Stavudine

Cellular Kinases Involved in Triphosphate Formation

The phosphorylation of this compound is carried out by several cellular kinases. The initial and often rate-limiting step involves the phosphorylation of this compound to this compound monophosphate (d4T-MP). oncohemakey.com This step is primarily mediated by cellular thymidine kinase 1 (TK1). oncohemakey.comnih.gov Subsequent phosphorylations convert d4T-MP to this compound diphosphate (d4T-DP) and then to the active this compound triphosphate (d4T-TP). These steps involve thymidylate kinase and nucleoside diphosphate kinase, respectively. oncohemakey.comresearchgate.net

Research findings indicate that while TK1 is a primary enzyme involved, it may not be the sole enzyme responsible for this compound's activation. nih.gov Studies have also explored the influence of prior exposure to other nucleoside analogs, such as zidovudine (AZT), on this compound phosphorylation. While some in vitro studies suggested potential competitive inhibition of phosphorylation by zidovudine, clinical studies have not consistently shown a significant difference in intracellular this compound triphosphate levels between zidovudine-naive and zidovudine-experienced patients. nih.govepividian.com However, the combination of zidovudine and this compound is generally not recommended due to the potential for competitive inhibition of intracellular phosphorylation. fda.goveuropa.eu

Competition with Endogenous Nucleoside Triphosphates

Once formed, this compound triphosphate (d4T-TP) acts by competing with the natural cellular substrate, deoxythymidine triphosphate (dTTP), for incorporation into the newly synthesized viral DNA by HIV-1 reverse transcriptase. nih.govfda.govfda.gov This competition is a key aspect of its inhibitory mechanism. The ratio of intracellular this compound triphosphate to endogenous deoxythymidine triphosphate is considered an important factor reflecting the direct competition at the level of reverse transcriptase. nih.govasm.org

Data from studies show the competitive nature of this interaction. For instance, the inhibition constant (Ki) of this compound triphosphate for HIV reverse transcriptase has been reported in the range of 0.0083 to 0.032 µM, indicating a high affinity for the enzyme's active site where dTTP would normally bind. nih.govfda.govfda.govfda.gov

Competitive Inhibition Mechanisms

This compound triphosphate acts as a competitive inhibitor of HIV-1 reverse transcriptase by vying with the natural substrate, deoxythymidine triphosphate (dTTP), for binding to the enzyme's active site. nih.govfda.govnih.govfda.gov Due to its structural similarity to dTTP, d4T-TP can bind to the polymerase active site of reverse transcriptase. mdpi.com This competition reduces the availability of the active site for the natural substrate, thereby hindering the synthesis of viral DNA. patsnap.comasm.org

Detailed research findings, including kinetic studies, have characterized this competitive inhibition. The relatively low Ki values for d4T-TP against HIV-1 reverse transcriptase demonstrate its potency in competing with dTTP. nih.govfda.govfda.gov

DNA Chain Termination Mechanisms

The most critical aspect of this compound's action is its ability to cause DNA chain termination. patsnap.comnih.govnih.gov Once this compound triphosphate is incorporated into the growing viral DNA chain by reverse transcriptase, it prevents further elongation of the DNA strand. patsnap.comnih.govmdpi.com This occurs because this compound lacks a hydroxyl (OH) group at the 3' carbon position of its deoxyribose sugar. patsnap.comnih.govoncohemakey.com The 3'-OH group is essential for forming the phosphodiester bond with the next incoming nucleotide, a step required for DNA chain elongation. patsnap.comnih.govresearchgate.net The absence of this group in incorporated this compound results in an obligate chain termination event, effectively halting the synthesis of the viral DNA. nih.govoncohemakey.com

This premature termination of the viral DNA chain renders it incomplete and non-functional, preventing the integration of the viral genetic material into the host cell genome and thus inhibiting viral replication. patsnap.comwikipedia.org

Inhibition of HIV-1 Replication in Cell Lines

This compound has demonstrated inhibitory activity against HIV-1 replication in various cell lines, including lymphoblastoid cell lines. fda.govfda.gov Studies have shown that this compound can inhibit HIV-1 vector virus titer in a single cycle of replication. asm.org The concentration required to inhibit HIV-1 replication by 50% (IC50 or EC50) in cell culture has been reported to range from 0.009 to 4 µM against laboratory and clinical isolates of HIV-1. fda.govfda.gov

