Impact of highly active antiretroviral therapy on hepatitis C virus protease quasispecies diversity in HIV co‐infected patients

Many hepatitis C virus (HCV)‐infected patients are also infected with HIV, and undergo antiretroviral (ARV) treatment for their human immunodeficiency virus (HIV) infection. Due to changes in HIV burden and immunologic status, HIV ARV treatment may have indirect effects on the HCV population, which could impact the effectiveness of subsequent HCV protease inhibitor (PI) treatment. The genetic variability of the protease‐encoding HCV NS3 gene was evaluated in 10 co‐infected patients initiating ARVs (both before and after ARV initiation), and compared to the genetic variability in 10 patients on stable ARV therapy. After RT‐PCR of plasma‐derived HCV RNA, a mean of 20 clones per patient time‐point were sequenced and analyzed for changes in the HCV quasispecies population. No significant differences in sequence diversity or complexity at the nucleic acid or amino acid levels were seen at baseline between groups or between the two time points in either group. HCV protease diversity in the pre‐ and post‐ARV treatment samples was not significantly different than samples from patients on stable ARV therapy. There was no significant development of amino acid substitutions known to confer HCV PI resistance in either group. Initiation of ARV for HIV infection does not significantly alter the genetic diversity or complexity of the HCV NS3 gene or result in increased number of HCV PI‐associated amino acid changes. These results suggest ARV treatment for HIV would not affect the efficacy of HCV PI treatment. J. Med. Virol. 82: 791–798, 2010. © 2010 Wiley‐Liss, Inc.     

Occult hepatitis B in persons infected with HIV is associated with low CD4 counts and resolves during antiretroviral therapy

Occult hepatitis B virus (HBV) is defined by the presence of plasma HBV DNA in individuals with HBV core antibodies (anti‐HBc), but without HBV surface antigen (HBsAg). The prevalence of occult HBV in HIV‐infected patients remains controversial, and the risk factors, clinical significance and effect of highly active antiretroviral therapy (HAART) are unknown. The aim of this study was to determine prevalence, risk factors, and clinical significance of occult HBV in HIV‐infected patients and to evaluate the effect of HAART. Plasma HBV DNA levels were determined in 191 HIV positive, antiretroviral naïve patients, who were anti‐HBc positive and HBsAg negative. Quantitative HBV DNA was determined using a Taqman real‐time nested PCR. Additionally, plasma HIV RNA levels, CD4 cell counts, anti‐HBs‐antibodies, anti‐HCV‐antibodies, ALT, AST, and γGT were determined. Occult HBV (a plasma HBV DNA level >50 copies/ml) was detected in 9/191 (4.7%) of the patients. Among 45 anti‐HBs‐negative patients (isolated anti‐HBc positive), the prevalence was 11.1%. Patients with occult HBV had significantly lower CD4 count compared to anti‐HBc‐positive/HBsAg negative/HBV DNA‐negative patients (105 ± 157 (median ± SD) vs. 323 ± 299 cells/mm³, P = 0.019). When HAART (including lamivudine) was initiated in the patients with occult HBV, HBV DNA was no longer detectable in any of the patients during 3 years of follow‐up. In conclusion, occult HBV was associated with low CD4 counts and may be viewed as opportunistic reactivation of HBV that resolves as a consequence of HAART induced immune reconstitution and/or the effect of lamivudine. J. Med. Virol. 81:441–445, 2009. © 2009 Wiley‐Liss, Inc.     

