Alpha-fetoprotein (AFP) belongs to the group of plasma proteins secreted from the yolk sac and fetal liver in early embryonic life . Following birth, AFP level decreases and remains at a low level (<10 ng/ml) throughout life in healthy persons. AFP is frequently employed as a screening test of hepatocellular carcinoma (HCC). Elevated serum AFP levels are also noted in 10–43% patients with chronic hepatitis C without HCC [2–5].
A recent paper in Egyptian patients infected by hepatitis C virus (HCV) genotype 4 shows that pretreatment-elevated serum AFP levels predict a poor response to HCV therapy . This result has not yet been confirmed in other settings.
We explored the association between serum AFP levels and virologic response in HIV-HCV coinfected patients who were enrolled in the ANRS HC02 RIBAVIC trial .
In brief, the Ribavic trial was a multicenter randomized controlled trial that evaluated the safety and efficacy of weekly subcutaneous injections of 1.5 μg/kg peginterferon alfa-2b (ViraferonPeg; Schering Corporation, Kenilworth, New Jersey, USA) plus daily ribavirin (Rebetol, ScheringCorporation) (800 mg), or thrice-weekly subcutaneous injections of 3 MU of interferon alfa-2b plus daily ribavirin (Rebetol) (800 mg), for 48 weeks, in HIV-HCV coinfected patients who had never received interferon or ribavirin. Virologic and histologic endpoints were centralized; all other laboratory tests, including AFP, were performed locally. Activity (grade) and fibrosis (stage) were scored with the Metavir scoring system . HCV-RNA was detected with a PCR assay (Amplicor 2.0 HCV Monitor; Roche Diagnostics Systems, Basel, Switzerland) with a detection limit of 50 IU × 103/l. Patients were classified in four groups: sustained virologic responders with undetectable HCV RNA at week 72, responders with relapse or relapsers with undetectable HCV RNA at week 48 and detectable HCV RNA at week 72, responders with a breakthrough with undetectable HCV RNA on-treatment and reappearance of HCV RNA before week 48 and nonresponders with persistent HCV RNA during treatment. Serum AFP values were assessed at baseline and weeks 48 and 72.
The Wilcoxon rank-sum test was used to compare quantitative variables between the groups and the Wilcoxon signed-rank test was used to compare pretreatment and posttreatment characteristics.
The analysis includes 383 patients who received at least one dose of study medication. Most patients were men (n = 282, 73.6%), white (n = 288, 75.4%) and the mean age was 39.7 (SD 5.4) years. HCV genotype 1 or 4 infection was found in 234 patients (61%). The mean HCV viral load was 5.9 (SD 0.7) log10 IU × 103/l. The mean Metavir fibrosis score was 2.3 (SD 1.0) and the mean activity score 1.8 (SD = 0.7). Patients had a mean CD4 cell count of 516 (SD 228) cells/μl, with HIV RNA <400 cp/ml in 252 (65.8%) cases (mean viral load in others: 3.2 (SD 1.0) log10 cp/ml) and belonged to the CDC class A, B and C in 199 (52.0%), 121 (31.6%) and 63 (16.4%), respectively. Three hundred and seventeen patients (82.7%) were receiving antiretroviral therapy.
Ninety-seven patients (25%) were sustained virologic responders, 26 (7%) were relapsers, 20 (5%) were responders with a breakthrough, 221 (58%) were nonresponders of which 113 (30% of the total) took at least 80% of the planned total dose. Nineteen patients (5%) did not achieve a sustained virologic response, but owing to missing early virologic endpoints could not be classified in one of the above category.
A low AFP level at baseline was associated with virologic response (Fig. 1). The mean pretreatment AFP level was 5.3 (SD 5.4) ng/ml in sustained virologic responders, and 15.2 (SD 45.5) ng/ml in nonresponders (P < 0.0001). Seventy-one patients (18.5%) had a raised pretreatment AFP level (≥10 ng/ml), of which 8 (11%) achieved a sustained response. When the pretreatment AFP level was categorized according to its median (<5.0 vs. ≥5.0 ng/ml), the odds ratio for a sustained virologic response was 2.28 [95% confidence interval (95% CI)] 1.41–3.69, P = 0.0006). The pretreatment AFP level was also higher in nonresponders than in relapsers or responders with a breakthrough (P = 0.046 and P = 0.001, respectively).
