Detection of hepatitis B virus genotype A3 and primary drug resistance mutations in African immigrants with chronic hepatitis B in Spain.

BACKGROUND: Universal vaccination and antiviral therapy have reduced chronic hepatitis B virus (HBV) in natives in the Western world. However, immigration from high HBV endemic areas continues to maintain a relatively stable prevalence of chronic hepatitis B in most developed countries. METHODS: All foreigners attending a referral infectious diseases department in Madrid, Spain, from January 2007 to December 2008, were evaluated for serum HBV surface antigen (HBsAg). Positive cases underwent further virological characterization. RESULTS: A total of 1718 foreigners were examined, of whom 1322 (77%) were sub-Saharan Africans. Serum HBsAg was positive in 121 (7%), HIV in 135 (7.9%) and hepatitis C virus antibodies in 212 (12.3%). HBV subgenotype A3, which so far had only been reported in people originating from Cameroon, was found in nearly half (14/29) of the tested specimens with detectable serum HBV-DNA. Interestingly, the lamivudine resistance mutation rtM204V was found in two Africans (6.9%), one infected with HBV-A3 and the other with HBV-E. Lack of prior exposure to antiviral therapy in these two patients was confirmed retrospectively. CONCLUSIONS: Circulation of uncommon HBV variants, including strains with primary drug resistance, may follow large immigrant flows from HBV endemic regions to Western countries. Close surveillance of this population is warranted, as early diagnosis and early antiviral therapy may reduce transmission and prevent clinical complications.

Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfected patients?

BACKGROUND: Hepatitis delta virus (HDV) has a unique replication process that requires coinfection with hepatitis B virus (HBV). Treatment is currently limited to interferon therapy. The role of potent nucleos(t)ide analogues active against HBV has not been well examined in chronic delta hepatitis (CDH). METHODS: HIV-positive patients with CDH attending our hospital were identified and longitudinally studied. Serum HBV DNA, HDV RNA and HIV RNA, treatment regimens, and biochemical and serological markers were assessed at yearly intervals. Liver fibrosis was measured by transient elastography during the last 2 years. RESULTS: Sixteen patients were identified and treated with anti-HBV therapy (median time 6.1 years). The majority were male and previous intravenous drug users. Median baselines were: HDV RNA 7 log10 copies/ml, HIV RNA 1.7 log10 copies/ml, HBV DNA 1.1 log10 IU/ml and alanine aminotransferase (ALT) 98 IU/ml. A significant correlation was found between HDV RNA and HBV DNA (r=0.226, P=0.015), aspartate aminotransferase (r=0.430, P<0.0001), ALT (r=0.441, P<0.0001) and hepatitis B surface antigen (HBsAg) (r=0.557, P<0.0001). Overall, 13 patients showed a reduction in HDV viraemia and ALT levels, and three of them achieved undetectable HDV RNA and normal ALT levels. CONCLUSION: Patients undergoing successful anti-HBV therapy with potent nucleos(t)ide analogues seem to indirectly benefit from suppression of HDV replication, albeit not very efficiently. Hypothetically, a significant and sustained reduction in serum HDV RNA might only be seen when a reduction in HBV covalently closed circular DNA or HBV surface antigen is achieved, which may require long periods of successful anti-HBV therapy. To our knowledge, this is the first evidence of the benefit of potent anti-HBV nucleos(t)ide analogue therapy in CDH.

Hepatitis B virus genotypes and resistance mutations in patients under long term lamivudine therapy: characterization of genotype G in Brazil.

