Higher Mortality Despite Early Antiretroviral Therapy in Human Immunodeficiency Virus and Hepatitis B Virus (HBV)–Coinfected Patients With High HBV Replication

Kouame, Gérard-Menan; Boyd, Anders; Moh, Raoul; Badjé, Anani; Gabillard, Delphine; Ouattara, Éric; Ntakpé, Jean-Baptiste; Emieme, Arlette; Maylin, Sarah; Chekaraou, Mariama Abdou; Eholié, S.; Zoulim, Fabien; Lacombe, Karine; Anglaret, Xavier; Danel, Christine; Groups, Anrs VarBVA Study

doi:10.1093/cid/cix747

Cited by 46 publications

(50 citation statements)

References 26 publications

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“…HBV mono‐infected individuals in sub‐Saharan Africa) are oftentimes not recommended for treatment based on most guidelines, but demonstrate increased risk of HCC . TDF‐containing antiretroviral therapy should be initiated as early as possible for all HIV‐HBV co‐infected patients . Despite these recommendations, there is a dearth of clear, large‐scale evidence that delaying therapy affects HCC incidence or liver‐related mortality in these subgroups .…”

Section: Discussionmentioning

confidence: 99%

Research gaps in viral hepatitis

2018

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IntroductionThe World Health Organization has aimed for global elimination of both hepatitis B virus (HBV) and hepatitis C virus (HCV) by 2030. Treatments available to cure HCV and control HBV, as well as vaccination to prevent HBV infection, have certainly allowed for such bold goals, yet the final steps to usher in elimination require further evidence.DiscussionWe broadly discuss the needs for three major public health approaches. First, an effective vaccine exists for HBV and mass‐vaccination campaigns have resulted in decreases in hepatitis B surface antigen seroprevalence and overall rates of liver‐related morality. Still, HBV vaccination coverage is poor in certain regions of the world, while the reasons for such low coverage require further study. A prophylactic vaccine is probably needed to eliminate HCV, but is not being readily developed. Second, identifying HBV/HCV infected individuals remains a priority to increase awareness of disease status, particularly for key populations. Research evaluating large‐scale implementation of novel, rapid and mobile point‐of‐care tests would be helpful to determine whether increased awareness is achievable in these settings. Third, antiviral therapy allows for strong HBV suppression and HCV cure, while its access depends on financial factors among many others. Although there is strong evidence to treat key populations and specific groups with progressed disease, as stated in current guidelines, the advantages of extending treatment eligibility to decrease onward spread of HBV/HCV infection and prevent further burden of disease are lacking “real world” evidence. Novel anti‐HBV treatments are being developed to target intrahepatocellular HBV replication, but are still in the early phases of clinical development. Each of the strategies mentioned above has specific implications for HIV infection.ConclusionsThere are certainly effective tools to combat the spread of viral hepatitis and treat infected individuals – yet how they are able to reach key populations, and the infrastructure required to do so, continue to represent the largest research gap when evaluating the progress towards elimination. Continuously adapted and informed research is required to establish the priorities in achieving elimination goals.

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Section: Discussionmentioning

confidence: 99%

Research gaps in viral hepatitis

2018

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“…HIV‐HBV co‐infection is known to increase the risk of severe liver disease and accelerate progression to liver‐related death compared to either infection individually . Circulating HBV is a strong contributor of the increased risk in both liver‐related and overall mortality; hence, the importance of reducing serum HBV‐DNA viral loads through effective antiviral therapy …”

Section: Introductionmentioning

confidence: 99%

“…1 HIV-HBV co-infection is known to increase the risk of severe liver disease and accelerate progression to liver-related death compared to either infection individually. 2,3 Circulating HBV is a strong contributor of the increased risk in both liver-related and overall mortality 4,5 ; hence, the importance of reducing serum HBV-DNA viral loads through effective antiviral therapy. 6,7 There are, however, certain virological factors of the HBV genome that might impact response during therapy with an anti-HBV nucleoside/nucleotide analogue (NA).…”

Section: Introductionmentioning

confidence: 99%

Precore G1896A mutation is associated with reduced rates of HBsAg seroclearance in treated HIV hepatitis B virus co‐infected patients from Western Africa

