Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors

Walker, Ulrich A.; Setzer, Bernhard; Venhoff, Nils

doi:10.1097/00002030-200211080-00009

Cited by 223 publications

(242 citation statements)

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“…3 In vitro studies point toward differences between the potencies of the individual NRTIs in depleting mtDNA, with the socalled "D drugs" zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) being relatively strong inhibitors of polymerase-gamma compared with the other currently licensed nucleoside analogues (so-called "non-D drugs"). 4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; mtDNA, mitochondrial DNA; ddC, zalcitabine; ddI, didanosine; d4T, stavudine; HCV, hepatitis C virus; nDNA, nuclear DNA; ULN, upper limit of normal; ALT, alanine aminotranferase.…”

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confidence: 99%

“…4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; mtDNA, mitochondrial DNA; ddC, zalcitabine; ddI, didanosine; d4T, stavudine; HCV, hepatitis C virus; nDNA, nuclear DNA; ULN, upper limit of normal; ALT, alanine aminotranferase. From…”

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confidence: 99%

“…4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because of pharmacokinetic differences between species and partly because of variations in the uptake and phosphorylation of nucleosides into tissues, cells, and mitochondria. To date, only limited observational mtDNA data of HIV patients receiving ART are available, 8,9 and a systematic study has not been conducted.…”

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confidence: 99%

“…Furthermore, the available data conflict with regard to zidovudine, because mtDNA depletion has also been observed despite the fact that this NRTI is not a strong inhibitor of gamma-polymerase at clinically relevant concentrations. 4,5,9 Slight and asymptomatic elevations of lactate are frequently associated with the prolonged use of NRTIs and may also be related to mtDNA depletion in tissues. 3,10 Such mild hyperlactatemia has to be distinguished from lactic acidosis or symptomatic hyperlactatemia, which have been reported in association with liver pathology.…”

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Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

et al. 2004

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A ntiretroviral therapy (ART) has significantly decreased the HIV-associated morbidity and mortality in industrialized countries. 1 ART usually consists of a combination of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either protease inhibitors (PIs) or a nonnucleoside reverse transcriptase inhibitor (NNRTI), or of three NRTIs. 2 With prolonged exposure to antiretroviral drugs, clinicians became aware of long-term side effects of individual ART components. Many adverse effects of the NRTI class of anti-HIV drugs are now related to the fact that NRTIs undergo intracellular triphosphorylation, then inhibit the replication of mitochondrial DNA (mtDNA) by interacting with gamma-polymerase. 3 In vitro studies point toward differences between the potencies of the individual NRTIs in depleting mtDNA, with the socalled "D drugs" zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) being relatively strong inhibitors of polymerase-gamma compared with the other currently licensed nucleoside analogues (so-called "non-D drugs"). 4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; mtDNA, mitochondrial DNA; ddC, zalcitabine; ddI, didanosine; d4T, stavudine; HCV, hepatitis C virus; nDNA, nuclear DNA; ULN, upper limit of normal; ALT, alanine aminotranferase. From

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confidence: 99%

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confidence: 99%

“…4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because of pharmacokinetic differences between species and partly because of variations in the uptake and phosphorylation of nucleosides into tissues, cells, and mitochondria. To date, only limited observational mtDNA data of HIV patients receiving ART are available, 8,9 and a systematic study has not been conducted.…”

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Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

et al. 2004

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“…As BMS-986001 is an analogue of d4T, and d4T has been associated with mitochondrial toxicity, 31 changes in mtDNA copy number were monitored during this study. No meaningful changes from baseline in mtDNA copy number were observed, consistent with the lack of lipoatrophy reported, for BMS-986001.…”

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confidence: 99%

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

Gupta

McComsey

Lombaard³

et al. 2016

The Lancet HIV

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MethodsAI467003 was a Phase 2b, randomised, active-controlled, blinded-to-BMS-986001 dose trial.HIV-1-infected adults with plasma HIV-1 RNA greater than 5000 copies per mL and CD4+ T-cell counts greater than 200 cells/mm 3 were randomised 2:2:2:3 to three BMS-986001 arms (100, 200 or 400 mg once daily), or reference arm (TDF 300 mg once daily), each with efavirenz (600 mg once daily) and lamivudine (300 mg once daily). Both subjects and investigators remained blinded to BMS-986001 dose, but not allocation, through Week 48. Proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL and safety (serious adverse events [SAEs] and AEs leading to discontinuation) through Week 24 were primary endpoints. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints.AI467003 is registered with ClinicalTrials.gov (NCT01489046). FindingsA total of 757 subjects were assessed for eligibility and 301 randomised. Randomised subjects were assigned to receive either BMS-986001 (n=67 for the 100 mg once-daily group, n=67 for the 200 mg once-daily group, n=66 for the 400 mg once-daily group) or TDF (n=101 In a Phase 2a, dose-escalating, monotherapy study conducted for 10 days in treatment-experienced, HIV-1-infected, subjects who were not exposed to any antiretroviral treatment in the previous 3months, BMS-986001 demonstrated a median decrease in HIV-1 RNA from baseline of at least 1 log10 copies per mL for all doses. 19 These findings were used to support the design of this dosefinding Phase 2b study, which assessed the efficacy and safety of three doses of BMS-986001 (100, 200, and 400 mg once daily) versus tenofovir disoproxil fumarate (TDF 300 mg once daily), when coadministered with efavirenz (EFV 600 mg once daily) and lamivudine (3TC 300 mg once daily) in treatment-naïve, HIV-1-infected subjects. A detailed assessment of bone, renal, metabolic and mitochondrial parameters was performed to assess the safety of BMS-986001. 6 METHODS Study designAI467003 was a Phase 2b, randomised, active-controlled, blinded-to-BMS-986001 dose trial carried out at 47 sites across South America, North America, South Africa, Australia, Asia, and Europe.This study was conducted in accordance with Good Clinical Practice (GCP), as defined by the ParticipantsEligible subjects were treatment-naïve (defined as no current or previous exposure to an antiretroviral drug for more than 1 week), HIV-1-infected adults aged at least 18 years with plasma HIV-1 RNA greater than 5,000 copies per mL and CD4+ T-cell counts greater than 200 cells/mm 3 at screening.Exclusion criteria included a history of phenotypic and/or genotypic drug resistance testing showing resistance to EFV, TDF, or 3TC, presence of hepatitis B surface antigen, hepatitis C virus antibody or RNA, history of abnormal liver transaminases (defined as greater than three times the upper limit of normal) at screening, and creatinine clearance less than 60 mL/min at screening. All subjects provided written informed consent in agreement wi...

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HIV Infection, Hepatitis C Infection, and HAART

Kottilil

Polis²,

Kovacs³

2004

JAMA

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Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors

Abstract: The data indicate additive or synergistic long-term mitochondrial toxicity in some NRTI combinations.

Cited by 223 publications

References 25 publications

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

HIV Infection, Hepatitis C Infection, and HAART

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