BACKGROUND: Lamivudine is an oral nucleoside analogue widely used for the treatment of chronic hepatitis B. The main limitation of lamivudine use is the selection of resistant mutations that increases with time of utilization. Hepatitis B virus (HBV) isolates have been classified into eight genotypes (A to H) with distinct geographical distributions. HBV genotypes may also influence pathogenic properties and therapeutic features. Here, we analyzed the HBV genotype distribution and the nature and frequency of lamivudine resistant mutations among 36 patients submitted to lamivudine treatment for 12 to 84 months. RESULTS: Half of the patients were homosexual men. Only 4/36 (11%) patients were HBV DNA negative. As expected for a Brazilian group, genotypes A (24/32 positive individuals, 75%), D (3/32, 9.3%) and F (1/32, 3%) were present. One sample was from genotype C, which is a genotype rarely found in Brazil. Three samples were from genotype G, which had not been previously detected in Brazil. Lamivudine resistance mutations were identified in 20/32 (62%) HBV DNA positive samples. Mean HBV loads of patients with and without lamivudine resistance mutations were not very different (2.7 x 107 and 6.9 x 107 copies/mL, respectively). Fifteen patients showed the L180M/M204V lamivudine resistant double mutation. The triple mutant rt173V/180M/204V, which acts as a vaccine escape mutant, was found in two individuals. The three isolates of genotype G were entirely sequenced. All three showed the double mutation L180M/M204V and displayed a large genetic divergence when compared with other full-length genotype G isolates. CONCLUSION: A high (55%) proportion of patients submitted to long term lamivudine therapy displayed resistant mutations, with elevated viral load. The potential of transmission of such HBV mutants should be monitored. The identification of genotypes C and G, rarely detected in South America, seems to indicate a genotype distribution different to that observed in non treated patients. Disparities in routes of transmission (genotype G seems to be linked to homosexual behavior) and in pathogenic properties (genotype C is very aggressive) among HBV genotypes may explain the presence of rare genotypes in the present work.

Emerging drugs for hepatitis C.

BACKGROUND: Chronic hepatitis C virus (HCV) infection remains a global health threat with approximately 200 million carriers worldwide. Current treatment consists of the use of peginterferon (pegIFN)/ribavirin (RBV) for 24 or 48 weeks depending on HCV genotype. Serious side effects and the fact that less than half of patients infected with HCV genotypes 1 and 4 (which are the most common) accomplish sustained virological response with this medication warrant the need for novel anti-HCV therapies. OBJECTIVE: Description of specifically targeted antiviral therapies for hepatitis C (STAT-C) designed to inhibit the serine protease and the RNA-dependent HCV-RNA polymerase. METHODS: Review of available data reported in peer-reviewed journals and medical conferences. RESULTS/CONCLUSIONS: Early preclinical studies using these compounds produced encouraging results, but the initial enthusiasm has been hampered by toxicity issues and rapid selection of resistance. Therefore, combination therapy with a backbone of pegIFN/RBV, or perhaps in the future using several of these small molecules, preferably having distinct modes of action and resistance profiles, will be required.

Lamivudine resistance and other mutations in the polymerase and surface antigen genes of hepatitis B virus associated with a fatal hepatic failure case.

BACKGROUND AND AIM: Resistance to lamivudine therapy of chronic hepatitis B virus (HBV) infection occurs by mutation in the YMDD motif of the reverse transcriptase (rt) domain (rtM204V/I) of the virus polymerase, and is usually accompanied by rtL180M mutation. Here we investigated virological factors associated with hepatic failure in a 58-year-old male, chronically HBV-infected patient who died after 33 months of lamivudine therapy. METHODS: Nucleotide sequencing was performed from one sample collected before and two samples collected during lamivudine therapy. RESULTS: A peak of alanine aminotransferase and aspartate aminotransferase levels occurred after 19 months of lamivudine treatment, associated with the rtM204I mutation. After 32 months, the rtM204V mutation was predominant, accompanied by the lamivudine-resistant rtL180M mutation. Furthermore, two rare polymerase (rtS117Y and rtV142A) and three HBsAg (L109I, F134L, and I208T) substitutions were observed. At that time, the patient was hospitalized with hepatic decompensation, followed by hepatic failure, and died one month later. HBV-DNA was detected at moderate levels (8.3 x 10(4)-2.6 x 10(6) copies/mL) throughout. CONCLUSION: The results suggest that substitutions in polymerase (rtS117Y, rtV142A) and surface antigens (L109I, F134L, and I208T), associated with lamivudine-resistant mutations at positions 180 and 204, were involved in this case of fatal hepatitis B.

[Long-term use of lamivudine for treating chronic hepatitis B in the State of Mato Grosso]. / Lamivudina por tempo prolongado no tratamento da hepatite B crônica no estado de Mato Grosso.

