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 Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 87-90

Probable lamivudine-resistant hepatitis B infection in children: A case report involving two Nigerian siblings at Ahmadu Bello University Teaching Hospital, Shika, Zaria


Department of Paediatrics, ABU/ABUTH-Zaria, Zaria, Nigeria

Date of Web Publication2-Apr-2018

Correspondence Address:
Sani M Mado
Department of Paediatrics, ABU/ABUTH-Zaria, Zaria
Nigeria
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DOI: 10.4103/ssajm.ssajm_21_17

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  Abstract 

Currently, up to 65 million Africans have chronic hepatitis B (CHB) infection, with the majority acquiring it in the first 5 years of life and living in Nigeria. Lamivudine is generally accepted for use as the first-line treatment of CHB in children under the age of 12 years. However, the drug has a low genetic barrier to resistance. Lamivudine-resistant CHB is a serious challenge in resource-limited settings. This case report is intended to study a probable lamivudine-resistant CHB in two siblings aged 9 and 11 years and to highlight the challenges of managing CHB in children from resource-limited settings. There is a need to develop national guidelines for the management of CHB in children. Other suitable antiviral agents should be subsidized, so that they could be used to salvage lamivudine-resistant cases.

Keywords: Lamivudine, resistance chronic hepatitis b infection, resource-poor settings


How to cite this article:
Mado SM, Idris HW, Abdullahi SM, Musa S. Probable lamivudine-resistant hepatitis B infection in children: A case report involving two Nigerian siblings at Ahmadu Bello University Teaching Hospital, Shika, Zaria. Sub-Saharan Afr J Med 2017;4:87-90

How to cite this URL:
Mado SM, Idris HW, Abdullahi SM, Musa S. Probable lamivudine-resistant hepatitis B infection in children: A case report involving two Nigerian siblings at Ahmadu Bello University Teaching Hospital, Shika, Zaria. Sub-Saharan Afr J Med [serial online] 2017 [cited 2019 Oct 17];4:87-90. Available from: http://www.ssajm.org/text.asp?2017/4/3/87/228974


  Introduction Top


Chronic hepatitis B virus infection affects 350 million individuals worldwide and causes about 1.2 million deaths annually.[1] It is endemic in sub-Saharan Africa (SSA), where its prevalence has been constantly above 7%.[2] In this region, most infections are acquired in childhood before the 5th year of life.[3] The main mode of transmission of the disease in SSA is by horizontal route, through close contact with infected individuals, medical or traditional procedures, and blood transfusion. This is quite unlike the other endemic regions in the world, where the vertical of transmission is equally important.[4]

In Nigeria, the prevalence of the infection ranges between 10.3 and 14.5%. However, record keeping is poorly maintained, which makes the figures unreliable.[5] Hepatitis B infection needs to be treated to prevent its serious late complications, particularly hepatocellular carcinoma and cirrhosis.

The major challenge to the management of chronic hepatitis B (CHB) has to do with the availability and high cost of the antiviral agents used and the fact that it is a lifelong management.[6] The drugs are not covered by the National Health Insurance Scheme; hence, all patients need to buy the drugs out of their pocket. There is an additional cost for investigations used for the diagnosis and monitoring of therapy.[7] Lamivudine monotherapy is the cheapest of all the available antiviral agents used for the treatment of CHB in Nigeria. It is more readily available and has better tolerability. Lamivudine is among the first five medications (interferon-alpha, lamivudine, adeforvir, entecavir, and tenofovir) that were approved by the U.S. Food and Drug Administration (FDA) for the treatment of children with CHB. Prior to the year 2013, tenofovir and adeforvir were initially restricted for use in children aged 12 years or more, whereas entecavir was to be used from 16 years of age.[8] Recently, tenofovir was shown to be well tolerated in children older than 3 years of age for the treatment of CHB. In 2014, entecavir was approved by FDA for use in children older than 2 years.

In recent times, however, lamivudine resistance has become a major stumbling block in the management of the disease. The drug has a lower genetic barrier to resistance, and its abuse leads to the inadequate suppression of viral replication leading to the emergence and selection of the mutant strains of the virus. The mutant strains then cultivate further resistance and cross-resistance, which ultimately leads to drug resistance.[8] This study aims to report two cases of probable lamivudine-resistant CHB infection in two Nigerian siblings and to highlight the challenges of management. Informed consent was obtained from the caregiver before writing the case report.


