Version May 2024
INTRODUCTION — Since the introduction of potent antiretroviral therapy (ART), the life expectancy of HIV-infected patients has improved enormously. However, the chronic administration of antiretroviral medications has led to the recognition of long-term complications of these therapies [1,2]. Mitochondrial toxicity is recognized as a major adverse effect of nucleoside analogue treatment and can lead to myopathy, peripheral neuropathy, and hepatic steatosis with lactic acidosis, which can be life-threatening.
The induction of mitochondrial dysfunction by nucleoside reverse transcriptase inhibitors (NRTIs) will be discussed here. The use of NRTIs for the treatment of HIV infection is discussed separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
ROLE OF MITOCHONDRIA — The main function of mitochondria is oxidative phosphorylation in which fatty acids and pyruvate are used as substrates to produce energy in the form of adenosine triphosphate (ATP). Normally there is tight coupling between oxidation and phosphorylation (OXPHOS) that is governed by normal mitochondrial enzymes, such as the cytochrome oxidases and other enzymes of the respiratory chain system. OXPHOS is also responsible for neutralization of free radicals and beta-oxidation of free fatty acids.
Mitochondria also play an important role in the generation of reactive oxygen species (ROS), which are produced physiologically during oxidative phosphorylation. Oxidative stress can occur if there is an imbalance between the production of ROS and cellular antioxidant defenses [3]. Mitochondrial DNA polymerase is a target of oxidative damage [4].
PATHOGENESIS — Nucleoside analogues are effective in inhibiting HIV replication due to their high affinity for the viral enzyme reverse transcriptase (a viral DNA polymerase) [5-7]. However, NRTIs can also bind to other human DNA-polymerases, like DNA polymerase beta (necessary for repair of nuclear DNA) and mitochondrial DNA polymerase gamma, which is exclusively responsible for the replication of mitochondrial DNA (mtDNA).
Mitochondrial DNA polymerase gamma — By inhibiting mtDNA enzyme polymerase-gamma, NRTIs can lead to depletion of mtDNA, resulting in organelle dysfunction and impairment of oxidative phosphorylation (figure 1) [2]. mtDNA encodes 13 mitochondrial polypeptides involved in the respiratory chain that are essential for oxidative phosphorylation (OXPHOS) [8]. A disruption of OXPHOS leads to energy loss (decreased ATP) and an increase in electron leakage from the electron-transport chain, which increases the production of reactive oxygen species (ROS) [9]. ROS, in turn, damage proteins, lipids, and mtDNA, leading to a cascade of further oxidative damage and lipid peroxidation. mtDNA is vulnerable to mutations since it has no introns or histones.
Although the so-called "pol-gamma hypothesis" still remains the most important explanation for the induction of mitochondrial dysfunction by NRTIs, nucleoside analogues can also influence intracellular nucleoside transporters, disturb the delicate balance of the intracellular nucleoside pools, or alter kinetics of phosphorylation of natural nucleosides [10-13]. Furthermore, the acceleration of mtDNA turnover as a compensatory mechanism for mtDNA depletion can lead to persistent accumulation of somatic mutations in mtDNA even after NRTI withdrawal [14]. The impact of all these effects on long-term mitochondrial function is still unclear.
Expression of mitochondrial toxicity may not occur until a specific biologic threshold of mitochondrial dysfunction has been reached. Onset of mitochondrial toxicity may vary depending on the individual cell type since copy numbers of mtDNA vary, as well as cellular dependence on energy production [15]. Mitochondria are found in all cells of the body except for erythrocytes.
Production of lactate — Early effects of mitochondrial toxicity include decreased energy production and increased production of lactate. During glycolysis, glucose is metabolized to pyruvate and energy is produced in the form of ATP. Under normal conditions, pyruvate is taken up by mitochondria and metabolized to acetyl-CoA, which feeds into the Krebs cycle. This pathway is responsible for most of the cell's energy production. In the presence of mitochondrial dysfunction, the metabolism of pyruvate is shifted to lactate, with a decrease in energy production.
A decrease in OXPHOS will impair ATP production, beta oxidation of fatty acids, and neutralization of free radicals leading to oxidative stress. Furthermore, since acetyl-co-A can no longer enter the Krebs cycle, it will alternatively be metabolized into ketone bodies, while lactate and triglycerides will accumulate (figure 2). Since every cell type has a different dependence on OXPHOS, cellular dysfunction will only emerge after the decrease in OXPHOS has dropped below a certain cell-dependent threshold [16,17].
