoms of influenza in some HIV-infected patients can be prolonged and serious.

A relationship between the evolution of hepatitis C virus variants, liver damage, and hepatocellular carcinoma in patients with hepatitis C viremia.

To clarify the mechanism of liver damage induced by hepatitis C virus (HCV) and to determine whether the damage is related to hepatocellular carcinoma (HCC), HCV RNA levels were measured serially, and HCV genome mutations were analyzed from serum of 274 Japanese patients with chronic HCV viremia during 1993-1998. All patients had alanine aminotransferase (ALT) levels measured during 1986-1998. Patients with consistently normal ALT levels had identical and highly conserved HCV core regions; however, those with consistently abnormal ALT levels had quasi species, and the population of the quasi species changed over time. HCV RNA levels did not change in the 274 patients. HCC developed in 31% of 80 patients with consistently abnormal ALT levels and in 4% of 92 patients with intermittently abnormal ALT levels but never in 102 patients with ALT levels consistently normal during 1993-1998. In patients with chronic HCV viremia, persistent liver damage plays an important role in the development of HCC.

Lower hepatitis G virus infection prevalence compared to hepatitis B and C virus infection prevalences.

To more accurately determine the seroprevalence of hepatitis G virus (HGV) infection, we surveyed antibody to HGV (anti-E2) by enzyme-linked immunosorbent assay (ELISA) and HGV RNA by nested polymerase chain reaction (PCR) in 298 residents of a hepatitis C virus (HCV)-endemic area of Japan and in 225 hemodialysis patients. We then compared these findings with known HCV and hepatitis B virus (HBV) infection prevalences. Anti-E2 and HGV RNA prevalences were 32 (10.7%) and 5 (1.7%) in the residents and 24 (10.7%) and 10 (4.4%) in the hemodialysis patients, respectively. Anti-E2 and HGV RNA concurrence was found in two of the hemodialysis patients. Total HGV marker (anti-E2 and/or HGV RNA) prevalences [37 (12.4%) in residents and 32 (14.2%) in hemodialysis patients], were significantly lower than the prevalences of antibody to HCV (anti-HCV) by ELISA [59 (19.8%) and 96 (42.7%)], and antibody to hepatitis B core antigen (anti-HBc) by radioimmunoassay (RIA) [87 (29.2%) and 101 (44.9%)] (P<0.05). The anti-HCV prevalence in subjects with total HGV marker was significantly higher than in those without total HGV marker. There was no significant difference in anti-HBc prevalence between those with and without total HGV marker. The viremic rate was highest in HCV infection (HCV RNA by PCR/anti-HCV) (83.2%), with HGV infection (HGV RNA/total HGV marker) (21.7%) intermediate, and HBV infection (hepatitis B surface antigen by RIA/anti-HBc) (5.3%) lowest (P<0.05). These findings indicate that HGV infection was less endemic than HCV and HBV. HGV was eliminated naturally more frequently than HCV infection and less frequently than HBV infection.

Hepatitis C virus infection in institutionalized psychiatric patients: possible role of transmission by razor sharing.

The objective of this study was to determine if HCV can be transmitted from patient to patient in psychiatric institutions and to determine possible routes of infection. We did a cross-sectional survey of 196 Japanese psychiatric patients tested for HCV and HBV markers and 400 age- and sex-matched controls. Anti-HCV was detected in 10.2% and antibody to hepatitis B core antigen was detected in 44.4% of the patients, a significantly higher prevalence than found among matched controls. A multiple regression logistic analysis was used to identify risk factors that could indicate the route of infection by HCV. Duration of hospitalization, age, razor sharing, and history of surgery proved to be statistically significant independent risk factors associated with positive anti-HCV results [odds ratio (OR), 4.00; 95% confidence interval (CI), CI, 1.74-9.19; OR, 2.19; 95% CI, 1.27-1.3.77; OR, 4.90; 95% CI, 1.29-18.86; OR, 3.35; 95% CI, 0.997-11.3, respectively]. These observations suggest that razor sharing played an important role in the spread of the HCV infection in the institutionalized psychiatric patients we studied.

Maintenance hemodialysis decreases serum hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection.