  Case report Top


Two siblings, girls, one 11-year old and the other 9-year old, were referred with CHB infection to our center from a federal medical center. Two and a half years earlier, they were diagnosed at the referring hospital when they presented with fever, abdominal pain, and jaundice. Their mother was being treated for both human immunodeficiency virus (HIV) and hepatitis B infection, while the father had expired (supposed to have died of acquired immunodeficiency syndrome (AIDS)-related complications). It was difficult to get a detailed history regarding when was the mother was diagnosed with both HIV and hepatitis B, for how long she was on treatment, and the detailed specific antiviral agents she was placed on. We could also not ascertain her adherence to antiretroviral drugs. The siblings had no past history of blood transfusion or any medical or traditional procedure. They were commenced on lamivudine monotherapy a year prior to their presentation; however, their compliance to the treatment had been poor, and at the time of presentation, they have not had the drug for 5 months.

However, they were generally stable, with normal weight and height for their age. They were anicteric and had no peripheral stigmata of chronic liver disease. The diagnosis was reconfirmed; they underwent routine baseline investigations and were recommenced lamivudine due to the prohibitive cost of alternative drugs that were suitable for their ages on presentation. Their initial viral loads were 86,718,000 and 843,900 copies/ml, respectively. The initial serum alanine amino transferase (ALT) level was twice the upper limit of normal; serum electrolytes and creatinine levels were normal; also in addition, the results of complete blood counts were within normal limits. Both siblings were HBeAg positive. Twelve months following the commencement of lamivudine, the viral load decreased to 1172.8 and 5362 copies/ml, respectively. A repeat viral load estimation performed 11 months later showed an upsurge in the viral load to 8145 and 8749 copies/ml, respectively. This was despite strict adherence to the drug. A diagnosis of lamivudine resistance was made, and they were switched over to tenofovir. We intended to treat the patients with tenofovir until virological response was achieved and then continue the treatment for another 12 months. The patients are going to be followed-up at 3-month intervals for a year and then at an interval of 6 months while monitoring hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and HBeAg/anti-HBe at 3–6 months interval to detect both serological and virological response to treatment.


  Discussion Top


The high level of viral replication and turnover is a major feature of HBV infection. The HBV reverse transcriptase (RT) enzyme is an error-prone enzyme lacking 3′–5′-exonuclease proofreading capacity with a resultant development of quasispecies.[9] It is recommended that antiviral therapy be considered for children with elevated serum ALT levels for 6 months (12 months in those who are HBeAg negative) to avoid treating patients who might be undergoing spontaneous HBeAg seroconversion.[8] Different treatment options exist for children with CHB. Laboratory investigations including serum ALT, renal functions test, complete blood count, and HBeAg and HBV DNA levels before, during, and after treatment are stopped. Renal functions test is recommended to evaluate baseline status and to assess the possible renal toxicities of some of the antiviral drugs. The upper limit of normal serum ALT is yet to be determined in children; however, values that are more than 1.5 times the laboratory upper limit of normal should be considered for commencing antiviral drugs in the presence of high HBV DNA levels. HBsAg, HBeAg, ALT, antibodies to HbsAg and HBeAg, and HBV DNA were also used to determine the biochemical, serological, and virological responses to treatment. Liver biopsy to identify necroinflammatory activity and fibrosis is also recommended before the initiation of treatment and during follow-up with rare serious complication, even though it is an invasive procedure. Recently, fibroscan, a noninvasive procedure could be used instead of liver biopsy especially during follow-up; however, currently, this noninvasive method is not a substitute for liver biopsy while deciding to treat a child. The different treatment options include the use of interferon (IFN)-alpha/pegylated INF for 6 months in HBeAg-positive or −negative children. The use of the interferon (conventional or pegylated) has the advantage of short duration of use, offering a chance of sustained off-treatment virological response and high protection against the emergence of resistance. The possible disadvantages of the use of interferons include high cost, unpredictable side effects, inferior tolerability, and parenteral administration. It is also contraindicated in children with renal failure, decompensated cirrhosis, or transplantation. Another treatment strategy includes the use of nucleoside/nucleotide analogs (NA). Some of these drugs include lamivudine, adeforvir, entecavir, and tenofovir. Tenofovir and entecavir are the first choice among the NAs for children if allowed by age. The advantages of NA are oral administration, good tolerance, potent antiviral activity, and affordability. On the other hand, the main drawbacks for their use include indefinite duration, unknown long-term safety, and a risk of resistance especially with the use of lamivudine. However, currently, no resistance was found with the use of tenofovir, whereas low resistance for entecavir was documented. In case of lamivudine resistance, most experts recommend switching over to tenofovir. The exact duration of treatment with NA is yet to be established;[8] however, it should be continued for at least 12 months after achieving a virological response of nondetectable HBV DNA levels and HBeAg seroconversion. Undetectable HBV DNA obtained by real-time PCR on follow-up was significantly associated with HBsAg loss. Children with HBeAg-negative CHB or those unable to undergo HBeAg seroconversion should be given long-term treatment. Serum ALT level should be measured every 3 months for 12 months; HBeAg and HBV DNA levels must be determined 6 and 12 months on treatment and after treatment. Lamivudine was among the first five medications approved by FDA for the treatment of chronic hepatitis B viral infection. The principal target for the drug is the YMDD (tyrosine-methionine-aspartate-aspartate) catalytic motif of HBV RT, located in the domain C of the polymerase molecule.[10] Lamivudine therapy results in about 3–4 log decline in plasma HBV DNA after weeks of therapy; however; long-term use frequently results in viral resistance, which is indicated by a re-increase in viral replication.[11] The incidence of lamivudine resistance ranges between 14 and 32% after a year of treatment to 38% after 2 years and 53–76% after 3 years of treatment.[12],[13] The HBV clearance rates of 99.9 and 99.4% were achieved for both the cases respectively following the administration of lamivudine for a year. However, the levels of HBV DNA were noted to have risen significantly by 11 months following initial decline. The patients probably developed resistance to lamivudine, which led to a viral breakthrough. The possible predisposing factor to resistance in these cases was a previous exposure to the drug. The major challenge observed in the management of these cases was the inability to use appropriate antiviral agents to treat the patients. This could be due to prohibitive cost, thereby resorting to the use of lamivudine. Laboratory detection to confirm the presence of YMDD mutation is a major limitation in the management of the cases. The best initial option for these patients at presentation was to use tenofovir because of its advantage of having good protection against resistance; however, it was not used because of limitations of age at the time of initiation of treatment (2013) based on the guidelines[8] we adapted in our unit. However, their treatment option was switched to tenofovir based on a more recently available evidence for its safety profile in children 3 years and above. Another identified constraint in the management of these cases was the unavailability of full laboratory services in our setting at the time of presentation of these patients; in addition, the few ones that could do HBV DNA PCR were privately owed and very expensive.