IMPLICATED DRUGS — Eight nucleoside reverse transcriptase inhibitors (NRTIs) are available for treatment of HIV. The most commonly used ones are lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF). Zidovudine (ZDV), didanosine (ddI), and stavudine (d4T) are less frequently used, and zalcitabine (ddC) was removed from the market in 2006. A discussion on selecting an antiretroviral regimen is presented separately. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
All NRTIs are chain terminators and result in the reversible termination of the viral DNA chain and also (if incorporated) of the mtDNA chain. This point is important since discontinuation of medications may lead to reversibility of mitochondrial toxicity if recognized early.
The NRTIs all have different affinities for mtDNA polymerase gamma, explaining in part the different propensity of the drugs to induce toxicity [18] (see 'Pathogenesis' above). In vitro, the order of strength of inhibiting polymerase gamma for the different NRTIs is: ddC >> ddI > d4T ≥ ZDV >>> TDF = 3TC = FTC = ABC [19-21]. There are insufficient data to speculate about TAF. Other factors that may explain the varying effects of individual drugs on DNA polymerase gamma include differences in cell entry, and transport to the mitochondrial membrane [9].
Some NRTIs (ddC, ddI, and d4T) are particularly associated with a decline in mtDNA content and ultrastructural changes, including swollen or enlarged mitochondria and loss and distortion of their cristae. Due to the significant risk of mitochondrial toxicity associated with ddI and D4T, these drugs are generally avoided for the treatment of HIV, and distribution by the original producer was stopped in September 2017. It is unclear how long generic d4T and ddI will be available thereafter.
Mitochondrial toxicity secondary to drug exposure had been described prior to the development of antiretroviral medications. These drugs included valproic acid, tetracycline, amiodarone, and others. Fialuridine (FIAU) was a nucleoside analogue in clinical development for the treatment of hepatitis B, but the clinical trial was prematurely halted when patients developed evidence of liver failure and hepatic steatosis that was secondary to mitochondrial toxicity [22]. FIAU was efficiently incorporated into internal positions of mtDNA in place of thymidine and led to ultrastructural changes in mitochondria and increased intracellular lipid droplets [23]. Histological findings of liver tissue demonstrated severe accumulation of microvesicular and macrovesicular fat, with minimal necrosis of hepatocytes [22]. Electron microscopy showed abnormal mitochondria and the accumulation of fat in hepatocytes. There was no known repair mechanism to remove the internal FIAU and the damage to mtDNA was permanent [24].
CLINICAL PRESENTATION — The clinical presentation of mitochondrial toxicity depends on the target organ that is involved (table 1). There is little doubt that mitochondrial toxicity is the major cause of NRTI-induced myopathy, neuropathy, lipoatrophy, and lactic acidosis [6,7,25]. Whether mitochondrial toxicity is involved in other clinical manifestations, such as pancreatitis, myelosuppression, cardiomyopathy, tubular dysfunction, or osteopenia, is not as clear [26].
Myopathy — The first reports of a toxic mitochondrial myopathy in HIV-infected patients were related to the use of ZDV [27]. Symptoms of myopathy included proximal muscle weakness, tenderness, and myalgia. The majority of patients have elevated serum creatine phosphokinase levels and may occasionally have elevated lactate levels [28,29]. Occasionally a patient may have electromyographic evidence of proximal muscle myopathy despite normal muscle enzymes [30].
ZDV affects the muscle mitochondria by inhibiting DNA polymerase gamma, resulting in termination of the DNA chain and depletion of muscle mtDNA [27,31]. Histological features include an inflammatory, destructive mitochondrial myopathy with "ragged-red" fibers seen on trichrome stain, indicative of abnormal mitochondria with paracrystalline inclusions [27]. Patients with ubiquitous "ragged-red" fibers also have significant lipid and glycogen accumulation in proximity to abnormal mitochondria, as seen in patients with inherited mitochondrial myopathies [32]. When mitochondria are structurally and functionally abnormal, long-chain fatty acids cannot be effectively utilized, resulting in lipid accumulation within the muscle [32]. Carnitine, which is essential for the transport of long-chain fatty acids into the muscle mitochondria, is depleted in ZDV-treated patients who have significant numbers of "ragged-red" fibers on muscle biopsy [32]. Two patients who had repeat biopsies after discontinuation of ZDV showed marked histologic improvement.