OBJECTIVE: Hepatitis C virus (HCV) infection is a major complication among hemodialysis patients the world over. To determine the natural course of HCV viremic levels in patients on maintenance hemodialysis, we prospectively quantified the HCV RNA levels in serial blood samples from hemodialysis patients and compared them with those in nonuremic subjects. METHODS: The population studied included 98 hemodialysis patients and 228 nonuremic subjects with chronic HCV infection. HCV RNA was detected by polymerase chain reaction (PCR) and the levels were determined by branched DNA probe assay. HCV RNA genotypes were determined by PCR using type-specific primers. RESULTS: HCV RNA levels were significantly lower in hemodialysis patients (median, 0.4x10(6) genome equivalent [Meq]/ml) than in nonuremic subjects (median, 3.0 Meq/ml) (p<0.05). HCV of genotype 1b was prevalent in the hemodialysis patients (81.6%) and nonuremic subjects (88.6%). HCV RNA levels in 20 hemodialysis patients with genotype 1b were significantly reduced after each hemodialysis procedure (p<0.05). The 3-yr prospective observation from 1995 to 1998 showed a significant decrease of HCV RNA levels in 47 hemodialysis patients with genotype 1b (median, 1.9-0.9 Meq/ml, p<0.05), whereas levels in 155 nonuremic subjects with genotype 1b did not decrease (median, 2.6-3.0 Meq/ml). There were no patients or nonuremic subjects with undetectable HCV RNA by a PCR assay during the observation period. CONCLUSIONS: These observations suggest that maintenance hemodialysis decreases the HCV RNA levels in hemodialysis patients with chronic HCV infection, but does not produce clearance of the viremia.

Seroepidemiology of TT virus infection and relationship between genotype and liver damage.

TT virus (TTV) has been identified in patients with posttransfusion hepatitis of unknown etiology and is thought to be a new hepatitis virus. We determined the extent of TTV infection in the Japanese general population and the relationship between TTV DNA genotype and liver damage. In 1998, we tested 847 serum samples for TTV. TTV DNA was assayed by a nested polymerase chain reaction and classified into three different genotypes and eight subtypes. TTV DNA was detected in 25.3% and 32.4% of the inhabitants of the two areas studied, respectively. The genotype distribution was similar in both areas. G1, G2, and G3 were 60%, 20%, and 5%, respectively. Of the 20 subjects with TTV DNA alone and elevated serum ALT levels, 18 were G1, one was G2, and one was G3. TTV infection is endemic in the Japanese general population studied. The main TTV genotype, G1, may be related to the ensuing liver damage.

Liver damage in hemodialysis patients with hepatitis C virus viremia: a prospective 10-year study.

Hepatitis C virus (HCV) infection is a major problem associated with hemodialysis. The extent of liver damage in hemodialysis patients with chronic HCV infection has not been thoroughly documented. The aim of this study was to evaluate liver damage of hemodialysis patients infected with HCV. A total of 233 hemodialysis patients were categorized into two groups at entry: group X, 80 positive for serum HCV RNA, and group Y, 153 negative for serum HCV RNA. All were tested for serum alanine aminotransferase (ALT) serially from 1989 to 1998, and serum hyaluronic acid (HA), serum type-IV collagen (IV-C), platelet counts, and ultrasonographic examination of the liver was done in 1998. In group X, 61.3% had continuously abnormal ALT levels for over six months followed by normal ALT levels. Of the group X patients, 11.3% had abnormal ALT levels in 1998, and in three, hepatocellular carcinoma occurred. Mean HA and IV-C levels in group X (648.8 and 188.7 ng/ml, respectively) were significantly higher than in group Y (213.1 and 165.5 ng/ml, respectively) (P < 0.05). Ultrasonographic findings significantly correlated with serum HA level and platelet counts and showed significantly more abnormalities in group X than in group Y (P < 0.05). From these findings, a combined examination with ultrasonography and serum fibrogenesis markers is useful for detection of liver damage in hemodialysis patients with HCV viremia.

Rapidly growing primary gastric B-cell lymphoma after eradication of Helicobacter pylori.

Helicobacter pylori (H. pylori) infection plays a decisive role in primary gastric B-cell lymphoma especially of mucosa-associated lymphoid tissue (MALT)-type. We treated a 47-year-old male patient with primary gastric B-cell lymphoma associated with H. pylori infection. Although antibiotic therapy for eradication of H. pylori caused great improvement in the low-grade MALT lymphoma-like lesion, the small areas of high-grade lesion rapidly formed a new bulky mass in only 8 weeks. This suggests that eradication of H. pylori is not effective for high-grade lymphoma.

