title: Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with the human immunodeficiency virus in a Dutch cohort.
abstract: BACKGROUND
  With the introduction of HAART, the HIV-1 has turned from a lethal into a chronic infection in the majority of patients. In homosexual populations, 20% of HIV-1 infected patients suffer from a chronic HBV infection, which may eventually lead to complications of the liver disease because of prolonged survival. Lamivudine is effective in reducing both HIV-1 and HBV viral replication. However, resistance for lamivudine may complicate the course of the HBV disease in HIV-1-infected patients. We, therefore, conducted a retrospective study in HIV-1-HBV co-infected patients on lamivudine therapy.
  
  
  METHODS
  All HIV-1-HBV co-infected patients who were treated with lamivudine for over 6 months in five major referral clinics in The Netherlands with HBV DNA above 2.0 x 10(5) geq ml(-1) at baseline, were evaluated. Retrospectively, the course of HBV DNA in available serum samples was established. If HBV DNA was detectable with the sensitive PCR-assay, YMDD-analyses of the polymerase gene of the hepatitis B virus was executed with the INNO-LiPA-DR-strip.
  
  
  RESULTS
  Forty-six patients were evaluated. The median level of HBV DNA at start of lamivudine therapy was 1.31 x 10(9) geq ml(-1) (range 3.5 x 10(5) - 2.0 x 10(10), n=43). Of three patients no baseline sample was available, but since HBV DNA was still above 2.0 x 10(5) geq ml(-1) at week 3, 7 and 11, these patients were included. Median duration of lamivudine therapy was 97 weeks (range 27-263). The percentage of detected mutations was 25 and 52% at 1 and 2 years, respectively. Twenty-two patients ultimately developed a mutation. Both baseline Body Mass Index (BMI) and the decrease in CD4 cell count as a time dependent factor were significantly related to the emergence of mutations. In 10 out of 12 evaluated patients, HBV DNA levels returned to baseline level or even above baseline level after the development of mutant virus. One patient (5%) developed a flare of serum transaminases (ALT>10 x ULN) 24 weeks after first detection of variant virus.
  
  
  CONCLUSIONS
  There is a linear time-dependent appearance of HBV mutations for lamivudine in our population. In a minority of patients (5%), development of a mutation was followed by a significant elevation of serum transaminases. A decline in CD4 cell count, which may indicate less response to HAART, induces a faster emergence of mutations and close surveillance of HBV co-infected patients on therapy may be indicated due to the prolonged survival of HIV-1 patients.
authors.affiliation: Department of Hepatology and Gastroenterology, Erasmus Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: L M M
authors.initials: LM
authors.lastname: Wolters
authors.forename: H G M
authors.initials: HG
authors.lastname: Niesters
authors.forename: B E
authors.initials: BE
authors.lastname: Hansen
authors.forename: M E
authors.initials: ME
authors.lastname: van der Ende
authors.forename: F P
authors.initials: FP
authors.lastname: Kroon
authors.forename: C
authors.initials: C
authors.lastname: Richter
authors.forename: K
authors.initials: K
authors.lastname: Brinkman
authors.forename: P L
authors.initials: PL
authors.lastname: Meenhorst
authors.forename: R A
authors.initials: RA
authors.lastname: de Man
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000821:virology*; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D015497:HIV-1; D006515:Hepatitis B virus / Q000187:drug effects; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D009426:Netherlands; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine