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ABSTRACT
Year : 2012  |  Volume : 33  |  Issue : 1  |  Page : 54-57
 

Abstracts from the current global literature: Mitochondrial toxicities due to nucleoside reverse transcriptase inhibitors


1 Department of Skin VD, M.G.I.M.S., Sewagram, Wardha, Maharashtra, India
2 Department of Skin VD, Government Medical College and S.S.G. Hospital, Vadodara, Gujrat, India

Date of Web Publication14-Mar-2012

Correspondence Address:
Sonia Jain
Department of Skin VD, M.G.I.M.S., Sewagram, Wardha, Maharashtra
India
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DOI: 10.4103/0253-7184.93830

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How to cite this article:
Jain S, Chotaliya K, Marfatia YS. Abstracts from the current global literature: Mitochondrial toxicities due to nucleoside reverse transcriptase inhibitors. Indian J Sex Transm Dis 2012;33:54-7

How to cite this URL:
Jain S, Chotaliya K, Marfatia YS. Abstracts from the current global literature: Mitochondrial toxicities due to nucleoside reverse transcriptase inhibitors. Indian J Sex Transm Dis [serial online] 2012 [cited 2014 Oct 25];33:54-7. Available from: http://www.ijstd.org/text.asp?2012/33/1/54/93830


Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India

Bender MA, Kumarasamy N, Mayer KH, Wang B, Walensky RP, Flanigan T, et al. Clin Infect Dis 2010;50:416-25.

In quest for better first-line antiretroviral (ART) for HIV-infected patients in limited resource settings WHO now recommends tenofovir or stavudine as cost-effective drugs. Aim: The objective of the study was to project the clinical outcome and cost-effectiveness of various first-line ART regimens in India. Here, the author has evaluated the results of including tenofovir in first-line ART. He has compared the results of four groups, i.e., stavudine-containing regimen, stavudine with zidovudine substitution after 6 months, zidovudine-, and tenofovir-containing regimen. All patients were shifted to second line ART as per guidelines and subjected to a change of drug if there was life-threatening toxicity. Results: Discounted mean survival rate with initial tenofovir therapy was 125.8 months compared with no ART (36.9 months), stavudine-containing ART (155.5 months), stavudine (6 months), zidovudine substitution (115.7 months), and zidovudine-containing ART (115.8months). Stavudine is associated with toxicities including lipodystrophy, neuropathy, pancreatitis, and rarely, fatal lactic acidosis. Anemia is common with zidovudine. Tenofovir may be nephrotoxic but in comparison it is well tolerated and more effective than other NRTI. Even as mortality rate from nephrotoxicity as high as 90%, it had little impact on mean total life expectancy. Also sensitivity analysis on nephrotoxicity did not outweigh the advantages conferred by tenofovir. The entire first regimen had crucial 24-week effectiveness. However, tenofovir had more long-term virologic failure. In a cost-effectiveness analysis, it was found that tenofovir shows better incremental cost-effectiveness ratio. Conclusion: Thus, initial stavudine and zidovudine resulted in lower life expectancy than initial tenofovir likely because of its better efficacy and toxicity profile resulting in a more durable regimen, fewer switches, and lower mortality. Recent price negotiations and introduction of generic medicines have reduced the cost of tenofovir making it a viable treatment option in Indian setting.

Implementing a tenofovir-based first-line regimen in rural Lesotho: Clinical outcomes and toxicities after 2 years

Bygrave H, Ford N, Cutsem G, Hilderbrand K, Jouquet G, Goemaere E, et al. J Acquir Immune Defic Syndr 2011;56:e75-8.

High rate of side effect with stavudine has forced developed nations to abandon the drug as first-line ART. In its revised guidelines in 2009, WHO also recommends usage of tenofovir/zidovudine in place of stavudine in resource-limited settings. The present study was done to assess the outcomes and toxicity of the various first-line ART namely tenofovir (in all nonpregnant women and adults with adequate renal function), zidovudine (in pregnancy and impaired renal function), and stavudine (who could not receive tenofovir or zidovudine). All regimens included lamivudine and nevirapine or efavirenz. The study was conducted over a period of 2 years and 1185 adult patients were included. The overall mortality rate for cohort was 6.5 per 100 person years, 5.1 per 100 person years for patients on tenofovir, and 7.5 and 8.3 per 100 person years for patients on zidovudine and stavudine, respectively. The multivariate analysis comparing the risk of mortality also showed similar results. In terms of switching of regimen due to toxicity, the patient on stavudine showed higher rates (18.8 per 100 patients years), followed by zidovudine (8.1 per 100 patient years) and tenofovir (3 per 100 patient years). The study further proves that tenofovir-based first-line ART is better as there is a tendency toward improved survival and lower rate of toxicity driven regimen substitution. It is also better in terms of ease of use and availability as once daily formulation.

Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine-A staccato trial substudy

Ananworanich J, Nuesch R, Cołte΄ HC, Kerr1 S, Hill A, Jupimai T, et al. J Antimicrob Chemother 2008;61:1340-3.

Lipoatropy of face and exterimities, rise in lipid levels, lactic acidosis, and mitochondrial toxicity along with decreased mitochondrial DNA are associated with administration of NRTI and protease inhibitor combination and stavudine in particular. In stavudine/didanosine-induced lipoatrophy, mitochondrial DNA depletion is an important factor. The study has been done to assess the reversibility of the side effects after shift from stavudine/didanosine and saquinivir/ritonavir (HAART) combination to tenofovir/lamivudine and saquinivir/ritonavir combination. 35 patients were included in this Thai study. They were assessed at 0 week (time of shift), 24 weeks, and 48 weeks for complete lipid profile, liver enzymes, and lipodystrophy questionnaire. Lipoatrophy was assessed by DEXA scan and mitochondrial DNA was measured from peripheral blood mononuclear cell (PBMC). Study showed that switching to tenofovir combination resulted in significant reduction in lipid and lactate levels and rise in limb and total fat mass and mitochondrial DNA. Patients found overall weight gain but no significant improvement of lipoatrophy since clinically lipoatrophy resolves slowly. It is still controversial whether PBMC DNA depletion is because of stavudine or didanosine. So it cannot be considered as a marker of lipoatrophy risk. Still in certain centres stavudine is preferred to tenofovir due to cost factor. However, the resource-limited centres should be promoted to switch to tenofovir as soon as signs and symptoms of mitochondrial toxicity appear.

Weight evolution in HIV-1-infected women in Rwanda after stavudine substitution due to lipoatrophy: Comparison of zidovudine with tenofovir/abacavir

Van Griensvena J, Zachariahb R, Rasschaertc F, Attéa E, Reidb T. Trans R Soc Trop Med Hyg 2009;103:613-9.

The objective of the present study was to assess weight evolution after stavudine substitution and also to assess whether zidovudine or tenofovir/abacavir was better. A total of 114 patints were included in the study. Severe cases (39) were substituted with tenofovir/abacavir and rest (75) with zidovudine . It was seen that patients shifted to zidovudine had progressive weight loss while patients on tenofovir/abacavir showed weight gain from 6 months. From 9 th month the difference between two groups was significant (2.3 kg; p = 0.02). Tenofovir was better alternative for substitution and switching should be done as early as possible.

Nano-NRTIs: Efficient inhibitors of HIV Type-1 in macrophages with a reduced mitochondrial toxicity

Vinogradov SV, Poluektova LY, Makarov E, Gerson T, Senanayake MT. Antivir Chem Chemother 2010;21:1-14.

Background: Macrophages serve as a depot for HIV type-1 (HIV-1) in the central nervous system. To efficiently target macrophages, we developed nanocarriers for potential brain delivery of activated nucleoside reverse transcriptase inhibitors (NRTIs) called nano-NRTIs. Materials and Methods: Nanogel carriers consisting of poly(ethylene glycol) (PEG)- or Pluronic-polyethylenimine (PEI) biodegradable networks, star PEG-PEI or poly(amidoamine) dendrimer-PEI-PEG dendritic networks, as well as nanogels decorated with brain-targeting peptide molecules, specifically binding to the apolipoprotein E receptor, were synthesized and evaluated. Nano-NRTIs were obtained by mixing aqueous solutions of zidovudine 5'-triphosphate or didanosine 5'-triphosphate and nanocarriers, followed by freeze-drying. Intracellular accumulation, cytotoxicity, and antiviral activity of nano-NRTIs were monitored in monocyte-derived macrophages (MDMs). HIV-1 viral activity in infected MDMs was measured by a reverse transcriptase activity assay following treatment with nano-NRTIs. Mitochondrial DNA depletion in MDMs and human HepG2 cells was assessed by quantitative PCR. Results: Nanogels were efficiently captured by MDMs and demonstrated low cytotoxicity, and no antiviral activity without drugs. All nano-NRTIs demonstrated high efficacy of HIV-1 inhibition at drug levels as low as 1 μmol/l, representing a 4.9- to 14-fold decrease in 90% effective drug concentrations as compared with NRTIs, whereas 50% cytotoxicity effects started at 200× higher concentrations. Nano-NRTIs with a core-shell structure and decorated with brain-targeting peptides displayed the highest antiviral efficacy. Mitochondrial DNA depletion, a major cause of NRTI neurotoxicity, was reduced threefold compared with NRTIs at application of selected nano-NRTIs. Conclusions: Nano-NRTIs demonstrated a promising antiviral efficacy against HIV-1 in MDMs and showed strong potential as nanocarriers for delivery of antiviral drugs to macrophages harboring in the brain.