Inhibition of HIV-1 Replication in Primary Cells (e.g., PBMCs, Monocytic Cells)

This compound's antiviral activity has also been evaluated in primary cells, such as peripheral blood mononuclear cells (PBMCs) and monocytic cells, which are key target cells for HIV-1 infection in vivo. fda.govfda.govplos.orgresearchgate.netresearchgate.net Studies have shown that this compound can potently inhibit HIV-1 replication in human PBMCs. asm.org The antiviral activity has been demonstrated against a range of clinical isolates of HIV-1 cultured in human PBMCs and primary monocytes. researchgate.net While effective in macrophages and PBMCs, studies have indicated that this compound may have reduced inhibitory activity in astrocytes compared to macrophages and PBMCs in vitro. plos.orgplos.org

Concentration-Dependent Antiviral Effects

The antiviral effect of this compound is concentration-dependent. In vitro studies assessing the concentration of this compound necessary to inhibit HIV-1 replication by 50% (IC50 or EC50) have shown a range of values depending on the specific cell type and HIV-1 isolate used. fda.govfda.gov For example, EC50 values against laboratory and clinical isolates of HIV-1 in cell culture ranged from 0.009 to 4 µM. fda.govfda.gov The antiviral efficacy is linked to the intracellular concentration of its active metabolite, this compound triphosphate (d4T-TP). nih.govnih.gov Studies have also investigated the interaction of this compound with other antiviral nucleoside analogs, showing synergistic interactions with some compounds like lamivudine (3TC) and additive to antagonistic activity with others like zidovudine. fda.govfda.govasm.org

Viral Load Reduction Studies

Clinical studies have demonstrated that this compound, particularly when used in combination with other antiretroviral agents, can lead to significant decreases in plasma viral load in patients with HIV-1 infection. i-base.infonih.gov Studies have shown that combinations including this compound can reduce viral load, often to undetectable levels. i-base.info In antiretroviral-naive patients, combinations of this compound with other nucleoside analogs like didanosine or lamivudine have been shown to effectively reduce viral loads. nih.gov Studies in surrogate models, such as the Hu-PBL-SCID mouse model, have also shown potent in vivo anti-HIV activity of this compound derivatives, exhibiting dose-dependent effects. asm.orgasm.org

CD4+ T-Lymphocyte Count Dynamics in Response to this compound

Here is a summary of some in vitro antiviral activity data:

Here is a summary of some in vivo virologic and immunologic response data:

Interactions with Other Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

In vitro studies have explored the interactions between this compound and other NRTIs, revealing a range of outcomes from synergy to antagonism. This compound in combination with zidovudine (AZT) has shown additive to antagonistic activity in cell culture. fda.govfda.gov This in vitro antagonism between zidovudine and this compound was also observed in a clinical setting, where HIV-1-infected patients responded better to this compound monotherapy than to the combination of this compound and zidovudine. nih.gov This antagonism is thought to be related to competitive inhibition of intracellular phosphorylation. fda.govnatap.org

Conversely, this compound has exhibited additive to synergistic anti-HIV-1 activity when combined with other NRTIs such as abacavir, didanosine (ddI), tenofovir, or zalcitabine (ddC) in vitro. fda.govfda.gov

Data on the interaction between this compound and other NRTIs is summarized in the table below:

Interactions with Other Antiretroviral Classes

Research has also investigated the interactions of this compound with antiretroviral drugs from other classes, including non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).

In cell culture, nevirapine, an NNRTI, demonstrated additive to synergistic activity against HIV-1 in combination regimens that included this compound and other NRTIs. fda.gov Studies evaluating combinations of tenofovir and emtricitabine with a third agent from major drug classes like NNRTIs or PIs have generally shown additive to synergistic anti-HIV-1 activity in vitro. asm.org While these studies may not have focused specifically on this compound in triple combinations, they suggest that NRTIs, as a class, can exhibit favorable interactions with NNRTIs and PIs.

