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      Hyperlactatemia in a group of HIV patients living in Yaounde-Cameroon

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          Abstract

          Background and aim

          Prolonged exposure to highly active antiretroviral therapy (HAART) is associated with adverse effects such as hyperlactatemia. We determined the prevalence and risk factors for developing hyperlactatemia among human immunodeficiency virus (HIV)-infected cameroonians on antiretroviral therapy (ART).

          Methods

          We conducted a cross-sectional study from January to April 2012 involving 91 HIV-infected patients receiving ART for at least 12 months and 30 HIV-infected patients who have never received ART (ART-naïve patients). Plasma lactate levels were determined after at least 12 hours of overnight fasting and hyperlactatemia defined as lactate concentrations ≥ 3 mmol/L. The prevalence of hyperlactatemia was determined and the risk factors were analyzed by a multivariate logistic regression model.

          Results

          The mean lactataemia was significantly higher in the group of HIV patients currently taking ART than in the ART-naïve one (2.3 ± 1.3 and 1.7 ± 0.7 mmol/L respectively, p = 0.002). Patients on first line ART regimens had significantly higher lactatemia than those on second line regimens (2.5 ± 1.5 and 1.9 ± 0.7 mmol/L respectively, p = 0.014). The prevalence of hyperlactatemia in HIV patients receiving ART and in ART-naïve HIV patients was respectively 18.7 and 6.7% (p = 0.095). ART-exposure (adjusted odds ratio (aOR) 5.44, 95% confidence interval (CI) 1.06 – 27.84; p = 0.042) and being on a first line regimen (aOR 16.22, 95% CI 1.57 – 167.91; p = 0.019) were independent strong predictors of hyperlactatemia.

          Conclusion

          Hyperlactatemia was not rare in our study population. Being on a first line regimen constitutes an important risk factor for developing hyperlactatemia. Measurement of plasma lactate may be useful in optimizing the management of HIV-positive persons on ART.

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          Most cited references30

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          Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy.

          Highly active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome of peripheral fat wasting and central adiposity. HIV-1 protease inhibitors are generally believed to be the causal agents, although the syndrome has also been observed with protease-inhibitor-sparing regimens. Here, we postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy, similar to the role of mitochondrial defects in the development of multiple symmetrical lipomatosis.
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            Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase.

            To examine the role of the mitochondrial polymerase (Pol gamma) in clinically observed toxicity of nucleoside analogs used to treat AIDS, we examined the kinetics of incorporation catalyzed by Pol gamma for each Food and Drug Administration-approved analog plus 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU), beta-L-(-)-2',3'-dideoxy-3'-thiacytidine (-)3TC, and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). We used recombinant exonuclease-deficient (E200A), reconstituted human Pol gamma holoenzyme in single turnover kinetic studies to measure K(d) (K(m)) and k(pol) (k(cat)) to estimate the specificity constant (k(cat)/K(m)) for each nucleoside analog triphosphate. The specificity constants vary more than 500,000-fold for the series ddC > ddA (ddI) > 2',3'-didehydro-2',3'-dideoxythymidine (d4T) > (+)3TC > (-)3TC > PMPA > azidothymidine (AZT) > Carbovir (CBV). Abacavir (prodrug of CBV) and PMPA are two new drugs that are expected to be least toxic. Notably, the higher toxicities of d4T, ddC, and ddA arose from their 13-36-fold tighter binding relative to the normal dNTP even though their rates of incorporation were comparable with PMPA and AZT. We also examined the rate of exonuclease removal of each analog after incorporation. The rates varied from 0.06 to 0.0004 s(-1) for the series FIAU > (+)3TC approximately equal to (-)3TC > CBV > AZT > PMPA approximately equal to d4T > ddA (ddI) > ddC. Removal of ddC was too slow to measure (<0.00002 s(-1)). The high toxicity of dideoxy compounds, ddC and ddI (metabolized to ddA), may be a combination of high rates of incorporation and ineffective exonuclease removal. Conversely, the more effective excision of (-)3TC, CBV, and AZT may contribute to lower toxicity. FIAU is readily extended by the next correct base pair (0.13 s(-1)) faster than it is removed (0.06 s(-1)) and, therefore, is stably incorporated and highly mutagenic. We define a toxicity index for chain terminators to account for relative rates of incorporation versus removal. These results provide a method to rapidly screen new analogs for potential toxicity.
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              Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway.

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                Author and article information

                Journal
                AIDS Res Ther
                AIDS Res Ther
                AIDS Research and Therapy
                BioMed Central
                1742-6405
                2014
                15 January 2014
                : 11
                : 2
                Affiliations
                [1 ]Laboratory of Biochemistry, Yaounde University Teaching Hospital, Yaounde, Cameroon
                [2 ]Department of Biochemistry and Physiological Sciences, University of Yaounde I, Yaounde, Cameroon
                [3 ]Department of Biochemistry, Faculty of Sciences, University of Yaounde I, Yaounde, Cameroon
                [4 ]Intensive Care Unit, Mother and Child Centre, Chantal Biya Foundation, Yaounde, Cameroon
                [5 ]Laboratory of Hematology, Yaounde University Teaching Hospital, Yaounde, Cameroon
                Article
                1742-6405-11-2
                10.1186/1742-6405-11-2
                3899605
                24428886
                f52d7330-a325-4e60-b807-9fb256793dfb
                Copyright © 2014 Mamiafo et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 17 June 2013
                : 10 January 2014
                Categories
                Research

                Infectious disease & Microbiology
                antiretroviral therapy,hiv,hyperlactatemia,first line regimen

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