BACKGROUND & AIMS: Replication markers exhibit substantial variation during chronic hepatitis B virus (HBV) infection, part of which can be explained by mutations on the surface (S) gene. We aimed to identify S-gene mutations possibly influencing the quantification of HBV replication markers (MUPIQH) in HBV genotype E infection, common to Western Africa. METHODS: 73 antiretroviral treatment (ART)-naive human immunodeficiency virus (HIV)-HBV co-infected patients from Cote d'Ivoire, initiating anti-HBV-containing ART, had available HBV S-gene sequences. S-gene MUPIQHs were screened at ART-initiation based on lower HBV-DNA or HBsAg quantification (qHBsAg) compared to wildtype. Their association with HBV virological response and qHBsAg slope during treatment was evaluated. RESULTS: Genotype E was predominant (95.9%). At ART-initiation, median HBV-DNA was 7.27 log10 copies/mL (IQR=5.26-8.33) and qHBsAg 4.08 log10 IU/mL (IQR=3.49-4.61). Twelve S-gene MUPIQHs were identified among 21 patients (28.8%): sS140L (n=4), sD144A (n=1), sS167L (n=2), sS174N (n=6), sP178Q (n=2), sG185L (n=2), sW191L (n=2), sP203Q/R (n=2), sS204N/I/R/K/T/G (n=7), sN207T (n=2), sF212C (n=1) and sV224A/Y (n=7). MUPIQHs at positions s185+s191+s224 and s178+s204 were within highly-covarying networks of S-gene mutations. Older age (p=0.02), elevated transaminases (p=0.03), and anti-hepatitis B "e" antibody-positive serology (p=0.009) were significantly associated with prevalent MUPIQHs at ART-initiation. During treatment, baseline MUPIQHs were not associated with time-to-undetectable HBV-DNA (p=0.7) and qHBsAg levels decreased at similar rates between those with versus without MUPIQHs (p=0.5). CONCLUSION: Several novel S-gene mutations were associated with reductions in replication markers among West African co-infected patients. These mutations, however, do not affect response during antiviral treatment. Their diagnostic and clinical consequences need clarification. This article is protected by copyright. All rights reserved.< Réduire