Researchers Urge Banning Use of Lamivudine Due to Inherent Drug Resistance

 —Christine. M. Kukka, Project Manager, HBV Advocate

A global team of researchers suggest lamivudine (Epivir-HBV) never be used to treat hepatitis B patients because it almost always induces drug resistance, and sets the stage for resistance to other antivirals, such as entecavir (Baraclude).

Lamivudine, the first antiviral approved for hepatitis B treatment, has fallen out of favor in North America and Europe because of its high drug resistance rate. But because of its low cost, it is still used here and as the primary treatment in Asia and other regions where the majority of hepatitis B patients live.

Their report, published in the July 30 isuse of PLoS One, examined the molecular make-up of the hepatitis B virus (HBV) in many patients who had been treated with lamivudine as well as patients who had never been treated. They found the many patients who generally fail to respond to treatment carry the mutation that allows the virus to quickly develop resistance to lamivudine.

"Our findings strongly suggest that the use of lamivudine will not benefit ...patients," they wrote. "Firstly, the preexisting (lamivudine) mutations can quickly lead to treatment failure due to drug resistance." Secondly, the development of lamivudine mutations in all patients who fail to respond to treatment even if lamivudine is not used, ..."will severely compromise the efficacy of lamivudine when used as a second-line drug," they added.

"Finally, since patients can quickly develop drug resistance to entecavir in the presence of lamivudine mutations, the lamivudine mutations can significantly compromise the efficacy of entecavir," they concluded.

They proposed that doctor screen patients for these mutations before prescribing or changing treatment "... to most effectively treat chronic hepatitis B patients by selecting only sensitive drugs."

Source for free full text:

Abstract: Association of Preexisting Drug-Resistance Mutations and Treatment Failure in Hepatitis B Patients

Jie Ma, Yingchun Zhang, Xinyue Chen, Yi Jin, Dexi Chen, Yun Wu, Jing Cui, Haitao Wang, Jia Liu, Ning Li, and Feng Gao, John E. Tavis, Editor.

The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naïve patients and determined linkage patterns of the drug-resistance mutations in individual viral genomes using a highly sensitive parallel allele-specific sequencing (PASS) method. Lamivudine resistance (LAMr) mutations were predominant in treatment-failure patients, irrespective of the inclusion of LAM in the regimen. 

The primary LAMr mutations M204V and M204I were detected in 100% and 30% of the treatment-failure patients, respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). The linkages containing these three mutations dominated the resistant viruses. Importantly, minority LAMr mutations present in <2% of the viral population were detected in 83% of the treatment-naïve patients. Moreover, the low-frequency same linked LAMr mutations (<0.15%) were detected in 24% of the treatment-naïve patients. 

Our results demonstrate that the selection of preexisting minority linked LAMr mutations may be an important mechanism for the rapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and -naïve hepatitis B patients, and underline the importance of the detection of minority single and linked drug-resistance mutations before initiating antiviral therapy.

PLoS One. 2013; 8(7): e67606. Published online 2013 July 30. doi: 10.1371/journal.pone.0067606

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