Improvement of mitochondrial toxicity in patients receiving a nucleoside reverse transcriptase inhibitor-sparing strategy: Results from the multicenter study with nevirapine and kaletra

Negredo E, Miró O, Rodríguez-Santiago B, Garrabou G, Estany C, Masabeu A, et al. Clin Infect Dis 2009;49:892-900.

Background: Nucleoside reverse-transcriptase inhibitor (NRTI)-related mitochondrial toxicity has been suggested as a key factor in the induction of antiretroviral-related lipoatrophy. This study aimed to evaluate in vivo the effects of NRTI withdrawal on mitochondrial parameters and body fat distribution. Materials and Methods: A multicenter, prospective, randomized trial assessed the efficacy and tolerability of switching to lopinavir-ritonavir plus nevirapine (nevirapine group; n = 34), compared with lopinavir-ritonavir plus 2 NRTIs (control group; n = 33) in a group of human immunodeficiency virus-infected adults with virological suppression. A subset of 35 individuals (20 from the nevirapine group and 15 from the control group) were evaluated for changes in the mitochondrial DNA (mtDNA) to nuclear DNA ratio and cytochrome c oxidase (COX) activity after NRTI withdrawal. Dual-energy X-ray absorptiometry (DEXA) scans were used to objectively quantify fat redistribution over time. Results : The nevirapine group experienced a progressive increase in mtDNA content (a 40% increase at week 48; P = 0.039 for comparison between groups) and in the COX activity (26% and 32% at weeks 24 and 48, respectively; P = 0.01 and P = 0.09 for comparison between groups, respectively). There were no statistically significant between-group differences in DEXA scans at week 48, although a higher fat increase in extremities was observed in the nevirapine group. No virologic failures occurred in either treatment arm. Conclusions: Switching to a nucleoside-sparing regimen of nevirapine and lopinavir-ritonavir maintained full antiviral efficacy and led to an improvement in mitochondrial parameters, which suggests a reversion of nucleoside-associated mitochondrial toxicity. Although DEXA scans performed during the study only revealed slight changes in fat redistribution, a longer follow-up period may show a positive correlation between reduced mitochondrial toxicity and a clinical improvement of lipodystrophy.

Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity

Walker UA, Venhoff N. Antivir Ther 2005;10 Suppl 2:M117-23.

Long - term side effects of antiretroviral therapy are attributed to the mitochondrial (mt) toxicity of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their ability to deplete mtDNA. Studies in hepatocytes suggest that uridine is able to prevent and treat mtDNA depletion by pyrimidine NRTls [zalcitabine (ddC) and stavudine (d4T)] and to fully abrogate hepatocyte death, elevated lactate production, and intracellular steatosis. Uridine was also found to improve the liver and hematopoietic toxicities of zidovudine (AZT), which are unrelated to mtDNA depletion, and to prevent neuronal cell death induced by ddC. Most recently, uridine was found to prevent the onset of a lipoatrophic phenotype (reduced intracellular lipids, increased apoptosis, mtDNA depletion, and mt depolarization) in adipocytes incubated long-term with d4T and AZT. Various steps of mt nucleoside utilization may be involved in the protective effect, but competition of uridine metabolites with NRTIs at polymerase y or other enzymes is a plausible explanation. Pharmacokinetic studies suggest that uridine serum levels can be safely increased in humans to achieve concentrations which are protective in vitro (50-200 μM). Uridine was not found to interfere with the antiretroviral activity of NRTIs. Mitocnol, a sugar cane extract which effectively increases uridine in human serum, was beneficial in individual HIV patients with mt toxicity and is now being tested in placebo-controlled randomized trials. Until these data become available, the risk-benefit calculation of using uridine should be individualized. The current safety data justify the closely monitored use of uridine in individuals who suffer from mt toxicity but who cannot be switched to less-toxic NRTIs.




 

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