江门市健康体检成人乙型肝炎血清流行病学调查

目的探讨江门市健康体检成人乙型肝炎病毒血清流行病学状况,为乙型病毒性肝炎防治提供可靠依据。方法收集2009年1-6月江门市体检成人共计11208人,分别统计分析年龄、性别、乙型肝炎＂两对半＂结果和肝功能。结果江门市健康体检成人HBsAg阳性率为9.06%,男性和女性HBsAg阳性率分别为10.8%和6.88%,男性明显高于女性;乙型肝炎病毒感染者中HBeAg阳性和HBeAg阴性分别占19.49%和80.51%;HBsAb阳性率为67.34%,乙型肝炎标志物全阴为22.08%。结论江门市健康体检人群HBsAg阳性率与全国平均水平相当,预防控制乙肝仍要加强以乙肝疫苗接种为主的综合预防措施。     

Eighteen-year follow-up cohort study on hepatitis B and C virus infections related long-term prognosis among hemodialysis patients in Hiroshima

This study aimed to investigate the prevalence trend of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and their genotype distribution among hemodialysis patients, determining their long-term prognosis and the risk factors to the mortality. This cohort study used both the medical data and the blood samples of hemodialysis patients at nine dialysis centers in Hiroshima from 1999 to 2017. Hepatitis B surface antigen (HBsAg) and anti-HCV were screened and then amplification was done to positive sera by polymerase chain reaction for genotyping. Data were employed for multiple regressions to determine the associated risk factors. A total of 3968 patients were subdivided into three groups: who started hemodialysis before 1990, during 1991 to 2001, and after 2002. The periodic prevalence of HBsAg decreased from 2.8% to 1.3% and that of anti-HCV from 33.3% to 9.5% in the three groups. By multiple regressions, the adjusted hazard ratio of diabetes mellitus (DM) ranges from 1.59 to 2.12 and that of HCV RNA positivity ranges from 1.18 to 1.48 (P < .05). Heart failure is the primary cause of death in all groups. Genotype C2 is predominant for HBV and genotype 1b is predominant for HCV. The decreasing trend of both HBV and HCV was found in the cohort. DM and HCV RNA were the significant risk factors leading to poor prognosis among hemodialysis patients. The similar genotype distribution of both HBV and HCV was found as general population. This alarmed to provide early diagnosis, prompt, and adequate treatment to HCV infection among hemodialysis patients.     

HIV,hepatitis B virus,hepatitis C virus,and syphilis among pregnant women attending antenatal care in Luanda,Angola: Seroprevalence and risk factors

Infectious diseases during pregnancy remain a public health concern, especially in a resource-limited setting. The study aimed to determine the seroprevalence and determinants of HIV and co-infection with hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis among pregnant women attending antenatal care in Luanda, the capital city of Angola. A cross-sectional study was conducted with 1612 pregnant women screened for HIV during antenatal care. HIV-reactive were also screened for the HBV, HCV, and syphilis using immunoassay kits. A logistic regression model, adjusted odds ratios (AOR) and their 95% confidence interval (CI) were calculated with a level of significance set at 5%. The overall seroprevalence of HIV was 2.6%. About 13% of HIV-positive pregnant women were coinfected. From which, 7.5% were reactive to HBV and 5% to syphilis. There was no reactivity to HCV. Pregnant women younger aged than 25 years were significantly protected from HIV-infection (AOR, 0.43 [95% CI, 0.20-0.91], P = .026). The co-infection was 1.3 times (AOR, 0.04-41.0) in younger aged than 25 years, 7.0 times (AOR, 0.50-99.2) to residents in urbanized areas, and 1.4 times (AOR, 0.10-20.9) in pregnant women with a high educational level. In conclusion, infectious diseases are a public health burden among pregnant women in Luanda. However, include an integrated antenatal screening mainly in urbanized areas is crucial to reduce the spread of infectious diseases in different communities of Angola.     

