I15090
I15090 Fibrosis progression after acute HCV infection in HIV-infected individuals
Van der Valk M, Kooij KW, Newsum AM, Smit C, Reiss P, Prins M, van der Meer J, MOSAIC study group, SHM hepatitis working group.
Date of approval: 27 July 2015
Background: HIV co-infection may accelerate the progression to liver fibrosis and cirrhosis in chronic HCV. Recently, a study among HCV mono-infected patients demonstrated an unexpectedly high rate of fibrosis progression, relatively soon after HCV seroconversion, as measured by the change in FIB-4 score over time. Data on the rate of liver fibrosis progression and its determinants soon after HCV seroconversion in those with underlying HIV infection are lacking. We will retrospectively study liver fibrosis progression, assessed by FIB-4 scores, in HIV-infected individuals within the Netherlands who acquired acute HCV.
Methods: Any HIV-positive individual with an acute HCV infection at or after January 1st 1999, identified in the SHM database, are included. In addition, cases identified in the MOSAIC study are included. Only men who have sex with men (MSM) are included. HCV infection prior to HIV infection is an exclusion criterion. Furthermore, patients need to have sufficient follow-up: inclusion criteria are ≥1 FIB-4 value available within 2 years before and ≥ 1 value one year after the estimated HCV infection date. Descriptive analyses and multivariate modeling to assess determinants of FIB-4 progression or regression are ongoing.
Acute HCV infection: At least one negative anti-HCV antibody test result or negative HCV-RNA test result, without any prior positive anti-HCV antibody or HCV-RNA tests, followed by a positive anti-HCV antibody test result or HCV-RNA positive test result. The maximum interval between the last negative and first positive test result is 12 months.
Estimated date of infection is the midpoint between last negative test result and first positive test result. If antibody seroconversion date is later than first RNA positive test, estimated date of acute infection is date of first RNA-positive test minus 28 days.
Individuals with antibody seroconversion, but never tested RNA-positive, are included if they have at least 2 antibody positive test results AND no subsequent antibody negative test result AND at least one RNA-negative test result.
Treatment success (SVR): Last detectable test before end of treatment AND (≥1 undetectable / negative test ≥144 days (~22 weeks) after end of treatment OR SVR in medical file <280 days after end treatment
Treatment failure: No undetectable / negative test during treatment OR undetectable / negative test during treatment but first detectable test <280 days (~40 weeks) after end of treatment OR "no SVR" in medical file <280 days after end of treatment.
Date of spontaneous clearance: First undetectable test.
Reinfection: Detectable test after (real) undetectable test in untreated patient OR Detectable test after SVR as defined previously. (Later than 280 days after end of treatment.) NB suspected reinfections are censored 180 days before first positive RNA test.
Definitions - outcome:
FIB-4: FIB-4 is calculated with age at time of measurement. Values of ALT, AST, platelets measured within 14 days from each other can be used to calculate 1 FIB-4 score. ≥2 measurements on 1 day, or ≥3measurements within 7 days are dropped, because this is likely to be during acute illness. Measurements during anti-HCV treatment were not analysed because treatment can influence the platelet level. Only FIB-4 measurements that are measured at a time point when also an HIV-RNA and/or a CD4 cell count is measured are used.
Liver-related adverse event: Based on definition used in SHM report 2016, based on biopsy/radiology/medical file/fibroscan value.
Definitions - covariates:
Baseline alcohol intake: Registered self-reported alcohol intake (yes/no) and number of weekly consumptions closest to estimated date of infection. This time point cannot be later than one year after the estimated date of infection.
Baseline cigarette smoking: Registered self-reported ever cigarette smoking (yes/no), and current smoking (yes/no). NB the SHM smoking dataset does not contain the date when smoking was reported and registered.
Baseline diabetes mellitus: HbAlc (IFCC) of at least 48 mmol/mol and/or blood glucose (non-fasting) of at least 11.1 mmol/l and/or blood glucose (fasting) of at least 7.0 mmol/l, and/or in those who initiated antidiabetic medication. To fulfil this definition, these events should have occurred on or before the date of the first positive HCV test.
Baseline cholesterol level: Total cholesterol level (mmol/l) measured at the time point closest to the estimated date of infection. This time point cannot be later than one year after the estimated date of infection.
Baseline statin use: Initiation of statins on or before the date of the first positive HCV test.
Baseline BMI: Measured BMI closest to the estimated date of infection. This time point cannot be later than one year after the estimated date of infection.