Boyd

Moh

Maylin

et al. 2018

Journal of Viral Hepatitis

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The nucleotide substitution G1896A on the precore (pc) region has been implicated in virological and serological responses during treatment in hepatitis B virus (HBV)-infected patients. Whether this mutation affects the therapeutic course of HIV-HBV co-infected patients, especially from Western Africa, is unknown. In this prospective cohort study, 86 antiretroviral (ARV)-naïve HIV-HBV co-infected patients from Côte d'Ivoire, initiating ARV-treatment containing lamivudine (n = 53) or tenofovir (n = 33), had available baseline pc sequences. Association of the pcG1896A mutation with time to undetectable HBV-DNA, hepatitis B "e" antigen (HBeAg) seroclearance (in HBeAg-positive patients), and hepatitis B surface antigen (HBsAg) seroclearance was evaluated using Cox proportional hazards regression. At ARV-initiation, median HBV-DNA was 6.04 log copies/mL (IQR = 3.70-7.93) with 97.7% harbouring HBV genotype E. Baseline pcG1896A mutation was identified in 51 (59.3%) patients, who were more commonly HBeAg-negative (P < .001) and had basal core promotor A1762T/G1764A mutations (P < .001). Patients were followed for a median 36 months (IQR = 24-36). Cumulative proportion of undetectable HBV-DNA was significantly higher in patients with baseline mutation (pcG1896A = 86.6% vs no pcG1896A = 66.9%, P = .04), but not after adjusting for baseline HBV-DNA levels and anti-HBV agent (P = .2). No difference in cumulative proportion of HBeAg seroclearance was observed between mutation groups (pcG1896A = 57.1% vs no pcG1896A = 54.3%, P = .7). Significantly higher cumulative proportion of HBsAg seroclearance was observed in patients without this mutation (pcG1896A = 0% vs no pcG1896A = 36.9%, P < .001), even after adjusting for baseline HBsAg quantification and anti-HBV agent (P < .001). In conclusion, lacking the pcG1896A mutation before ARV initiation appeared to increase HBsAg seroclearance rates during treatment. The therapeutic implications of this mutation need further exploration in this setting.

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“…1 Increased rates of morbidity/mortality have been observed in co-infected patients on the continent, yet are mostly attributed to higher or uncontrolled HBV replication. [2][3][4][5] However, HBV replication alone might not explain these results and other indicators of viral activity could help elucidate the pathogenic mechanisms giving rise to increased rates of morbidity/mortality during HBV infection. 6 One such marker is hepatitis B surface antigen quantification (qHBsAg), which has been useful in predicting more active phases of chronic HBV infection and severe liver-related disease.…”

Section: Introductionmentioning

confidence: 99%

“…Among individuals infected with human immunodeficiency virus (HIV) living in sub‐Saharan Africa (SSA), roughly ten per cent are also infected with hepatitis B virus (HBV) . Increased rates of morbidity/mortality have been observed in co‐infected patients on the continent, yet are mostly attributed to higher or uncontrolled HBV replication . However, HBV replication alone might not explain these results and other indicators of viral activity could help elucidate the pathogenic mechanisms giving rise to increased rates of morbidity/mortality during HBV infection …”

Section: Introductionmentioning

confidence: 99%

Effect of hepatitis B virus (HBV) surface‐gene variability on markers of replication during treated human immunodeficiency virus‐HBV infection in Western Africa

Boyd

Moh

Maylin

et al. 2018

Liver International

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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 Seventy‐three antiretroviral treatment (ART)‐naïve human immunodeficiency virus (HIV)‐HBV co‐infected patients from Côte 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 vs 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.

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Higher Mortality Despite Early Antiretroviral Therapy in Human Immunodeficiency Virus and Hepatitis B Virus (HBV)–Coinfected Patients With High HBV Replication

Abstract: NCT00495651.

Cited by 46 publications

References 26 publications

Research gaps in viral hepatitis

Research gaps in viral hepatitis

Precore G1896A mutation is associated with reduced rates of HBsAg seroclearance in treated HIV hepatitis B virus co‐infected patients from Western Africa

Effect of hepatitis B virus (HBV) surface‐gene variability on markers of replication during treated human immunodeficiency virus‐HBV infection in Western Africa

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