Specific drug interaction studies with efavirenz and NRTIs other than lamivudine and zidovudine have not always been performed, but clinically significant interactions are not typically expected because NRTIs are metabolized differently than efavirenz, reducing the likelihood of competition for metabolic enzymes and elimination pathways. fda.gov

Combinations involving CCR5 antagonists, a class of entry inhibitors, have also been studied. For instance, a novel CCR5 antagonist, TAK-220, showed interactions ranging from low-level antagonism at low inhibitory concentrations to synergy at higher inhibitory concentrations when combined with reverse transcriptase and protease inhibitors. asm.org Another CCR5 antagonist, SCH-C, demonstrated strong synergy with representative drugs from all classes of currently used antiretroviral agents, including NRTIs. nih.gov

While comprehensive data specifically detailing this compound's interactions with every drug in other antiretroviral classes is extensive and varied, the general trend in vitro studies suggests that combinations of NRTIs with NNRTIs, PIs, and entry inhibitors can result in additive to synergistic antiviral effects. fda.govasm.orgasm.orgnih.gov

Zidovudine-Resistance Associated Mutations (e.g., M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) and Cross-Resistance to this compound

A key group of mutations associated with resistance to thymidine analogs, including both zidovudine (AZT) and this compound (d4T), are known as Thymidine Analogue Mutations (TAMs) plos.orgnih.govasm.org. These mutations include M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E nih.govasm.orgiasusa.org. TAMs are selected for during treatment with either zidovudine or this compound plos.orgnih.govasm.orgiasusa.org.

TAMs confer cross-resistance to this compound and a varying degree of cross-resistance to most other NRTIs stanford.edunih.govtandfonline.comasm.orgiasusa.org. The mechanism by which TAMs mediate resistance involves enhancing the ATP-dependent phosphorolytic removal of the incorporated nucleoside analog from the 3' end of the viral DNA primer, effectively "unblocking" the primer and allowing DNA synthesis to continue nih.govtandfonline.comasm.org.

Two main pathways for the accumulation of TAMs have been described:

TAM-1 pathway: Typically involves mutations at positions M41L, L210W, and T215Y plos.orgnih.govasm.orgiasusa.org.

TAM-2 pathway: Typically involves mutations at positions D67N, K70R, T215F, and K219Q/E plos.orgnih.govasm.orgiasusa.org.

The accumulation of multiple TAMs generally leads to increasing levels of resistance to this compound and other NRTIs tandfonline.comiasusa.orgiasusa.org. Prior exposure to zidovudine and the presence of TAMs, especially at codon 215 (T215Y/F), have been shown to negatively impact the virological response to subsequent this compound-containing regimens stanford.edu.

Multi-Nucleoside Resistance Associated Mutations (e.g., Q151M)

Another important mutation associated with resistance to this compound, particularly in the context of multi-nucleoside resistance, is Q151M nih.govasm.orgplos.org. The Q151M mutation is often considered a marker for a broader multi-nucleoside resistance profile asm.org. This resistance pattern frequently involves the accumulation of the Q151M mutation along with other specific mutations, including A62V, V75I, F77L, and F116Y, forming the Q151M complex nih.govasm.orgstanford.educsic.es.

The Q151M complex confers high-level resistance to a range of NRTIs, including zidovudine, didanosine, zalcitabine, and this compound nih.govasm.orgstanford.educsic.es. While the full complex leads to high-level resistance, the Q151M mutation alone can confer low-level resistance to these drugs asm.org. Unlike the TAM-mediated resistance which involves phosphorolytic removal, the mechanism of resistance conferred by Q151M appears to be related to reduced binding of the NRTI triphosphate to the reverse transcriptase enzyme, independent of ATP asm.org. The Q151M mutation has been specifically associated with this compound use in some clinical settings plos.org. Importantly, viruses with the Q151M mutation generally retain susceptibility to tenofovir plos.orgiasusa.orgnih.govplos.orgstanford.edu.