HBV infection Baseline: HBV status recorded on or before the date of the first positive HCV test. The following categories are distinguished based on serology: 1) Vaccinated: hepatitis B surface antibody (HBsAb) positive, hepatitis B core antibody (HBcAb) negative at most recent test and never tested HBcAb positive. 2) Immune due to natural infection: HBsAb positive and HBcAb positive test result, but hepatitis B surface antigen (HBsAg) negative test at most recent test. 3) Active infection: HBsAg positive test result at most recent test. 4) No contact with HBV: HBsAb negative at most recent test, and never tested HBcAb or HBsAg positive 5) Incomplete data: no HBsAb test result recorded, and never tested HBcAb or HBsAg positive. 6) Incomplete data: HBsAg negative at most recent test, but historically HBsAg positive; never tested HBsAb positive.
Time-updated: new infection defined as positive HBcAb or HBsAg test in someone susceptible to HBV infection (i.e. category 4 of 5) after the first positive HCV test. Resolved infection defined as HBsAb positive test in someone with active HBV infection (i.e. category 2 or 6) after the first positive HCV test.
AIDS diagnosis: Baseline: registered CDC-C event on or before the date of the first positive HCV test. Time-updated: registered CDC-C event after the date of first positive HCV test.
CD4 count Nadir: nadir CD4 count. Baseline: measured CD4 count closest to the estimated date of infection. This time point cannot be later than one year after the estimated date of infection. Time-updated.
HIV RNA Baseline: as continuous variable (HIV RNA viral load) and categorized (detectable yes/no). Measured RNA count closest to the estimated date of infection. This time point cannot be later than one year after the estimated date of infection. Time-updated: as continuous variable and categorized.
Antiretroviral medication: Receiving ART at baseline: yes/no, assessed at estimated date of infection. ART-naïve at baseline: yes/no, assessed at estimated date of infection. Ever (before or at estimated date of infection) use of didanosine, or d-drugs (defined as didanosine, zalcitabine, stavudine OR alternatively as didanosine, zalcitabine, stavudine and zidovudine).
Statistical analysis
The following analyses are ongoing:
1. Descriptive analyses: a. FIB-4 slope, modelled using spline regression b. FIB-4 slope, modelled using spline regression and compared for the different categories of course of HCV infection: spontaneous clearance, successfully treated, never treated/unsuccessfully treated
2. Multivariable model to assess determinants of FIB-4 progression / regression: Stages of FIB-4 <3.25 (no/mild fibrosis) and FIB-4≥3.25 (severe fibrosis) are modelled as a homogenous continuous-time Markov process and determinants of transition rates using a multivariable multistate Markov model.
Results: Characteristics of included patients Of 312 MSM included, median age at acute HCV infection was 43 years (IQR=36-48) and 198 (63.5%) were on combination antiretroviral therapy. Following acute HCV infection, median follow-up was 4.0 years (IQR=2.2-6.4) and median FIB-4 values per MSM was 9 (IQR=5-15). Following acute HCV infection, 41 MSM (13.1%) spontaneously cleared HCV and 224 (71.8%) were treated for HCV at least once, of whom 161 (71.9%) achieved SVR after their first treatment.
FIB-4 course over time appeared mostly stable over time with peaks observed in some patients shortly after acute HCV infection. Prior to acute HCV infection, 307 MSM (98.4%) had FIB-4 <3.25, of whom 47 (15.3%) progressed to FIB-4 ≥3.25 a median of 0.3 years (IQR=0.2- 0.8) after acute HCV infection. However, 40/47 had reverted to FIB-4 <3.25 by the end of follow-up.
Determinants of FIB-4 progression and regression: In multivariable analysis, higher CD4 cell count (per log10 mm3; aHR=0.14, 95% CI=0.04-0.50) and undetectable HIV RNA (<50 vs ≥50 copies/mL; aHR=0.24, 95% CI=0.11-0.51) were associated with a lower rate of transitioning to FIB-4 ≥3.25. Older age was associated with a lower rate of reverting from FIB-4 ≥3.25 to FIB-4 <3.25 (per year; aHR=0.95, 95% CI=0.92-0.98).
Conclusions (preliminary): Most MSM with acute HCV infection who developed a FIB-4 ≥3.25 did so during the first year following HCV infection. A FIB-4 ≥3.25 was uncommon by the end of follow up. Well-controlled HIV infection appeared to attenuate FIB-4 progression.