  Conclusion and recommendation Top


There is a need to develop national guidelines for the management of CHB. The management of CHB infection should be incorporated into the National Health Insurance Scheme. Other suitable antiviral agents should be subsidized, so that they could be used to salvage lamivudine-resistant cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgements

We thank all the doctors and nurses who were involved in the management of these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11:97-107.  Back to cited text no. 1
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Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global burden of disease study. Lancet 1997;349:1269-76.  Back to cited text no. 2
    
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Vardas E, Mathai M, Blaauw D, McAnerney J, Coppin A, Sim J. Preimmunization epidemiology of hepatitis B virus infection in South African children. J Med Virol 1999;58:111-5.  Back to cited text no. 3
    
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Roingeard P, Diouf A, Sankale JL, Boye C, Mboup S, Diadhiou F et al. Perinatal transmission of hepatitis B virus in Senegal, West Africa. Viral Immunol 1993;6:65-73.  Back to cited text no. 4
    
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Olayinka AT, Oyemakinde A, Balogun MS, Ajudua A, Nguku P, Aderinola M et al. Seroprevalence of hepatitis B infection in Nigeria: A national survey. Am J Trop Med Hyg 2016;95:902-7.  Back to cited text no. 5
    
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Maud L, Shevanthi N, Mark T. Viral hepatitis in resource-limited countries and access to antiviral therapies: Current and future challenges. Future Virol 2013;8:371-80. doi: 10.2217/fvl.13.11  Back to cited text no. 6
    
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Nwokediuko SC. Chronic hepatitis B: Management challenges in resource-poor countries. Hepat Mon 2011;11:786-93. doi: 10.5812/kowsar.1735143X.757  Back to cited text no. 7
    
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Etienne MS, Massimiliano P, Stefan W, Piotr S, Pietro V, Florence L et al. Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines. J Hepatol 2013;59:814-29.  Back to cited text no. 8
    
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Fischer KP, Gutfreund KS, Tyrrell DL. Lamivudine resistance in hepatitis B: Mechanisms and clinical implications. Drug Resist Updat 2001;4:118-28. doi: 10.1054/drup.2001.0190  Back to cited text no. 9
    
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Cane PA, Mutimer D, Ratcliffe D, Cook P, Beards G, Elias E et al. Analysis of hepatitis B virus quasispecies changes during emergence and reversion of lamivudine resistance in liver transplantation. Antivir Ther 1999;4:7-14.  Back to cited text no. 10
    
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Das K, Xiong X, Yang H, Westland CE, Gibbs CS, Sarafianos SG et al. Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC). J Virol 2001;75:4771-9.  Back to cited text no. 11
    
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Pallier C, Castéra L, Soulier A, Hézode C, Nordmann P, Dhumeaux D et al. Dynamics of hepatitis B virus resistance to lamivudine. J Virol 2006;80:643-53. doi: 10.1128/JVI.80.2. 643-653. 2006  Back to cited text no. 12
    
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Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36:687-96.  Back to cited text no. 13
    




 

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