Lipoatrophy — Clinical alterations in adipose tissue and metabolic changes, such as insulin resistance and hyperlipidemia, are observed in patients taking antiretroviral therapy. This constellation of findings is referred to as the "lipodystrophy syndrome". Lipoatrophy, or fat atrophy, is associated with nucleoside reverse transcriptase inhibitor use, particularly d4T [33-36]. As an example, in a large prospective, randomized trial conducted over 96 weeks, a 50 percent dose reduction in d4T induced significantly more lipodystrophy compared with TDF (5.6 versus 0.2 percent) [36].
Several groups have demonstrated profound mtDNA depletion and morphologic alterations in subcutaneous fat biopsies of these patients [37-40]. Some have speculated that lipoatrophy is secondary to adipocyte apoptosis rather than necrosis, because the loss of fat is neither painful nor inflammatory. Furthermore, mitochondria are closely involved in apoptotic pathways, again implying a role for NRTI-induced toxicity [15,41]. Others have suggested that HIV itself may cause mitochondrial dysfunction, either directly or indirectly through the induction of inflammatory cytokines [40].
The epidemiology, clinical features, and treatment of lipoatrophy are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy".)
Hepatic steatosis — Hepatic steatosis and hepatic failure together with lactic acidosis have been reported as rare but serious adverse effects of nucleoside analogue therapy [30,42]. In 1993, eight cases of severe hepatomegaly with diffuse steatosis were reported in HIV-infected patients without AIDS, six of which were fatal [43]. All had received zidovudine for a minimum of six months prior to the onset of gastrointestinal symptoms and mild elevations of transaminases. Case reports of liver failure and hepatic steatosis have since been reported, especially in association with ddI and d4T [44].
Microvesicular hepatic steatosis has been identified in most of these cases, which is related to mitochondrial dysfunction [45]. Decreased mitochondrial oxidation of fatty acids leads to increased esterification of triglycerides and a decreased egress of triglycerides from the liver, which accumulate as small lipid droplets. Prior to the era of potent ART, it was well recognized that other drugs that inhibit mitochondrial oxidation, including valproate, tetracycline, amiodarone, ethanol, and salicylic acid, can lead to these histologic findings [46].
Hyperlactatemia and lactic acidosis — Hyperlactatemia and lactic acidosis are associated with NRTI use and typically occur in the absence of systemic hypoperfusion (called type B lactic acidosis) [47]. (See "Causes of lactic acidosis", section on 'Type B lactic acidosis'.)
Lactic acidosis represents a serious metabolic manifestation of mitochondrial toxicity that can lead to death [47]. Hepatic dysfunction may be an essential prerequisite for the development of lactate accumulation, since the liver is the most important organ for clearance of lactate [48].
Symptoms of hyperlactatemia or lactic acidosis may be nonspecific and include nausea, vomiting, abdominal pain, weight loss, and severe fatigue (table 2). Serum aminotransferases are only mildly elevated in most cases [43].
Lactic acidosis usually follows a minimum of six months of treatment, but may occur precipitously. Due to the nonspecificity of symptoms, hyperlactatemia may not be recognized for weeks to months [49]. Without intervention, lactic acidosis leads to a fatal outcome, most often due to liver failure and cardiac arrhythmias. NRTIs should be stopped promptly, and supportive medication should be initiated. The use of NRTI-sparing regimens is discussed elsewhere. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)
In the pre-ART era, lactic acidosis was described in patients on monotherapy with high-dose ZDV (1200 mg/day) and ddI with an estimated incidence of 1.2 per 1000 treated patient-years [42]. In the early era of combination therapy, d4T and ddI were most closely associated with this syndrome, sometimes in combination with each other [30,49-52].
In a prospective study in South Africa, 1771 HIV-infected participants were randomly assigned to a nucleoside backbone of d4T/3TC or ddI/AZT plus either efavirenz or lopinavir/ritonavir. Lactic acidosis was defined as a serum lactate concentration >5 mmol/L with an arterial pH <7.35 or a serum bicarbonate concentration <20 mmol/L. Symptomatic hyperlactatemia was defined as serum lactate >2.2 mmol/L with symptoms consistent with increased lactate (eg, nausea, anorexia, fatigue). A total of 13 cases with lactic acidosis (0.7 percent) and 28 cases with symptomatic hyperlactatemia (1.6 percent) were observed and two patients died. The risk of lactic acidosis or symptomatic hyperlactatemia was higher in female patients and among those taking d4T/3TC [53]. These observations were confirmed in similar studies from Botswana, Malawi, and Cambodia [54-56].