Markedly high seroprevalence of hepatitis B virus infection in comparison to hepatitis C virus and human T lymphotropic virus type-1 infections in selected Solomon Islands populations.

To determine the prevalences of hepatitis B virus (HBV), hepatitis C virus (HCV), and human T lymphotropic virus type-1 (HTLV-1) infections in residents of the Solomon Islands, we surveyed 1,610 serum samples from 1,113 outpatients and 497 healthy volunteer blood donors at the Central Hospital in Honiara, the Solomon Islands. The prevalence of hepatitis B surface antigen (HBsAg) by radioimmunoassay (RIA) (n = 315, 19.6%) was significantly different from that of antibody to HCV (anti-HCV) by a second-generation enzyme immunoassay (EIA) (n = 4, 0.2%) and antibody to HTLV-1 (anti-HTLV-1) by an ELISA with Western blot analysis to verify the positivity (n = 49, 3.0%) (P < 0.0001, respectively). There were no significant differences in the prevalences of these markers between outpatients and blood donors. Hepatitis B e antigen (HBeAg) was detected by RIA in 130 (41.3%) of 315 HBsAg-positive samples. The distribution of HBsAg subtypes by EIA was 190 adr (60.3%), 111 ayw (35.2%), and 14 (0.4%) other subtypes. The HBeAg prevalence decreased with age in all groups for each subtype. There were no significant differences in the prevalence of HBeAg among HBsAg subtypes. We conclude that HBV infection is highly endemic in selected Solomon Islands populations, and that the high prevalence of HBeAg may be associated with the spread of HBV infection there.

Differences between interferon-alpha and -beta treatment for patients with chronic hepatitis C virus infection.

To compare virological, biochemical, and immune responses to human lymphoblastoid interferon (IFN-alpha) and human fibroblast interferon (IFN-beta) in patients with chronic hepatitis C virus (HCV) infection, 120 patients were randomly assigned to three groups (group A, 60 patients receiving IFN-alpha, 6 million units (MU) once a day, daily for one month and thrice weekly for five months; group B, 40 patients receiving 6 MU IFN-beta once a day daily for two months; and group C, 20 patients receiving 3 MU IFN-beta twice a day (6 MU/day) daily for two months). Serum soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay. Patients with sustained clearance of serum HCV RNA detected by polymerase chain reaction (PCR) at six months after IFN treatment were defined as having complete response to IFN treatment. A low level of HCV RNA (< or = 10(4) copies/50 microl, measured by competitive PCR) and HCV RNA of genotype 2a were favorable factors for a complete response to both IFNs. Complete response in group A treatment was strongly associated with early HCV RNA clearance, in contrast with group B. A significantly higher HCV RNA negativity at the second week from start of treatment was noted in group C (80.0%), compared with groups A (41.6%) and B (27.5%). sIL-2R levels rose in each group during IFN administration. In group C, alanine aminotransferase (ALT) and IL-6 levels were remarkably elevated. These findings indicate that timing of serum HCV RNA negativity in sustained response differs between IFN-alpha and IFN-beta administrations and that early HCV RNA clearance was induced by twice-a-day IFN-beta treatment.

Clinical course of chronic hepatitis C virus infection is not influenced by concurrent hepatitis G virus infection.

To determine the effects of hepatitis G virus (HGV) infection on chronic hepatitis C virus infection (HCV) and to evaluate HGV response to interferon, we investigated HGV RNA by polymerase chain reaction in 247 Japanese patients with chronic HCV infection (166 men and 81 women; 124 had chronic hepatitis and 26 cirrhosis, and 97 hepatocellular carcinoma). HGV RNA was detectable in 22 (8.9%) patients, among whom 21 were men: this male predominance was statistically significant (P < 0.01). There were no differences in age, aminotransferase level, stage of liver disease, HCV RNA level by competitive polymerase chain reaction, genotype, or interferon response to HCV RNA between patients with HCV infection alone or with HCV/HGV coinfection. Sustained elimination of HGV RNA was found in 28.6% of the 14 treated patients with HCV/HGV coinfection. In the 14 treated patients, sustained elimination of both viruses was seen in two, HCV alone was eliminated in two, and HGV alone was eliminated in two. Aminotransferase level improvement by interferon treatment was associated with clearance of HCV, but not of HGV. Thus, HGV infection had no apparent effects on HCV infection, and the sensitivity of HGV to interferon is comparable to but independent of HCV.

