Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lactic acidosis is an uncommon but potentially life-threatening adverse effect of didanosine. When given concomitantly with tenofovir disoproxil fumarate (DF), the area under the concentration-time curve of didanosine is increased by 48-60%. A 63-year-old man with human immunodeficiency virus (HIV) infection tolerated several didanosine-containing antiretroviral regimens. He developed generalized weakness, loss of appetite, weight loss, nausea, and vomiting 1.5 years after tenofovir DF was added to his didanosine-containing regimen. He was diagnosed with lactic acidosis and died after a 13-day hospital stay, when his lactate level increased to 189.7 mg/dl and his arterial blood gas pH value fell to 6.75. Health care providers should maintain a high index of suspicion for lactic acidosis in patients with HIV infection who receive didanosine and tenofovir DF concurrently. For patients receiving antiretroviral regimens containing this drug combination, it would be prudent to monitor lactate levels periodically. This is especially important when patients experience symptoms suggestive of lactic acidosis, such as weakness, abdominal pain, weight loss, nausea and vomiting, and shortness of breath.
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PMID:Fatal lactic acidosis associated with coadministration of didanosine and tenofovir disoproxil fumarate. 1533 57

Over the past decade, the course of human immunodeficiency virus (HIV) infection has been markedly altered by highly active antiretroviral therapy (HAART). As advances in early diagnosis and aggressive therapy, as well as better supportive care, become available to more HIV-infected patients, survival is being prolonged and more patients are experiencing cardiac abnormalities. Cardiovascular manifestations of pediatric HIV infection have especially proven to be an ongoing challenge to practicing physicians, who face cardiac abnormalities ranging from asymptomatic cardiomyopathy to severe heart failure. Antiretroviral therapy has substantially decreased vertical transmission of HIV; however, studies of adults receiving HAART have found increased peripheral and coronary artery disease. Children exposed to this therapy in utero are thus at an increased risk for toxicity and cardiac abnormalities, regardless of their HIV status. Preliminary studies have reported complications including lactic acidosis and mitochondrial toxicity, as well as cardiomyopathy. Further studies are needed to explore the long-term effects and possible toxicities of prophylactic antiretroviral therapy on infants born to HIV-infected mothers.
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PMID:Cardiovascular effects of HAART in infants and children of HIV-infected mothers. 1547 Feb 74

Carnitine and its congeners may regulate the immune networks, and their influence on functions of immune cells predominantly or exclusively relies on carnitine-dependent energy production from fatty acids. A reduced pool of carnitines has been demonstrated in either serum or tissues, or both, from patients with a wide spectrum of disorders characterized by unregulated or impaired immune responses ranging from sepsis syndrome to systemic sclerosis, infection with human immunodeficiency virus, and chronic fatigue syndrome. Furthermore, experimental studies have consistently reported that the deranged immune responses and the less efficient inflammation towards infectious organisms associated with aging may be enhanced or modulated by treatment with carnitines. There is also evidence that carnitine deprivation could adversely affect the course of the sepsis syndrome, at least in experimental models, and preliminary studies suggest that carnitine deficiency is ultimately implicated in the pathophysiology of endotoxin-mediated multiple organ failure. Several data indicate that carnitine deficiency is a contributing factor to the progression of infection with human immunodeficiency virus, and carnitine therapy in those patients could counteract the unregulated process of lymphocyte apoptosis and improve CD4 counts. Some case reports have suggested the use of carnitine for the treatment of the severe lactic acidosis that complicates in some patients the use of reverse transcriptase inhibitors.
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PMID:Carnitines and its congeners: a metabolic pathway to the regulation of immune response and inflammation. 1559 Oct 10

Nucleoside reverse-transcriptase inhibitors (NRTIs) have been associated with functional and structural mitochondrial abnormalities, leading to several adverse events, such as increased serum lactic acid levels and lactic acidosis. Mild-to-moderate, asymptomatic hyperlactataemia has been frequently reported in human immunodeficiency virus (HIV)-infected patients treated with NRTIs, with an estimated prevalence between 15% and 35%. On the contrary, symptomatic, severe hyperlactataemia and lactic acidosis are less common, with an incidence ranging from 1.7 to 25.2 cases per 1000 person-years of antiretroviral treatment, and are associated with a remarkable mortality rate, which varies from 30% to 60% in different studies. The clinical presentation of lactic acid syndrome is non-specific and includes asthenia, malaise, nausea, vomiting, abdominal pain, weight loss, tachypnoea, dyspnoea, liver steatosis and increased transaminase levels, and risk factors include previous or concurrent therapy with stavudine or didanosine. Management of symptomatic lactic acid alterations involves NRTI-therapy interruption and supportive care, while natural history of hyperlactataemia is still unknown, and it is uncertain whether asymptomatic patients with increased lactate concentrations are at increased risk of developing lactic acidosis.
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PMID:Hyperlactataemia and lactic acidosis in HIV-infected patients receiving antiretroviral therapy. 1568 Oct 97

Mitochondrial dysfunction has been associated with long-term toxicities of human immunodeficiency virus (HIV) therapy, particularly with the nucleoside analog reverse transcriptase inhibitors (NRTIs). Lactic acidosis, hepatic steatosis, myopathies, cardiomyopathies, neuropathies, and lipodystrophy are frequently attributed to mitochondrial toxicity. Since mitochondrial toxicity could pose a major threat to the long-term success of HIV therapy, the scientific evidence underlying an association between mitochondrial toxicity and antiretroviral therapies, must be carefully examined. There is some data to support the association between NRTIs and mitochondria dysfunction. In this review, we examine human, animal, and in vitro data implicating mitochondrial dysfunction as the causal mechanism of NRTI-associated toxicity in HIV-infected patients.
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PMID:Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities: what is the evidence? 1612 Feb 93