Asymptomatic hyperlactatemia (lactate <5 mmol/L) has been described in much higher prevalence (10 to 40 percent) and has also been observed in association with the use of d4T ± ddI [47,57-60]. Hyperlactatemia does not appear to be a constant phenomenon despite continuation of medication; some of these paradoxical observations may be related to incorrect blood sampling.
The natural history of hyperlactatemia is unclear since cases of lactic acidosis have been described where normal lactate levels were documented just prior to onset. In order to interpret the importance of an elevated lactate, decision algorithms have been developed (algorithm 1) [61].
Pancreatitis — The dideoxynucleoside analogues are most closely associated with pancreatitis (ddI>d4T). It has not been clearly established that pancreatitis is related to mitochondrial toxicity. However, concomitant chemical pancreatitis has been described in patients who had developed symptomatic lactic acidosis on NRTI therapy, suggesting a common mechanism [30,51].
Evidence that mitochondrial toxicity may be implicated in pancreatitis also comes from the clinical trial of FIAU for the treatment of hepatitis B. Seven of 15 patients who developed liver failure and hepatic steatosis secondary to mitochondrial toxicity also had biochemical evidence of pancreatitis [22]. All five patients who died had both gross and microscopic evidence of pancreatitis at autopsy.
Bone marrow suppression — The use of ZDV is associated with bone marrow suppression, which may be related to mitochondrial toxicity [34].
Neuropathy — The use of didanosine and stavudine has been linked to the development of peripheral neuropathy.
Nephrotoxicity — Tenofovir, in particular, tenofovir disoproxil fumarate (TDF), can induce proximal tubular dysfunction with subsequent renal failure. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir' and "Overview of kidney disease in patients with HIV", section on 'Medication nephrotoxicity'.)
Accumulation of tenofovir in proximal tubular cells has been demonstrated in experimental models, with a pivotal role for membrane transporters as OAT1 and MRP4 [62]. Although in one animal study it was suggested that mtDNA content was altered (increased) in isolated proximal tubular cells, mitochondrial dysfunction was not shown. Since tenofovir lacks affinity for DNA polymerase-gamma, it seems very unlikely that this drug can affect mtDNA levels via this pathway. However, in one study, more somatically mutated mtDNA could be demonstrated in association with TDF exposure, suggesting that TDF-associated renal damage was at least in part mitochondrially mediated [63].
Osteopenia/osteoporosis — Although the occurrence of decreased bone mineral density during chronic HIV infection has been associated with the use of antiretroviral treatment, in particular with the use of tenofovir disoproxil fumarate, it has not yet been demonstrated that mitochondrial dysfunction plays any role in this feature.
PATHOLOGY — Electron microscopy demonstrates markedly swollen mitochondria with loss of cristae, matrix dissolution, and scattered vesicular inclusions, consistent with the theory that the mitochondrion is the main target of injury. Other specific findings in various tissues are discussed below.
RISK FACTORS — Not all individuals will develop mitochondrial toxicity, even after several years of exposure to the most toxic drugs (eg, ddC or d4T/ddI combinations). Several studies have tried to identify specific mitochondrial DNA (mtDNA) haplotypes that would make someone more sensitive to the effects of NRTI treatment; however, these reports have been unrevealing due to limitations such as heterogeneous methods and outcomes, limited racial/ethnic groups, and inadequate statistical power [64].
However, based upon observations that have been reported in patients with HIV and inherited mitochondrial diseases, factors that might be important include:
●Female sex [49,52,54,56,65,66]
●Concomitant use of ribavirin with ddI for the treatment of hepatitis C [67-69]
●Increased age [52]
The risk in females may be even higher during pregnancy [70-72]. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)
DIAGNOSIS — The gold standard for the diagnosis of nucleoside-related mitochondrial toxic effects is a muscle or liver biopsy.
When a patient presents with symptoms consistent with hyperlactatemia or lactic acidosis, a blood sample for lactate should be sent in a fluoride oxalate tube on ice and delivered within four hours to the laboratory for processing. Levels need to be assessed with the strictest of quality control measures since elevated lactate can be an artifact of collection techniques [73]. Therefore, it is critically important to avoid certain factors that can artificially elevate lactate levels. Ideally samples should be drawn without use, or prolonged use, of a tourniquet. Whenever possible, it is also best to monitor levels in patients who have not exercised shortly before sampling.