Cellular Uptake Mechanisms

The parent compound, this compound, enters cells, including peripheral blood mononuclear cells, via passive diffusion. oncohemakey.com Research involving liposomes has explored methods to enhance the cellular uptake of this compound, particularly in macrophages. Studies with liposomes containing dipalmitoyl phosphatidylcholine (DPPC) showed maximal this compound uptake. researchgate.net The presence of sphingomyelin decreased uptake, while a negative charge on the liposome bilayer enhanced it compared to a positive charge. researchgate.net Polysaccharide coatings on lipid nanoparticles have also been investigated as a means to improve cellular uptake, potentially through specific receptors involved in tissue addressing and transport mechanisms. omicsonline.org

Pathways of Intracellular Phosphorylation to this compound Triphosphate

This compound is a prodrug that requires intracellular phosphorylation by cellular kinases to become the active metabolite, this compound triphosphate (d4T-TP). patsnap.comdrugbank.comoncohemakey.comwikipedia.orgfda.govontosight.aipatsnap.com This sequential phosphorylation involves the enzymes thymidine kinase, thymidylate kinase, and nucleoside diphosphate kinase. researchgate.netresearchgate.net The initial phosphorylation step, catalyzed by thymidine kinase, appears to be the rate-limiting step in the activation of this compound. oncohemakey.com Unlike zidovudine, this compound does not result in the accumulation of the monophosphate form. oncohemakey.com The mono-, di-, and triphosphate forms of this compound are present in an approximately 1:1:1 ratio intracellularly, and increasing the extracellular concentration of this compound leads to proportional increases in the intracellular concentration of the active triphosphate form. oncohemakey.com this compound triphosphate inhibits HIV-1 reverse transcriptase by competing with the natural substrate, thymidine triphosphate, and by causing DNA chain termination due to the absence of a 3'-hydroxyl group necessary for DNA elongation. patsnap.comdrugbank.comoncohemakey.comwikipedia.orgfda.govontosight.aipatsnap.comeuropa.eunih.govmims.com this compound triphosphate also inhibits cellular DNA polymerases β and γ, which can lead to a reduction in mitochondrial DNA synthesis. fda.govpatsnap.comnih.gov

The intracellular half-life of this compound triphosphate has been reported as approximately 3.5 hours in CEM T-cells and peripheral blood mononuclear cells. europa.eu

Glucuronidation Pathways

Glucuronidation is one of the metabolic pathways identified for this compound. wikipedia.orgontosight.ai This process involves the conjugation of this compound or its oxidized metabolite with glucuronic acid, forming glucuronide conjugates. ontosight.aieuropa.eueuropa.euvulcanchem.comcymitquimica.com Enzymes of the UDP-glucuronosyltransferase (UGT) family are involved in this phase II metabolism of this compound. researchgate.netresearchgate.net Glucuronidation typically increases the water solubility of compounds, facilitating their excretion. wikipedia.org

Inhibition of DNA Polymerase Gamma Leading to Mitochondrial DNA Depletion

Mitochondrial DNA is replicated by DNA polymerase gamma (Pol γ), an enzyme encoded by the nuclear gene POLG. oup.com this compound, after being anabolized to its active triphosphate form (d4TTP), acts as a potent inhibitor and alternative substrate for Pol γ. nih.govnih.govasm.org This competitive inhibition and incorporation into the growing mtDNA chain by d4TTP leads to premature chain termination and a significant reduction in mtDNA copy number within cells. oup.comoup.comnatap.org

Studies have shown that this compound can induce a higher degree of mtDNA depletion compared to other NRTIs like zidovudine and abacavir. natap.org This depletion of mtDNA is a key factor in the pathogenesis of this compound-associated mitochondrial toxicity. natap.org

Data from studies comparing mtDNA levels in different tissues of patients on NRTI therapy highlight the impact of this compound. For instance, one study observed that NRTI treatment was associated with a significant reduction in adipocyte mtDNA copies per cell, with individuals receiving this compound showing a mean mtDNA depletion of 87.1% compared to 52.1% in those receiving zidovudine. natap.org

Cellular and Tissue-Specific Mitochondrial Impairment

The consequences of mtDNA depletion and Pol γ inhibition by this compound manifest as impaired mitochondrial function, affecting various tissues and cell types to different extents. oup.commdpi.com Tissues with high energy demands, such as muscle, liver, and adipose tissue, appear particularly vulnerable to this compound-induced mitochondrial toxicity. oup.comnatap.orgmdpi.com

Mitochondrial dysfunction can lead to a decrease in the activity of the electron transport chain (ETC), which is crucial for oxidative phosphorylation and ATP production. mdpi.com This energy deficiency can contribute to the observed clinical toxicities. Studies have shown impaired mitochondrial enzyme activities, such as complex I, in patients with this compound-associated lipoatrophy. natap.org

