NRTI toxicity

However, not all effects of NRTls on mitochondria can be explained by the DNA polymerase y hypothesis. Other mechanisms, either secondary to or independent of inhibition of DNA polymerase y are involved in NRTI toxicity (Moyle 2000a, 2000b Lewis et al. 2003). AZT is a potent inhibitor of mitochondrial DNA polymerase y but does not cause neuropathy in HIV patients (Dalakas 2001). Keswani and colleagues showed that NRTls caused direct mitochondrial toxicity through... 

The phenotype and clinical presentation of antiretroviral toxic neuropathy (ATN) are similar to those of HIV-associated DSP. However, ATN is more likely to be painful, and has an abrupt onset and rapid progression. The main diagnostic clue is the temporal relationship of peripheral neuropathy to the start of NRTI therapy and stabilization, or at least the partial resolution when therapy is interrupted (Moyle and Sadler 1998). ATN most often develops after a mean of 16 to 20 weeks of treatment, unless there are other conditions that lower the threshold. Symptomatic improvement over weeks to months has been reported in two thirds of patients after discontinuation of the offending drug, but may be preceded by an initial period of worsening symptoms, also known as coasting (Berger et al. 1993). Despite the improvement, most patients do not return to a completely asymptomatic state (Hoke and Comblath 2004). 

Hoschele D (2006) Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. Toxicol In Vitro 20(5) 535-546 Itescu S, Brancato LJ et al (1989) A sicca syndrome in HIV infection association with HLA-DR5 and CDS lymphocytosis. Lancet 2(8661) 466 68 Itescu S, Brancato LJ et al (1990) A diffuse infiltrative CDS lymphocytosis syndrome in human immunodeficiency virus (HIV) infection a host immune response associated with HLA-DR5. Ann Intern Med 112(1) 3-10... 

Lewis W, Dalakas MC (1995) Mitochondrial toxicity of antiviral drugs. Nat Med 1(5) 417 22 Lewis W, Day BJ et al (2003) Mitochondrial toxicity of NRTI antiviral drugs an integrated cellular perspective. Nat Rev Drug Discov 2(10) 812-822 Lin-Greenberg A, Taneja-Uppal N (1987) Dysautonomia and infection with the human immunodeficiency virus. Ann Intern Med 106(1) 167... 

Zalcitabine (ddC) Hivid (anticipated discontinuation of distribution in 2006) 0.375-, 0.75-mg tab 0.75 mg tid CrCI Dose (mL/minute) 10-40 0.75 mg bid less than 10 0.75 mg qday No data on hemodialysis None Peripheral neuropathy stomatitis, lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs) pancreatitis Renal excretion... 

D/C all antiretrovirals symptomatic support with fluids some patients require IV bicarbonate, hemodialysis, parenteral nutrition, or mechanical ventilation once syndrome resolves, consider using NRTIs with 4- mitochondrial toxicity (ABC, TDF, 3TC, or FTC) monitor lactate after restarting NRTIs some clinicians use NRTI-sparing regimens. 

Comparison studies in HepG2 cells indicate that the potency of the NRTIs to reduce mtDNA varies, with ddC > ddl > d4T > ATT > ABC = 3TC = TDF [73] and this is in accord with their observed toxicity in the clinic. It should also be noted that HIV infection per se also significantly lowered mtDNA in PMBCs independent of NRTI exposures [74]. 

The NRTIs inhibit cellular and mitochondrial DNA polymerases and various cellular kinases, resulting in toxicity. Toxicity varies with the state of the immune system early in the infection there is less toxicity, while late in the infection there is substantially more. All NRTIs... 

Tenofovir is taken once daily and is generally well tolerated, perhaps because it produces less mitochondrial toxicity than the NRTIs. Nausea, vomiting, flatulence, and diarrhea occur in 10% or fewer patients. Resistance to tenofovir has been documented, and cross-resistance to NRTIs may occur. 

Tenofovir should not be given to patients with renal insufficiency. Its coadministration with didanosine results in increased plasma levels of didanosine that can produce toxicity. Because lactic acidosis and severe hepatomegaly with steatosis have been reported with NRTIs, it is important to monitor patients with known risk factors during treatment with tenofovir. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

Metabolic disturbances are frequent in patients with HIV infection and represent a multifactorial condition related both to the underlying disease and to the antiviral treatment. HIV infection itself appears to cause hyperlipidemia and insulin resistance in some patients. Protease inhibitor therapy is a major contributor to fat accumulation, hyperlipidemia, and insulin resistance. NNRTIs contribute mainly through augmentation of lipid concentrations and NRTIs to the development of lipid-associated toxicity. NRTIs can cause mitochondrial dysfunction. 