Patients with pancreatitis (either chemical or clinical) should also have measurements of serum lactate, since these clinical entities have occurred concomitantly. (See 'Pancreatitis' above.)
PATIENT MONITORING — Routine monitoring for lactic acidosis is not warranted since prospective monitoring is not predictive of risk [55,74-77]. Although hyperlactatemia can be a correlate of mitochondrial dysfunction, chronic hyperlactatemia found on routine testing in asymptomatic patients has a poor predictive value [75,77]. As an example, in a prospective study of 253 patients in Malawi using stavudine, hyperlactatemia (>2.2 mg/dl measured with a point-of-care analyzer) was identified on at least one occasion in 210 patients (83 percent), but was only sustained in 65 (26 percent) over the course of one year [55]. Only one patient fulfilled a diagnosis of lactic acidosis.
The role of monitoring mitochondrial DNA (mtDNA) on venous blood has also been explored [78,79]. Although early reports were promising [78], subsequent studies could not confirm the value of monitoring mtDNA measurements in PBMCs and other tissues [40,80-84]. Furthermore, significant variance has been reported among laboratories assessing the same clinical sample [85].
SPECIAL SITUATIONS: IN UTERO EXPOSURE TO NRTIS — Antiretroviral drugs play an essential role in the prevention of mother-to-child-transmission (MTCT) of HIV. In utero exposure to NRTIs has been demonstrated to induce transient anemia, leucopenia, and hyperlactatemia in the newborns, without further sequelae [86-88]. This topic is discussed in detail elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Mitochondrial toxicity'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in nonpregnant adults and adolescents".)
SUMMARY AND RECOMMENDATIONS
●Mitochondrial toxicity is recognized as a major adverse effect of treatment with nucleoside reverse transcriptase inhibitors (NRTIs) and can lead to myopathy, peripheral neuropathy, and hepatic steatosis with lactic acidosis, which can be life-threatening. (See 'Introduction' above.)
●Mitochondria play an important role in the generation of reactive oxygen species (ROS), which are produced physiologically during oxidative phosphorylation. Oxidative stress can occur if there is an imbalance between the production of these reactive metabolites and cellular antioxidant defenses. (See 'Role of mitochondria' above.)
●NRTIs are effective in inhibiting HIV replication due to their high affinity for the viral enzyme reverse transcriptase. However, NRTIs can also bind to human DNA-polymerases, like mitochondrial DNA polymerase gamma, which is exclusively responsible for the replication of mitochondrial DNA. By inhibiting this enzyme, NRTIs can cause depletion of mitochondrial DNA, resulting in organelle dysfunction and mitochondrial toxicity. (See 'Pathogenesis' above.)
●The various NRTIs have different affinities for mitochondrial DNA polymerase gamma; those with the highest affinity (such as didanosine and stavudine) are associated with the highest risk of mitochondrial toxicity. Due to the significant risk of mitochondrial toxicity associated with didanosine and stavudine use, these drugs are no longer recommended for the treatment of HIV. (See 'Implicated drugs' above.)
●The nucleoside analogues lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), and tenofovir (TDF) lack affinity for mitochondrial DNA polymerase gamma; thus, it seems unlikely that these drugs can induce mitochondrial dysfunction of clinical significance. (See 'Implicated drugs' above.)
●The clinical presentation of mitochondrial toxicity depends on the target organ that is involved. Mitochondrial toxicity is the major cause of NRTI-induced myopathy, neuropathy, lipoatrophy, and lactic acidosis. Whether mitochondrial toxicity is involved in other clinical manifestations, such as pancreatitis, myelosuppression, cardiomyopathy, proximal tubular dysfunction, or osteopenia, is not as clear. (See 'Clinical presentation' above.)
●The gold standard for the diagnosis of nucleoside-related mitochondrial toxic effects is a muscle biopsy in cases of myopathy, or a liver biopsy in cases of suspected lactic acidosis with steatosis. When a patient presents with symptoms consistent with hyperlactatemia or lactic acidosis, a blood sample for lactate should be sent in a fluoride oxalate tube on ice and delivered within four hours to the laboratory for proper processing. (See 'Diagnosis' above.)
●Routine monitoring for lactic acidosis is not warranted since prospective monitoring is not predictive of risk. (See 'Patient monitoring' above.)
ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.
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