Serologic markers of viral hepatitis A,B, C,and D in patients with hemophilia

Forty-one patients with hemophilia A were studied for the prevalence of serological markers for hepatitis A, hepatitis B, hepatitis C (non-A and non-B hepatitis), and delta hepatitis (hepatitis D). Ten of 41 (24.4%) patients demonstrated hepatitis A antibody and 31 of 41 (75.6%) patients had a serologic marker for previous hepatitis B infection; four of these 31 patients (13%) also demonstrated antibody to delta agent (hepatitis D). Thirty-seven of 41 (90.2%) patients demonstrated antibody for hepatitis C. Nine of 31 (29%) patients with a hepatitis B marker (no hepatitis B vaccinees) were negative for anti-HBc but positive for anti-HBs; all of these nine patients were HIV antibody positive, although they had no overt immunodeficiency. Twenty-six of 41 (63.5%) patients were HIV antibody positive. Of HIV antibody positive patients, 27%, 88%, and 100% demonstrated evidence of a previous hepatitis A, hepatitis B, or hepatitis C, respectively. Of HIV antibody negative patients; 20%, 53%, and 73% of the patients demonstrated evidence of a previous hepatitis A, hepatitis B, or hepatitis C infections, respectively. The difference between HIV antibody positive and HIV antibody negative groups was not significant for hepatitis A but was significant for hepatitis B (P < 0.001) and hepatitis C (P < .001). Of the 31 patients with a hepatitis B serologic marker, all had antibody to hepatitis C. Of 10 patients, without a hepatitis B serologic marker, only 6 (60%) had antibody to hepatitis C. Clinically, none of our patients demonstrated any evidence of liver disease; however, 10 patients reported a previous history of hepatitis. These data suggest that patients with hemophilia in the United States, particularly those with HIV antibody, have high prevalence of hepatitis B and C infections.     

Treatment of chronic hepatitis C in patients with HIV/HCV coinfection

Hepatitis C virus (HCV) infection is one of the most frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCV-genotype 1, both for the HCV-monoinfected and HIV/HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.     

Kinetics of HBV DNA and HBsAg in acute hepatitis B patients with and without coinfection by other hepatitis viruses

The kinetics of hepatitis B virus (HBV) and its surface antigen (HBsAg) during acute hepatitis has not yet been studied accurately in a representative number of patients. The influence of coinfecting hepatitis viruses during the acute phase of infection is not known. Three to four serum samples from 21 patients with acute HBV monoinfection and 27 with coinfection were taken at intervals of 6-10 days and analyzed for the number of HBV genome equivalents (ge) by real time polymerase chain reaction (PCR) and for HBsAg quantity using Laurell electrophoresis. Log HBV ge/ml decreased during the follow-up from 6.8 +/- 1.1 to 5.1 +/- 1.0 to 4.2 +/- 0.8 to 3.3 +/- 1.1 (mean +/- SD). The half-life times of HBV ge increased from 1.6 days at the beginning to 4 days at the end. HBsAg decreased much slower: from 38 to 23 to 12 to 3.8 microg/ml. Half-life time was around 8 days at the beginning and 5.7 days at the end, but 11 patients showed a rapid elimination of HBsAg and HBV DNA. Hepatitis C virus (HCV) coinfection did not change the kinetics of HBV ge and HBsAg significantly. A moderate but significant suppression of HBV ge levels was observed in hepatitis D virus (HDV) coinfected patients. HBsAg levels were, however, enhanced in this cohort. In conclusion, the data suggest that expression and elimination of HBV is in most patients with acute hepatitis B not altered by coinfecting hepatitis viruses. The initial decrease of HBV ge and HBsAg in serum appears to be caused by decay or non-specific removal in the absence of replacement.     

Prevalence of hepatitis B, C, and delta virus infections among children in Mongolia: progress in childhood immunization

Mongolia is highly endemic for hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) infections among apparently healthy adults. However, the age-specific prevalence of ongoing HBV, HCV, and HDV infections among children in Mongolia remains unknown. Therefore, samples obtained from a total of 655 apparently healthy children of 0.3-15 years of age (307 boys and 348 girls; age, mean +/- standard deviation [SD], 8.4 +/- 4.2 years) living in Mongolia, between October 2005 and January 2006, were tested for serological and molecular markers of HBV, HCV, and HDV infections. Although 88.7% of the 655 children studied were immunized against hepatitis B, 64 (9.8%) tested positive for hepatitis B surface antigen (HBsAg) and/or HBV DNA and 13 (2.0%) for HDV RNA. Twenty-seven children (4.1%) had detectable HCV RNA. Collectively, 82 (12.5%) were viremic for one or more of these viruses, including eight children with dual viremia of HBV/HCV and one child with triple HBV/HCV/HDV viremia. When children without anti-HBc, anti-HCV and anti-HDV IgG (n = 510) served as a control, a history of hospitalization was significantly associated with HBV viremia (P < 0.0001), anti-HBc positivity (P < 0.0001), and HCV viremia (P = 0.0001). HBsAg mutation was found in 18 (31.6%) of the 57 children with viremia, including those at amino acid position 126, 127, 129, 131, 134, 143 or 144. There were no significant differences in the frequency of HBsAg mutation in relation to age, sex, and hepatitis B vaccination status of the children, suggesting that HBsAg mutation plays a limited role in failure of vaccination in Mongolia.     

