Okanda 2015 Abstract MiPschool Cape Town 2015

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Hyperlactatemia and mtDNA polymerase - gene mutations in HIV infected Zulu patients on stavudine-based HAART.

Link:

Okanda D (2015)

Event: MiPschool Cape Town 2015

Highly active antiretroviral therapy (HAART) has immensely abridged HIV linked mortality and morbidity. Unfortunately, in some patients, HAART has been associated with adverse drug toxicities. Among them, are the life threatening symptomatic hyperlactatemia and lactic acidosis (SHL/LA) related with the use of nucleoside reverse transcriptase inhibitors (NRTIs) d4T (stavudine) and AZT (zidovudine), the backbone of HAART regimen in many African countries[1]. These NRTIs are attributed to mitochondrial toxicity, possibly owing to their capacity to impede human mitochondrial DNA polymerase-γ which is uniquely accountable for the replication of mitochondrial DNA. The aim of this study was to determine if known monogenic polymerase gamma (POLG) polymorphisms [2,3] could be linked with the unexpected high incidence of SHL/LA observed in HIV infected Zulu patients exposed to NRTI stavudine or zidovudine in their antiretroviral therapy. One hundred and sixteen patients from Edendale Hospital consented to be investigated between March-August 2014; fifty nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for 124 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0-4.99 mmol l-1, and 46 had LA with lactate 15 mmol l-1. Females (73.6%) were 25 times more likely to be cases [AOR 25.67; 95%CI (6.1-123.6)] as compared to males (26.1%). The cases presented with SHL/LA between 4 and 18 months on stavudine. Weight loss (98.3%), loss of appetite (86.2%), abdominal pains (59.6%), peripheral neuropathy (56.9%) and the presence of vomiting (40%) were the clinical parameters documented on the SHL/LA patient files. 113 genomic DNA samples of sufficient yield and purity were utilised for subsequent allelic discrimination PCR screening for the R964C and E1143G SNPS of POLG. Sequencing was done for 20/113 randomly selected samples for confirmation of the genotyping results. There were none of the two POLG mutations observed [4]. The findings suggest that association of the known monogenic POLG mutations with SHL/LA in the South African Zulu population is not common. This study in addition to confirming known clinical risk factors concludes an improved understanding of R964C and E1143G genetic predisposition in hyperlactatemia experienced in this study population. We encourage use of improved remedies with fewer side effects and minimised drug resistance.


Labels: MiParea: mtDNA;mt-genetics, Patients  Pathology: Other 

Organism: Human 





HIV 

Affiliations

dtyachieng@hotmail.com

References

  1. Tressler R, Godfrey C (2012) NRTI backbone in HIV treatment: will it remain relevant? Drugs 72:2051-62.
  2. Yamanaka H, Gatanaga H, Kosalaraksa P, Matsuoka-Aizawa S, Takahashi T, Kimura S (2007) Novel mutation of human DNA polymerase γ associated with mitochondrial toxicity induced by anti-HIV treatment. J Infec Dis 195:1419-25.
  3. Chiappini F, Teicher E, Saffroy R, Debuire B, Vittecoq D, Lemoine A (2009) Relationship between polymerase gamma (POLG) polymorphisms and antiretroviral therapy-induced lipodystrophy in HIV-1 infected patients: a case-control study. Curr HIV Res 7:244-53.
  4. van Oosterhout JJ, Gardner K, Mallewa J, Kaunda S, Kampira E, Payne B (2013) Severe toxicity and polymerase-gamma gene abnormalities in Malawian adults on stavudine-based antiretroviral therapy. Pharmacogen genomics 23:624-6.