Other effects associated with NRTIs include pancreatitis, CNS toxicity (headache, irritability, insomnia), and gastrointestinal disturbances (nausea, diarrhea). Abacavir can cause an allergic (hypersensitivity) reaction that produces symptoms such as fever, joint and muscle pain, skin rashes, abdominal pain, nausea, diarrhea, and vomiting.32 In severe cases, this reaction can progress to anaphylactic shock and possibly death. 

Initially, most of the adverse effects seen with zidovudine use (in particular hematological effects) were attributed to interference with cellular DNA replication. However, DNA replication also occurs in mitochondria. Mitochondrial DNA encodes some of the enzymes used for oxidative phosphorylation. Only recently has it been hjrpothesized that inhibition of this pathway could lead to mitochondrial toxicity and be responsible for most of the toxicity seen with NRTIs, including polyneuropathy, myopathy, cardiomyopathy, steatosis, lactic acidosis, exocrine pancreas failure, bone marrow failure, and proximal tubular dysfunction (11). These adverse effects are also a compilation of the clinical features seen in several genetic mitochondrial cytopathies. 

In vitro, NRTIs reduce mitochondrial DNA, most likely by inhibiting mitochondrial DNA polymerase gamma. Heterogeneous toxicity profiles of different NRTIs in vivo may be related to variable tissue sensitivity, cell entry, and drug phosphorylation. Therefore, each NRTI has a specific adverse effect profile (Table 2 (11)), but any feature of mitochondrial toxicity must be considered with all NRTIs. A major problem of mitochondrial toxicity is its delayed onset, sometimes after several months of treatment. 

The NRTIs are toxic to hemopoietic progenitor cells in vitro (24) and can cause anemia (25,26), neutropenia (25), and thrombocytopenia (27,28). 

Two HIV-1-positive women, both of whom had taken regimens containing stavudine and didanosine for at least 2 years, presented in the third trimester of pregnancy, one with acute lactic acidosis and one with acute pancreatitis and lactic acidosis (32). In the first case both mother and baby died. It is not known whether pregnancy is a risk factor for NRTI-induced lactic acidosis, perhaps in combination with riboflavin deficiency or a metabolic defect in the fetus, or whether NRTIs independently cause lactic acidosis through mitochondrial toxicity. 

As with any medication, adverse effects occur with antiretroviral agents that may limit the patient s ability to tolerate medication. Several important adverse effects have been recognized with the currently available antiretrovirals. These include mitochondrial toxicity with NRTIs, rash with NNRTIs, and metabolic perturbations with Pis. A discussion on the specific presentation and management of these adverse effects is beyond the scope of this chapter but can be found elsewhere. " ... 

The basic mechanism of their action is identical to that of zidovudine—they each require metabolic activation to nucleotide forms that inhibit reverse transcriptase. Resistance mechanisms are similar but involve specific point mutations in the RT gene, so there is not complete cross-resistance between NRTIs. The drugs differ, however, in their toxicity profiles. 

I Lamivudine, 3TC Least toxic of the NRTIs, but some GI effects and neutropenia— active in hepatitis B... 

The two Pis used most in the last 5 to 6 years, nearly always in combination regimens with two NRTIs, are indinavir and ritonavir. Saquinavir, one of the least toxic, has very low (and variable) oral bioavailability that predisposes to resistance development. 

NRTI [82-93]. NRTI-related mitochondrial toxicity may also present with rhabdomyolysis and acute renal failure [%]. Mortality related to NRTl-induced acute lactic acidosis is high, in the range of 50% to 100%, despite drug discontinuation. 

Drugs in this class include delavirdine, efavirenz, and nevirapine. These drugs bind to viral reverse transcriptase and block DNA polymerase activity. Unlike the NRTIs, these drugs do not require intracellular phosphorylation and are not incorporated into viral DNA. None of these drugs has been associated with any clinically significant renal toxicities or specific fluid-electrolyte complications, and they do not appear to affect mitochondrial DNA polymerases. There is a... 

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