Serum soluble interleukin-2 receptor levels before and during interferon treatment in patients with chronic hepatitis B virus infection.

To determine the role of serum soluble interleukin-2 receptor (sIL-2R) in chronic hepatitis B virus (HBV) infection, the level of serum sIL-2R was measured in sera of 105 patients with chronic HBV infection and in 21 healthy controls, using enzyme-linked immunosorbent assay. Serum sIL-2R levels were significantly higher in chronic HBV-infected patients with chronic hepatitis (508+/-310 units/ml) and liver cirrhosis (543+/-283 units/ml) than in healthy controls (331+/-106 units/ml, P < 0.05). Moreover, serum sIL-2R levels were significantly higher in patients with chronic hepatitis or liver cirrhosis than in asymptomatic HBV carriers (341+/-150 units/ml, P < 0.01). There was no difference in serum sIL-2R levels between asymptomatic HBV carriers and healthy controls or between patients with chronic hepatitis and liver cirrhosis. A significant relationship was found between serum sIL-2R and ALT levels (P < 0.05) in patients with chronic HBV infection, although there was no correlation between sIL-2R and HBV DNA levels. Serum sIL-2R levels in most patients decreased to the same level as asymptomatic HBV carriers and healthy controls at 48 weeks after the end of treatment, and serum ALT and HBV DNA levels were decreased to within the normal range at 96 weeks. Thus, serum sIL-2R levels indicate the degree of liver damage among patients with chronic HBV infection. The serum sIL-2R levels one year after interferon administration may be a useful marker of determined at the effectiveness by this treatment.

A ten year serological survey of hepatitis A, B and C viruses infections in Nepal.

BACKGROUND: In 1987, we reported that the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in Nepal was low, as compared to hepatitis A virus (HAV) infection, and that no human T-lymphotropic type-1 (HTLV-1) infection was found in Nepal. OBJECTIVES: To determine changes in the prevalence of HAV, HBV, and HCV infections between 1987 and 1996 in inhabitants of Bhadrakali (suburban) and Kotyang (rural) villages in Nepal. STUDY DESIGN: We did a cross-sectional survey of 458 inhabitants of two Nepalese villages, to assess the prevalence of antibody to HAV (anti-HAV), antibody to hepatitis B core antigen (anti-HBc), hepatitis B surface antigen (HBsAg), antibody to HCV (anti-HCV), and antibody to HTLV-I (anti-HTLV-I). RESULTS: Anti-HAV was detected in 454 (99.1%), HBsAg in 5 (1.1%), anti-HBc in 33 (7.2%) and anti-HCV in 8 (1.7%) of serum samples tested in 1996. Statistically significant differences by gender or age group were nil. The prevalence of HCV infection was significantly higher in 1996 than in 1987 after adjusting for age of subjects living in the two villages (p < 0.01). The prevalence of HBsAg was significantly higher in 1996 than 1987 in Bhadrakali after adjusting for the factor of age (p < 0.05). Between 1987 and 1996, evidence for HTLV-1 positive residents was nil. CONCLUSION: These results suggest that HAV has been endemic in Nepal for long time while not of HBV, and that HCV infection tends to be increased recently.

Hepatitis G virus in the general population and in patients on hemodialysis.

To determine the routes of transmission of hepatitis G virus (HGV) and the relationship between HGV and hepatitis C virus (HCV) infections, we tested for HGV RNA by polymerase chain reaction and antibody to HCV (anti-HCV) in 494 hemodialysis patients, 638 inhabitants of two HCV endemic areas, and in 400 blood donors in Japan. HGV RNA was detected in 6.9% of hemodialysis patients, in 1.4% of inhabitants, and in 0.8% of donors, and anti-HCV was detected in 39.3%, 12.4%, and 1.8%, respectively. Of HGV RNA-positive hemodialysis patients, and HGV RNA-positive inhabitants, 64.7% and 11.1%, respectively, had been given blood transfusions. The prevalences of HGV RNA and anti-HCV significantly increased with the duration of hemodialysis. Of all HGV RNA positives, 74.4% were coinfected with HCV and subjects with HGV RNA alone had normal liver function. In conclusion, HGV is transmitted by blood transfusion and within the hemodialysis unit itself. HGV does not seem to injure hepatocytes.