Low hepatitis B prevalence among pre-school children in Denmark: saliva anti-HBc screening in day care centres

Although Denmark has a low hepatitis B virus (HBV) prevalence, HBV transmission has been reported in Danish day-care centres. The aim of this study was to validate saliva anti-HBc testing as a method for HBV screening, the applicability of saliva sampling to pre-school children, and to determine the HBV prevalence in Danish day-care centres with a high proportion of immigrants. For validation, paired saliva and plasma samples were obtained from blood donors and injecting drug users. Employees and children in day-care centres with a high proportion of immigrant children were offered saliva screening followed by blood test if positive. The specificity and sensitivity of anti-HBc tests on saliva was 100% (102 blood donors and four injecting drug users) and 85.9% (61 of 71 anti-HBc-positive injecting drug users), respectively. In all samples from HBsAg (n = 7) or anti-HBc IgM-positives (n = 9), anti-HBc was detected in saliva. Adequate saliva samples were obtained from 93% (588/634) of children and 100% (166/166) of employees participating in the day-care centre survey. Among children 55% were of non-Scandinavian origin and only one (0.2%, 95% CI [0.0; 1.0]) was HBV positive. Among employees the corresponding values were 22% and 7 (4.2%). The positive predictive value of the saliva test was 25% (1/4) among children and 88% (7/8) among adults. In conclusion, saliva testing is feasible for HBV screening among children in low prevalence populations, but any anti-HBc reactivity should be confirmed by plasma analysis. The HBV prevalence in pre-school children in Denmark is low even among immigrants from endemic areas.     

Interference of replication between hepatitis B and C viruses in patients infected with HIV

The clinical and cellular interactions between hepatitis B virus (HBV) and hepatitis C virus (HCV) were investigated in patients co-infected with the human immunodeficiency virus (HIV). One hundred ninety-nine patients followed for 6 years were evaluated to compare the level of HBV DNA and HCV RNA in patients co-infected with HIV and HBV, and patients co-infected with HIV, HBV, and HCV. A full-length HBV genome and HCV JFH1 RNA were co-transfected into HuH-7.5.1 cells in vitro to examine the impact of co-infection and dependence on the HBV PreC mutant for replication interference. Before 2',3'-dideoxy-3'-thiacytidine (3TC)-based antiretroviral therapy (ART) was initiated, HBV DNA was found in 56/123 (45.4%) patients co-infected with HIV and HBV, and in 19/76 (25.0%) patients co-infected with HIV, HBV, and HCV. After 3TC-based ART was initiated, detectable HBV DNA decreased to 7/76 (9.2%) in patients co-infected with HIV, HBV, and HCV, but HCV RNA increased from 43/76 (56.6%) to 60/76 (78.9%) (P = 0.003). In vitro HBV and HCV co-infection led to decreased replication of both viruses. The primary factors that influenced the decreased replication were the order of the HBV and HCV infection and the HBV PreC mutation.     

