In October 2010, while visiting Angola, the one year old South African-born male, whose parents originated in Guinea, first became ill and was admitted to the hospital and received two blood transfusions. The child arrived in Johannesburg acutely ill. He was profoundly anemic with bruises, in respiratory distress, and congestive cardiac failure. Before admission, the patient was transfused with packed cells, received alkalinizing fluid, and two full days of Amoxicillin and Clavulanate prescribed by his pediatrician in Johannesburg. He was referred and admitted to the Pediatric Haematology and Oncology Unit, Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), Johannesburg, South Africa. Initial assessment showed the patient had the signs and symptoms of significant lymphadenopathy, anemia, thrombocytopenia, and neutropenia. A bone marrow aspiration analysis showed 97% blasts, which were small to intermediate in size of high nuclear-to-cytoplasm (NC) ratio, basophilic cytoplasm with occasional folded nuclei and vacuolated cytoplasm. Immunophenotype analysis of bone marrow sample showed 85% CD19/CD10 co-expressing cells, small to intermediate-sized cells expressing the following antigens: CD45+, CD10++, CD19++, CD22+/++, HLA-DR++ and CD38+++, one half of these cells express CD13+ and one third expressed CD15 dim. Cytogenetic analysis revealed diploid karyotype with a chromosomal t(1;19) translocation. Available data characterized this case as precursor B acute lymphoblastic leukemia (ALL), with aberrant myeloid marker expression. At the time of diagnosis, the patient was one year and 11 months old. Although hepatitis B status is routinely assessed prior to commencement of chemotherapy, there was no available hepatitis B serology result on this patient. In November 2010, he was started on a Modified Berlin-Frankfurt-Munster (BFM)-95 protocol (high risk) and treatment was completed in November 2013. In January 2014, at the age of 5 years, while on a follow up visit for his ALL to the Pediatric Hematology and Oncology Unit, CMJAH, the child was first detected to have asymptomatic HBV infection, without clinical signs of acute hepatitis. Even though the boy had received the complete HBV vaccination schedule at 7, 11 and 24 weeks after birth, he tested positive for HBsAg. The laboratory panel showed normal alkaline phosphatase, normal total bilirubin and conjugated bilirubin, normal aspartate aminotransferase (AST), mildly elevated, alanine aminotransferase (ALT), negative for anti-HBs and anti-HBc, positive for HBeAg and HBeAb. The decision was to monitor the patient, with regular assessment. In late 2013, the mother of the child had been diagnosed with acute HBV infection and resolved the infection without treatment. Immediately after the mother’s diagnosis, the other family members were screened for HBV infection. The father tested negative for HBsAg and anti-HBs but was positive for anti-HBc. The younger female sibling of the boy tested negative for HBV infection. In February 2015, during a follow-up, a high HBV viral load (1.7 × 108 IU/mL) was detected. Further laboratory tests revealed elevated AST: 44 IU/L and ALT: 61 IU/L, with positivity for HBsAg and HBeAg, and undetectable anti-HBs. The patient was referred to the Pediatric Hepatology Unit at CMJAH and diagnosed as chronic hepatitis B (CHB) infection in the immune-tolerant phase transitioning into HBeAg-positive immune-active phase and started on oral LAM (100 mg, daily). Upon monitoring, the first partial viral response (PVR) was detected at 36 weeks of LAM therapy. PVR is defined as more than 1 log10 IU/mL decrease in HBV DNA but still detectable by real-time PCR, after at least 24 weeks of therapy of low genetic barrier (48 weeks for high genetic barrier) to resistance nucleot(s)ides analogue (NA) treatment [, ]. Thus, tenofovir (TDF)-based rescue monotherapy was introduced after 61 weeks of LAM therapy. The TDF dosage assessed by age and body weight was 225 mg once a day. After switching to TDF, the HBV DNA viral load continued to decline for 18 weeks. Thereafter, the patient experienced viral breakthrough (VBT), at 46 weeks after the initiation of TDF. VBT is defined as ≥1 log10 IU/ml increase in serum HBV DNA level from nadir in two consecutive samples, 1 month apart, in patients who have responded and have been compliant with antiviral medication []. The level of ALT increased further to 146 IU/L, at the VBT event. Hepatitis D virus (HDV) is known to affect HBV viral load. To preclude the possibility of HDV/HBV co-infection or superinfection, the HDV RNA PCR test was ordered after 78 weeks of TDF treatment (National Health Laboratory Services, South Africa). The patient was HDV-negative. Concurrently, HBV DNA was extracted from serum, using the QIA Amp DNA mini kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. The complete full-length HBV genome was amplified using the methods described previously, with the Platinum™ SuperFi™ PCR master mix (Invitrogen, Carlsbad, CA, USA) after 78 weeks of TDF treatment []. PCR products were directly sequenced using the Sanger protocol (Inqaba Biotech, Pretoria, South Africa). Assembly of the sequenced fragments was performed using an in-house developed bioinformatic tool [] and the generated full length consensus sequence blasted on the NCBI database (). The complete nucleotide sequence of HBV isolate has been deposited in GenBank under the accession number OM256457. The alignment of the sequenced full-length HBV to representative full-length genotype A to E sequences available in the public repository was performed by MUSCLE v3.8 algorithm (Edgar Robert C). Phylogenetic analysis with bootstrap evaluation was performed using the maximum likelihood method with the Gamma Generalized Time Reversible (GRT + G) model of nucleotide substitution as implemented in the RAxML version 8.0.20 []. The resulting phylogenetic tree was converted to midpoint rooted, annotated and visualized using the Interactive Tree of Life version 5.7 []. Phylogenetic analysis of full-length HBV genome revealed the patient was infected with genotype E, clustering with reference sequences from Angola. When compared to the consensus genotype E sequence, LAM but no TDF resistance mutations were detected. Analysis from deduced amino acid sequences showed the presence of specific substitutions. Most of the mutations were localized to HLA class I- and II-restricted epitopes, CD4+ T-, CD8+ T-, and B-cells immune epitopes. With the absence of TDF mutation, the decision was to continue with TDF-treatment. TDF dosage was further adjusted to 300 mg after 141 weeks of TDF rescue-therapy when body weight was above 35 kg. Between 113 to 141 weeks of TDF rescue-therapy, another two events of VBT were observed, with the overall trend of decreasing serum HBV DNA, and progressively declining serum AST and ALT activities. However, the patient remained HBeAg-positive, HBsAg-positive and HBsAb-negative throughout his drug therapy. The HDV RNA PCR test was repeated when the low viral load persisted after 141 weeks of TDF treatment. The second HDV PCR test was also negative. In view of the recognised TDF associated nephrotoxicity, renal function was regularly monitored by use of urinalysis, serum urea & electrolytes, serum phosphorus, magnesium, calcium, creatinine and calculation of estimated glomerular filtration rate (eGFR) []. Values of all these parameters were normal throughout the patient’s follow-up and will continue to be monitored while the patient remains on TDF. Since prolonged low HBV viremia is associated with a higher risk of HCC, the patient will be continuously monitored until the treatment target is reached.