To assess the results from lamivudine treatment (100 mg or 150 mg) for chronic hepatitis B, 34 patients were followed at a clinic in Cuiabá, Mato Grosso, Central Brazil. Among them, 21 (62%) had liver cirrhosis and 24 (70%) were HBeAg-positive. The viral genotype was determined for 18 patients, among whom genotype A was the most prevalent (12). The median follow-up was 27 months (range from 7 to 64 months). Among the total, 23 (67%) presented a biochemical response after 2 to 24 months of treatment. Among the 24 HBeAg-positive subjects, 13 (54%) became HBeAg-negative during the follow-up. Among the anti-HBe-positive patients, 70% obtained normalization of aminotransferase levels. Fourteen (41%) did not present any initial biochemical or serological response or presented breakthrough. The L180M and M204V mutations were found in six of the non-responders. Four patients died after at least 21 months of lamivudine and three patients with liver cirrhosis developed liver cancer after 24 months. From the third year onwards, complications such as digestive system hemorrhage or liver cancer started to emerge. The present findings suggest that an early response to lamivudine treatment may be associated with better control over chronic hepatitis B.

Management of hepatitis B virus co-infection on and off antiretroviral therapy.

Chronic hepatitis B virus (HBV) infection is recognized in 5% to 10% of persons with HIV. Co-infected individuals show an accelerated course of HBV-associated liver disease with faster progression to cirrhosis. The number of anti-HBV drugs has increased in the past few years, and some agents (eg, lamivudine, emtricitabine, tenofovir) also exert activity against HIV-1. Emergence of drug resistance challenges the long-term benefit of anti-HBV monotherapy. Data derived from studies using new more potent anti-HBV drugs are very promising, and strategies to use these antiretrovirals sequentially or in combination are being developed. Appropriate diagnosis and monitoring of chronic hepatitis B, including the use of noninvasive tools for assessing liver fibrosis, measurement of serum HBV-DNA, and drug-resistance testing, along with wise use of antivirals may convert HBV/HIV co-infection in to a manageable disease. Hopefully, this success will translate into a halt of liver-related complications and death in the co-infected population.

The implications of antiviral drugs with activity against hepatitis B virus and HIV.

PURPOSE OF REVIEW: Around 10% of individuals infected with HIV suffer from chronic hepatitis B virus infection. This represents at least 4 million people worldwide. HIV infection modifies the course of hepatitis B virus associated liver disease with faster progression to cirrhosis. The number of anti-hepatitis B virus drugs has increased within the last few years, and some of them also exert activity against HIV-1. The aim of this article is to update the current knowledge on antiviral therapy for chronic hepatitis B in HIV-infected patients. RECENT FINDINGS: In the absence of successful anti-hepatitis B virus therapy, morbidity and mortality associated with liver disease are increased in hepatitis B virus/HIV coinfected individuals. Data derived from studies using new more potent anti-hepatitis B virus drugs are very promising, and strategies to use these antivirals sequentially and/or in combination are being developed. Hopefully, this success will help bring a halt to liver-related complications and death in the hepatitis B virus/HIV coinfected population. SUMMARY: Appropriate diagnosis and monitoring of chronic hepatitis B, including the use of noninvasive tools for assessing liver fibrosis, measurement of serum hepatitis B virus-DNA, and drug resistance testing, along with wise use of antivirals may convert hepatitis B virus/HIV coinfection into a manageable disease.

Lamivudina por tempo prolongado no tratamento da hepatite B crônica no estado de Mato Grosso / Long-term use of lamivudine for treating chronic hepatitis B in the State of Mato Grosso

Para avaliar resultados do tratamento da hepatite B crônica com lamivudina, 100mg ou 150mg diários, foram acompanhados 34 pacientes em um serviço em Cuiabá, Mato Grosso. Entre os 34, 21 (62 por cento), eram cirróticos e 24 (70 por cento) HBeAg positivos. Genótipo viral foi determinado em 18, sendo predominante o genótipo A (12). O acompanhamento teve mediana de 27 meses (7 a 64). Do total, 23 (67 por cento) apresentaram resposta bioquímica entre dois e 24 meses de tratamento. Dos 24 pacientes com positividade para o HBeAg, 13 (54 por cento) apresentaram negativação do HBeAg durante o acompanhamento. Entre os anti-HBe positivos, 70 por cento tiveram normalização das aminotransferases. Quatorze (41 por cento) não apresentaram resposta bioquímica ou sorológica de início ou apresentaram breakthrough. Em seis dos que não responderam, foram encontradas as mutações L180M e M204V. Quatro pacientes faleceram após pelo menos 21 meses de lamivudina e três cirróticos desenvolveram hepatocarcinoma após 24 meses. A partir do terceiro ano surgiram complicações, como hepatocarcinoma ou hemorragia digestiva. Os presentes achados sugerem que resposta precoce ao tratamento com lamivudina pode estar associada a um melhor controle da hepatite B crônica.

