Evaluation of antiretroviral effect on mitochondrial DNA depletion among HIV-infected patients in Bali

Abstract

Sri Masyeni,1 Erly Sintya,1 Dewi Megawati,1 Ni Made Hegard Sukmawati,1 Dewa GA Budiyasa,2 Sri Agung Aryastuti,1 Siti Qamariyah Khairunisa,3 IGKN Arijana,4 N Nasronudin3 1Faculty of Medicine and Health Sciences, University of Warmadewa, Denpasar, Bali, Indonesia; 2Internal Medicine Department, Sanjiwani Hospital, Gianyar, Bali, Indonesia; 3Indonesia-Japan Collaborative Research Center for Emerging and Reemerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya, Indonesia; 4Histology Department of Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of highly active antiretroviral therapy combination regimens for HIV infection. Unfortunately, NRTIs have been noticeably associated with many adverse effects related to mitochondrial toxicity leading to mitochondrial deoxyribonucleic acid (mtDNA) depletion. However, similar mitochondrial dysfunction has recently been found even in antiretroviral therapy-naïve patients, suggesting HIV itself could contribute to this abnormality. In this study, we determine whether mtDNA depletion was present in either antiretroviral therapy-naïve or NRTI-treated patients at Sanjiwani Hospital, Bali, Indonesia. Patients and methods: A cross-sectional study was conducted from the peripheral blood mononuclear cells of HIV patients. Specifically, the relative content of mtDNA (mtRNR1 gene) to nuclear DNA (ASPOLG gene) was determined by real-time polymerase chain reaction. Data were analyzed with SPSS 16.0 software and GraphPad Prism 7.02. Results: A total of 84 samples (67 on NRTIs and 17 HIV-naïve) were suitable for analysis. We identified 21.4% of the samples (18/84) with mtDNA:nDNA ratio <1. Although it was not significant (P=0.121), the median mtDNA:nDNA ratio of HIV-naïve group was slightly higher (median 1.8; interquartile range [IQR]: 1.1–2.1) than NRTI-treated patients (median 1.5; IQR: 1.3–2.85). Tenofovir-based NRTI was more frequently used (73.13%) than zidovudine -based NRTI (26.86%). The period for which NRTI was used probably contributed to the ratio of mtDNA:nDNA. The median ratio of mtDNA:nDNA zidovudine-treated patients was slightly lower (median 1.2; IQR: 1.08–1.98) when compared to tenofovir-based NRTI (median 1.6; IQR: 1.05–2.10), with the median period of former treatment being significantly longer (P<0.001). Although these data overall indicate that NRTI treatment had no effect on mtDNA:nDNA ratios, patients who undergo more than 12 months of NRTIs treatment show a decrease in the ratio; however, further study is required. Conclusion: Almost one-fourth of the samples showed a lower mtDNA:nDNA ratio. The decreasing of the ratio mtDNA:nDNA was most likely present after 12 months of NRTI treatment. Keyword: mitochondrial, nuclear DNA ratio, HIV, ART

Keywords

• mitochondrial
• nuclear DNA ratio
• HIV
• ART