Previous analyses of RIBAVIC ANRS HC02 data showed that peginterferon treatment, genotype other than 1 or 4, ‘no protease inhibitor treatment’, age under 40 years, baseline alanine aminotransferase more than three times the upper limit of normal, HCV viral load under 5.7 log10 IU × 103/l, antiretroviral treatment with abacavir, total bilirubin were independently associated with virologic response [7,9]. These variables plus serum AFP were entered in a multivariate logistic model. The adjusted odds ratio for serum AFP (<5.0 vs. ≥5.0 ng/ml) was 1.83 (95% CI 1.05–3.20, P = 0.03).
End-of-treatment levels of serum AFP were decreased from baseline in all groups of patients (P < 0.002 for all comparisons between baseline and week 48), but the decrease was not sustained in nonresponders (P < 0.0001 for comparisons between week 48 and week 72).
In HIV-HCV coinfected patients, serum AFP level is an independent predictor of HCV treatment outcome. This confirms previous findings in HIV-seronegative HCV genotype 4 infected patients .
The mechanisms linking increased AFP levels with response to treatment are not defined [1,3] but the correlation of AFP levels with other measures of disease activity such as ALT, AST (not shown) and the strong decrease in AFP levels with therapy suggests that the liver necro-inflammatory process might regulate AFP serum level. AFP as well as GGT and certain cytokeratins (CK7, CK19) are expressed by hepatic progenitor cells. The expansion of these hepatic progenitor cells has been demonstrated in chronic hepatitis C in relation with fibrosis stage  and expression of AFP protein and AFP mRNA in liver biopsies have been shown to strongly correlate with the severity of disease and with response to treatment . Thus, serum AFP level could be a surrogate of hepatic progenitor cells proliferation. Further investigation is warranted to confirm this hypothesis and explain why AFP predicts SVR independently of liver fibrosis stage.
In conclusion, in HIV-HCV coinfected patients, there is a strong association between serum AFP levels and HCV treatment outcomes. We recommend integrating serum AFP measurement in pretreatment assessment of prognostic factors associated with a sustained virologic response.
This study was supported by Agence Nationale de Recherches sur le Sida, hépatites virales B et C (ANRS).
There is no conflict of interest.
1. Bayati N, Silverman AL, Gordon SC. Serum alpha-fetoprotein levels and liver histology in patients with chronic hepatitis C. Am J Gastroenterol 1998; 93:2452–2456.
2. Chen TM, Huang PT, Tsai MH, Lin LF, Liu CC, Ho KS, et al
. Predictors of alpha-fetoprotein elevation in patients with chronic hepatitis C, but not hepatocellular carcinoma, and its normalization after pegylated interferon alfa 2a-ribavirin combination therapy. J Gastroenterol Hepatol 2007; 22:669–675.
3. Chu CW, Hwang SJ, Luo JC, Lai CR, Tsay SH, Li CP, et al
. Clinical, virologic, and pathologic significance of elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C. J Clin Gastroenterol 2001; 32:240–244.
4. Di Bisceglie AM, Sterling RK, Chung RT, Everhart JE, Dienstag JL, Bonkovsky HL, et al
. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C trial. J Hepatol 2005; 43:434–441.
5. Hu KQ, Kyulo NL, Lim N, Elhazin B, Hillebrand DJ, Bock T. Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol 2004; 99:860–865.
6. Males S, Gad RR, Esmat G, Abobakr H, Anwar M, Rekacewicz C, et al
. Serum alpha-foetoprotein level predicts treatment outcome in chronic hepatitis C. Antivir Ther 2007; 12:797–803.
7. Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al
. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292:2839–2848.
8. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24:289–293.
9. Bani-Sadr F, Denoeud L, Morand P, Lunel-Fabiani F, Pol S, Cacoub P, et al
. Early virologic failure in HIV-coinfected hepatitis C patients treated with the peginterferon-ribavirin combination: does abacavir play a role? J Acquir Immune Defic Syndr 2007; 45:123–125.
10. Clouston AD, Powell EE, Walsh MJ, Richardson MM, Demetris AJ, Jonsson JR. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis. Hepatology 2005; 41:809–818.
11. Tsamandas AC, Syrokosta I, Thomopoulos K, Zolota V, Dimitropoulou D, Liava A, et al
. Potential role of hepatic progenitor cells expression in cases of chronic hepatitis C and their relation to response to therapy: a clinicopathologic study. Liver Int 2006; 26:817–826.