To assess the results from lamivudine treatment (100 mg or 150 mg) for chronic hepatitis B, 34 patients were followed at a clinic in Cuiabá, Mato Grosso, Central Brazil. Among them, 21 (62 percent) had liver cirrhosis and 24 (70 percent) were HBeAg-positive. The viral genotype was determined for 18 patients, among whom genotype A was the most prevalent (12). The median follow-up was 27 months (range from 7 to 64 months). Among the total, 23 (67 percent) presented a biochemical response after 2 to 24 months of treatment. Among the 24 HBeAg-positive subjects, 13 (54 percent) became HBeAg-negative during the follow-up. Among the anti-HBe-positive patients, 70 percent obtained normalization of aminotransferase levels. Fourteen (41 percent) did not present any initial biochemical or serological response or presented breakthrough. The L180M and M204V mutations were found in six of the non-responders. Four patients died after at least 21 months of lamivudine and three patients with liver cirrhosis developed liver cancer after 24 months. From the third year onwards, complications such as digestive system hemorrhage or liver cancer started to emerge. The present findings suggest that an early response to lamivudine treatment may be associated with better control over chronic hepatitis B.

Estudos do vírus da hepatite B em pacientes sob tratamento antiviral e caracterização de seqüências nucleotídicas completas do genótipo G no Brasil / Studies of the virus of hepatitis B in patients under antiviral treatment and characterization of complete nucleotídics sequences of genotype G in Brazil

A infecção causada pelo vírus da hepatite B (HBV) pode levar à doenças hepáticas graves, tais como cirrose e carcinoma hepatocelular. Os genótipos do HBV foram classificados de A-H. No Brasil, os genótipos A, D e F são os mais prevalentes. Nesta tese observamos os genótipos mais difundidos no Brasil, assim como relatamos o genótipo C, prevalente na Ásia e raro no Brasil, o qual foi encontrado em um paciente de origem asiática. O genótipo G, nunca detectado na América do Sul, é descrito pela primeira vez no Brasil em 3 pacientes com mutações de resistência à lamivudina. A lamivudina, um análogo de nucleosídeo, é utilizada para o tratamento da infecção do HBV e HIV. No entanto, o seu uso prolongado está relacionado à resistência. Nesta tese apresentamos os resultados do acompanhamento molecular do HBV de um caso de falência hepática em um paciente que veio a óbito durante tratamento com lamivudina, avaliamos as respostas bioquímica, sorológica e molecular do HBV em 34 pacientes em tratamento com lamivudina por tempo prolongado, assim como fazemos uma relação entre genótipos do HBV e a freqüência das mutações de resistência à lamivudina. Inicialmente, a lamivudina apresentou uma resposta bioquímica e/ou virológica favorável. No entanto, após 24 meses de tratamento, esse efeito não foi mantido, ocorrendo resistência molecular e morte. No caso de falência hepática, além da dupla mutação de resistência à lamivudina (rtL 180M/rtM204V), 3 mutações (L109I, F134L e I208T) que alteram o gene S e 2 mutações (rtS117Y e rtV142A) que alteram a polimerase viral foram observadas próximo ao óbito do paciente. O entecavir, um análogo de guanosina, é indicado no tratamento da hepatite B crônica em pacientes resistentes à lamivudina. Seis pacientes co-infectados HIV/HBV, todos HBeAg positivos, foram acompanhados, com uma média de 52 semanas, no primeiro ensaio clínico com o entecavir, realizado no Brasil, mantendo-se a lamivudina. Observou-se a normalização dos níveis de ALT...