Hepatitis B and hepatitis C among institutionalized psychiatric patients in Taiwan

To investigate the seroprevalence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) in a psychiatric institution in Taiwan, where hepatitis B virus (HBV) is hyperendemic, a total of 780 patients with psychiatric disorders were studied. Enzyme-linked immunosorbent assays (ELISA) were used for testing HBsAg and anti-HCV. The prevalence of HBsAg was higher than that of anti-HCV among these patients (18.1% vs. 6.8%, P < 0.0001). The HBsAg carrier rate in these patients was consistent with that of the general population, with a trend for HBsAg carrier rate to be lower in the aged and in females. In contrast, the prevalence of anti-HCV was higher in these patients than in general population. Anti-HCV positivity was found more frequently in patients who had received blood transfusion previously (24% vs. 6.4%, P < 0.05). The majority (92%) of patients with positive anti-HCV did not have a history of apparent parenteral exposure. The prevalence of anti-HCV increased significantly with duration of the psychiatric disorder. The prevalence of anti-HCV also tended to increase with duration of hospitalization but without reaching statistical significance. These findings suggest that these institutionalized psychiatric patients contract hepatitis B, as does the general population in Taiwan, and they should be considered as a specific risk group for hepatitis C infection. © 1993 Wiley-Liss, Inc.     

High prevalence of hepatitis B,C, and E markers in young sexually active adults from The Central African Republic

The Central African Republic is located in tropical Africa, where both the human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are highly endemic. The exact prevalence of hepatitis C virus (HCV) and hepatitis E virus (HEVI markers in this country is unknown. The aim of the study was to determine, according to HlV and HBV serostatus, the prevalence of these markers in young sexually active adults in the Central African Republic. One hundred and fifty-seven consecutive patients attending the National Centre for Sexually Transmitted Diseases in Bangui were included. The following serological markers were examined: (i) anti-HIV1 and anti-HIV2 antibodies; (ii) markers of HBV infection; (iii) anti-HCV antibodies; (iv) anti-HEV antibodies. Anti-HIV1 antibodies were found in 31 of the 157 patients (20%). The prevalence of anti-HBc antibodies, reflecting exposure to HBV, was 140/157 (89%) and 45 had detectable anti-HBs antibodies. Twenty-two patients (14%) were chronic carriers of hepatitis B surface antigen (HBsAg), but only one was HBe antigen-positive. Anti-HCV antibodies were found in 8 persons (5%) and antiHEV antibodies in 38 (24%). No difference was found in the prevalence of these markers according to the presence or absence of anti-HIV antibodies. This study confirms the high rate of HIV infection, HBV exposure and chronic carriage of HBsAg in sexually active young adults in the Central African Republic. A high prevalence of HCV markers was found in this population, similar to that reported in neighbouring countries, together with a high rate of HEV markers, suggesting that HEV is endemic in this region. © 1995 Wiley-Liss, Inc.     

Horizontal transmission of hepatitis B virus among children and adults in five rural villages in Zambia

To determine whether horizontal transmission of the hepatitis B virus contributes to the high prevalence of infection with this virus in an endemic region, residents of five villages in Zambia were tested for hepatitis B serologic markers. The prevalence of hepatitis B was determined by testing samples from 620 residents. By examining paired serum samples from 79 children and 80 adults, it was determined that new infections occurred during the five years of this study in at least 14 children (18%) (aged 4-17 years) and ten adults (12%) (aged 23-65 years). These 24 new infections were distributed among 20 households and were not associated with active HBV infections in the mother or, in most cases, other family members. Intervention to prevent hepatitis B in regions such as rural Zambia will require vaccination of susceptible children and adults as well as newborn infants.     

Changing seroepidemiology of hepatitis B, C, and D virus infections in high-risk populations