Antiretroviral medications have significantly improved the prognosis of individuals infected with the human immunodeficiency virus (HIV) by maintaining immune integrity and limiting the impact of opportunistic infections. However, these benefits have not come without a price as long-term complications of therapy are increasingly recognized as significant causes of morbidity and mortality. Many of these complications are thought to be mediated through mitochondrial injury, which appears to be the result of nucleoside analogue toxicity. A syndrome of fatty liver (steatosis) with lactic acidosis represents the most fulminant presentation of such antiretroviral toxicity, though milder variants of hepatic steatosis with or without lactate elevations have also been described in HIV-seropositive individuals. The spectrum of hepatic steatosis and hyperlactatemia is likely multifactorial and may share some features with non-alcoholic fatty liver disease (NAFLD), which is the hepatic component of the metabolic syndrome described in the general population. As antiretrovirals are also known to contribute to metabolic syndrome components including insulin resistance, hypertriglyceridemia, and central adiposity, the possibility of common pathophysiologic mechanisms underlying NAFLD and antiretroviral-associated fatty liver seem likely. However, lactate elevations are not a component of NAFLD, suggesting other factors must also be involved. A review follows which details the role of mitochondrial damage in hepatic steatosis among HIV-infected individuals and the general population, as well as the association of this damage to the pathogenesis of hyperlactatemia.
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PMID:Mitochondrial injury in the pathogenesis of antiretroviral-induced hepatic steatosis and lactic acidemia. 1612 Mar 75

Advances in anti-retroviral therapy (ART) has led to improved survival of patients infected with the human immunodeficiency virus (HIV). ART for HIV patients is composed of a combination of nucleoside reverse transcriptase inhibitors (NRTI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and/or a protease inhibitor (PI). The long-term exposure to ART and HIV are causing mitochondrial toxicities, such as myopathies, neuropathy, myelopoiesis, pancreatitis, lactic acidosis, hepatic steatosis, and lipodystrophy. The mitochondrial pathogenesis has been believed to be due exclusively to NRTI-induced inhibition of DNA polymerase-gamma; it is now apparent that the etiology is far more complex, involving multiple mechanisms as well as an effect by HIV per se. Current therapy for patients includes interruption or change in medications and mitochondrial co-factors.
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PMID:Mitochondrial dysfunction in AIDS and its treatment. 1612 Apr 31

The efficacy of antiretroviral drugs has improved the prognosis for infection by human immunodeficiency virus (HIV); it is nonetheless accompanied by toxicity specific to these agents. Adverse effects of these treatments are a major cause of poor compliance as well as of the cessation or change of treatment. Knowledge of these effects allows physicians to choose an individualized and effective treatment for each patient, one that is well tolerated and appropriate to the patient's sometimes complex medical history. Although some of these adverse effects can be life-threatening (drug eruptions with nevirapine and abacavir, pancreatitis with didanosine, or lactic acidosis with nucleoside analogs), most are reversible. Lipodystrophies, sometimes combining morphologic and metabolic disorders, are observed in some patients after several years of treatment and appear to increase cardiovascular risk. They are one of the major disadvantages of combined treatments.
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PMID:[Adverse effects of antiretroviral treatments]. 1631 16

The introduction of highly active antiretroviral therapy (HAART) for treatment of human immunodeficiency virus (HIV) infection has led to substantial reduction in morbidity and near-complete suppression of HIV-1 replication. But since HAART is unlikely to eradicate HIV-1, antiviral therapy may be required a lifelong, leading to an increase in attention on the long-term safety of HAART. A major toxicity of HAART is the mitochondrial toxicity. Mitochondrial toxicity becomes apparent particularly over the medium-term to long-term therapy and is attributed to treatment with nucleoside reverse transcriptase inhibitors (NRTIs), leading to a wide range of severe adverse events in HIV-infected patients. These include lactic acidosis, hepatic steatosis, neuropathy, (cardio-) myopathy, pancreatitis, and probably lipodystrophy. Furthermore, lactic acidosis and encephalopathy have been reported in children exposed in-utero and/or postnatally to NRTIs. Mitochondrial toxicity could pose a major threat to long-term success of HIV-therapy, and is of great concern for children exposed in-utero and/or postnatally to NRTIs. Therefore, investigation of mitochondrial toxicity of new compounds or new combinations is of growing interest for the clinical application of antiretroviral agents. However, at present no standardized and validated screening model system exists for the investigation of NRTI-induced mitochondrial toxicity. There is a need for the generation of a relevant in vitro assay system that can assess the mitochondrial toxicity in early preclinical development. This paper gives an overview of cell culture models currently used for the investigation of NRTI-induced mitochondrial toxicity and discusses the relevance and suitability of these models for prediction of clinical toxicity.
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PMID:Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. 1640 76

Several drugs are currently used that can significantly prolong the course of the infection with the human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS). Among these drugs, the nucleosidic inhibitors of viral reverse transcriptase can alter mitochondrial (mt) function by inhibiting the mitochondrial DNA polymerase gamma (the enzyme responsible for the replication of mtDNA). Decreased mtDNA content provokes a diminished synthesis of respiratory chain enzymes, leading to alterations in mt function. These are in turn responsible for a variety of side effects frequently observed in HIV+ patients, that range from hyperlactatemia and lactic acidosis to lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance and fat wasting in face and limbs. In this paper, data concerning the effects of different compounds on mitochondria, their role in the pathogenesis of lipodystrophy, and problems related to studies on the mt toxicity of antiviral drugs are reviewed and thoroughly discussed.
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PMID:Anti-HIV drugs and the mitochondria. 1678 42


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