HBsAg loss in patients treated with peginterferon alfa-2a and adefovir is associated with SLC16A9 gene variation and lower plasma carnitine levels

Jansen, Louis; Niet, A. de; Stelma, F.; Iperen, Erik P.A. van; Dort, Karel A. van; Plat-Sinnige, Marjan J. Tempelmans; Takkenberg, R. Bart; Chin, Daniel J.; Zwinderman, A. H.; Lopatin, Uri; Kootstra, Neeltje A.; Reesink, H. W.

doi:10.1016/j.jhep.2014.05.004

Cited by 21 publications

(16 citation statements)

References 33 publications

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“…In the past, many studies have assessed predictive markers of response to pegIFN mono‐ or combination therapy . Due to a low number of patients, the current study was underpowered for multivariable analyses of factors associated with HBsAg loss.…”

Section: Discussionmentioning

confidence: 99%

“…In the past, many studies have assessed predictive markers of response to pegIFN mono-or combination therapy. 15,[21][22][23] Due to a low number of patients, the current study was underpowered for multivariable analyses of factors associated with HBsAg loss. Univariable analyses resulted in a high level of significance for low baseline HBsAg level as a predictor for HBsAg loss in HBeAg-negative patients.…”

Section: Discussionmentioning

confidence: 99%

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HBsAg loss after peginterferon‐nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow‐up

Stelma

Ree

Jansen

et al. 2017

Journal of Viral Hepatitis

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Combining peginterferon-alfa-2a (pegIFN) with a nucleotide analogue can result in higher rates of HBsAg loss than either therapy given alone. Here, we investigated the durability of the response to combination therapy in chronic hepatitis B (CHB) patients after 5 years of follow-up. In the initial study, 92 CHB patients (44 HBeAg-positive, 48 HBeAg-negative) with HBV DNA >100 000 c/mL (~20 000 IU/mL) and active hepatitis were treated for 48 weeks with pegIFN 180 μg/week and 10 mg adefovir dipivoxil daily. For the long-term follow-up (LTFU) study, patients were followed up for 5 years after the end of treatment. At year 5, 70 (32 HBeAg-positive, 38 HBeAg-negative) patients remained in the study. At year 5, 19% (6/32) of HBeAg-positive patients and 16% (6/38) of HBeAg-negative patients lost HBsAg, and no HBsAg seroreversion was observed. The 5-year cumulative Kaplan-Meier estimate for HBsAg loss was 17.2% for HBeAg-positive patients and 19.3% for HBeAg-negative patients. Fourteen of sixteen patients who lost HBsAg at any time point during follow-up developed anti-HBs antibodies (>10 IU/L). At year 5, in total 63% (20/32) of HBeAg-positive and 71% (27/38) of HBeAg-negative patients were retreated with nucleos(t)ide analogues during follow-up. The cumulative Kaplan-Meier estimate for retreatment was 60% of patients at year 5. At year 5 of follow-up, 18% of CHB patients treated with pegIFN/nucleotide analogue combination therapy had durable HBsAg loss and 88% of these had developed anti-HBs antibodies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HBsAg loss after peginterferon‐nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow‐up

Stelma

Ree

Jansen

et al. 2017

Journal of Viral Hepatitis

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“…For HBeAg‐positive patients, these include levels of HBV DNA, ALT and HBsAg/anti‐HBs immune complexes at baseline , as well as the HBV genotype and HBsAg decline . In HBeAg‐negative patients, response to therapy has been associated with baseline HBsAg and ALT levels , specific SNPs and more recently, levels of HBV DNA and HBsAg early during therapy are taken into account. Thus far, no studies have been performed linking KIR‐HLA‐C genotype to treatment outcome for CHB.…”

Section: Discussionmentioning

confidence: 99%

HLA‐C and KIR combined genotype as new response marker for HBeAg‐positive chronic hepatitis B patients treated with interferon‐based combination therapy

Stelma

Jansen

Sinnige

et al. 2016

Journal of Viral Hepatitis

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Current treatment for chronic hepatitis B infection (CHB) consists of interferon-based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy.

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“…24 The five SNP haplotype comprises a synonymous as well as four missense variants in SLC16A11, of which one was predicted to be damaging, indicating that SLC16A11, encoding for MCT11, is the causal gene for the link with T2DM. Simultaneously, Hara et al 55 identified rs312457, an intronic variant within the SLC16A13 gene, in East Asian populations, which is in linkage disequilibrium with the five SNP haplotypes found in Mexicans. A study investigating Mexican families with children <18 years with T2DM found a link between a SLC16A11 variant (rs13342232) and early onset of the disease.…”

Section: Type 2 Diabetes Mellitusmentioning

confidence: 95%

“…The functional mechanisms and the clinical relevance of MCT9 and its contribution to the variability of SUA and the susceptibility to resulting diseases, especially gout, are, therefore, not fully clarified and need further investigations. Interestingly, Jansen et al 55 identified that the SLC16A9 gene variant rs12356193 was associated with lower plasma carnitine levels and led to enhanced www.cts-journal.com Relevance of the monocarboxylate transporter family in disease and therapy Fisel et al proliferative capacity of CD8 T-cells and improved response to peginterferon alfa-2a/adefovir treatment in patients with chronic hepatitis B.…”

Section: Goutmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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HBsAg loss in patients treated with peginterferon alfa-2a and adefovir is associated with SLC16A9 gene variation and lower plasma carnitine levels

Cited by 21 publications

References 33 publications

HBsAg loss after peginterferon‐nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow‐up

HBsAg loss after peginterferon‐nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow‐up

HLA‐C and KIR combined genotype as new response marker for HBeAg‐positive chronic hepatitis B patients treated with interferon‐based combination therapy

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

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