Needle-sharing and sexual contact are important transmission routes of hepatitis B, C, and D virus (HBV, HCV, HDV) infection. This study aimed to investigate the current status of these viral infections among high-risk populations including prostitutes and intravenous (i.v.) drug users, compared with the prevalence rate reported previously to examine the changing seroepidemiology. Of the 916 female prostitutes, 79 (9%) were positive for antibody to HCV (anti-HCV), 111 (12%) were positive for HBV surface antigen (HBsAg), and 5 (5%) had antibody to HDV (anti-HDV). The prevalence rate was significantly lower compared to that in 1989-1991 (12%, P = 0.037) for HCV infection, and to that in 1988 (59%) and 1996 (40%) (P < 0.0001) for HDV infection. Of the 494 i.v. drug users, 87 (18%) patients were HBsAg carriers and 12 (14%) were anti-HDV-positive. The prevalence rate of HDV infection was significantly lower than that reported in 1985 (79%, P < 0.0001). Among the 443 tested i.v. drug users, 182 (41%) were anti-HCV-positive, significantly lower than that in 1985 (53%, P = 0.026). Of the 263 male prostitutes, 11 (4%) were anti-HCV-positive, 45 (17%) were HBsAg-positive, and 7 (16%) were anti-HDV-positive. Of the 129 illegal immigrant prostitutes, 7 (5%) were anti-HCV-positive, 15 (12%) were HBsAg-positive and none were positive for anti-HDV. In conclusion, the findings indicate a declining prevalence of HCV and HDV infections among drug users and prostitutes over the past 16 years. Male prostitutes and immigrant prostitutes are new "high-risk" populations and may become a reservoir for disease transmission.     

Long-term follow-up of hepatitis B virus and hepatitis C virus replicative levels in chronic hepatitis patients coinfected with both viruses

Dual infection with hepatitis B and C viruses is often encountered in endemic areas of both viruses. However, understanding of the clinical and virological implications is limited. The aim of this study was to investigate the role of each virus in liver injury and the interaction between the two viruses in dual infection with hepatitis B and C viruses. Three patients who had chronic infection with both hepatitis B and C viruses were examined, and a longitudinal study of both serum hepatitis B virus DNA and hepatitis C virus RNA levels over 4 years was undertaken. The results were correlated with serum alanine aminotransferase levels. Serum alanine aminotransferase values showed a relationship with hepatitis B virus replicative levels, but not with hepatitis C virus replicative levels in all 3 patients. Serial changes of replicative levels of both viruses were studied, and it was found that hepatitis C virus replicative levels were enhanced after the decline of hepatitis B virus replication in 1 of the 3 patients. In the remaining 2 patients, a transient rise of hepatitis C virus replicative levels in association with a decrease of hepatitis B virus replication was also observed during part of the follow-up period. These findings indicate that hepatitis B virus may play a dominant etiological role in liver injury, and that a suppressive action between hepatitis B and C viruses may occur in dual infection with both viruses. © 1995 Wiley-Liss, Inc.     

Distribution of hepatitis C virus genotypes among hemodialysis patients in Tehran--a multicenter study

Hepatitis C virus has substantial heterogeneity of genotypes throughout the world. The aim of this study was to determine the frequency of HCV genotypes, risk factors and clinical implications in cases of hemodialysis living in Tehran. A total of 155 patients treated by hemodialysis, who had been identified to be anti-HCV positive at 45 medical centers in Tehran, were enrolled. Genotyping was using restriction fragment length polymorphism (RFLP) on HCV-RNA positive samples. HCV-RNA was detected in 66 (42.6%) patients. Genotyping of HCV-RNA positive serum samples demonstrated that subtypes 3a and 1a were predominant accounting for 30.3 and 28.8%, respectively. The distribution of other HCV genotypes showed genotype 1b, 18.2%; genotype 4, 16.7%; mixed genotypes 1a and 1b, 3%; and genotype 3b, 3%. Genotype 2 was not detected in this study. Statistically significant differences were identified between HCV infected and non-HCV infected patients regarding history of hemodialysis unit changes more than two times (P = 0.01), and history of hemodialysis for more than 20 years (P = 0.02). However, blood transfusion, mean duration of hemodialysis therapy and the history of solid organ transplantation did not differ between these two groups. This study indicates that the dominant HCV genotypes among patients treated by hemodialysis living in Tehran were 3a and 1a, and considering previous reports from the general population, genotype 4 was strongly associated with hemodialysis. The duration of treatment by hemodialysis and, in turn, more hemodialysis unit changes will lead to more frequent HCV infections.