Research in different cell types, including adipocytes and hepatocytes, has demonstrated this compound's ability to induce mitochondrial dysfunction. nih.govnih.govnih.gov While severe mtDNA depletion has been observed in both white and brown adipocytes exposed to this compound, the specific mechanisms of toxicity can vary depending on the cell type. nih.gov Some studies suggest that this compound might also affect mitochondrial function through mechanisms independent of mtDNA depletion, such as altering fatty acid oxidation enzymes or cofactors. nih.govnih.govresearchgate.net

Genetic Predisposition to Mitochondrial Toxicity (e.g., DNA Polymerase Gamma Mutations like R964C)

Genetic factors can influence an individual's susceptibility to this compound-induced mitochondrial toxicity. Variations in the nuclear gene encoding DNA polymerase gamma (POLG) have been implicated in predisposing patients to adverse events. oup.comfrontiersin.org

A specific mutation in POLG, resulting in an arginine to cysteine substitution at codon 964 (R964C), has been linked to increased susceptibility to this compound-mediated mitochondrial toxicity and severe lactic acidosis. oup.comnih.govnih.govasm.org Studies utilizing pre-steady-state kinetics have shown that the R964C mutation in Pol γ leads to a decreased efficiency in incorporating the natural substrate (dTTP) and a reduced ability to discriminate against the incorporation of this compound's active metabolite (d4TTP). nih.govnih.govasm.org This altered discrimination increases the likelihood of d4TTP incorporation into mtDNA, exacerbating the mtDNA depletion and subsequent mitochondrial dysfunction. nih.govnih.govasm.org

Research on lymphoblastoid cell lines harboring the R964C mutation has demonstrated significantly reduced mtDNA levels when cultured with this compound compared to cell lines with wild-type Pol γ. oup.com This provides a mechanistic basis for the observed genetic predisposition to this compound toxicity in individuals carrying this mutation. nih.govnih.govasm.org

Mitochondrial Dysfunction in Hepatocytes

Hepatocytes, the primary cells of the liver, are rich in mitochondria and highly dependent on their function for various metabolic processes, including energy production and lipid metabolism. mdpi.commedcraveonline.com this compound-induced mitochondrial toxicity in hepatocytes plays a central role in the development of hepatic steatosis and lactic acidosis. natap.orgacpjournals.orgnih.govjwatch.org

The inhibition of Pol γ and subsequent mtDNA depletion in hepatocytes impair the function of the mitochondrial respiratory chain, which is essential for oxidative phosphorylation. mdpi.com This leads to decreased ATP production and can disrupt cellular energy homeostasis. mdpi.com

Studies have shown that this compound can cause mtDNA depletion in cultured hepatocytes. nih.gov Liver biopsies from patients treated with this compound have also revealed decreased hepatic mtDNA content. nih.gov This mitochondrial impairment in hepatocytes contributes to the metabolic derangements observed in lactic acidosis and hepatic steatosis. natap.orgmdpi.comjwatch.org

Impairment of Lactic Acid and Fatty Acid Metabolism

Mitochondrial dysfunction in hepatocytes directly impacts the metabolism of both lactic acid and fatty acids. Under normal conditions, the mitochondria are involved in the clearance of lactate through the Cori cycle and the efficient oxidation of fatty acids to produce energy. mdpi.comjwatch.org

Impaired mitochondrial function due to this compound toxicity can lead to a reduced capacity of hepatocytes to metabolize lactic acid. natap.orgmdpi.comjwatch.org This can result in the accumulation of lactate in the bloodstream, leading to hyperlactatemia and, in severe cases, lactic acidosis. europa.eunatap.orgacpjournals.orgnih.govjwatch.org

Furthermore, mitochondrial dysfunction impairs fatty acid oxidation (FAO), a process primarily carried out in the mitochondria to break down fatty acids for energy. mdpi.comnih.govmdpi.com When FAO is inhibited, there is an increased esterification of fatty acids into triglycerides, leading to the accumulation of fat droplets within hepatocytes, a condition known as hepatic steatosis. mdpi.comnih.govmdpi.com While mtDNA depletion is considered a primary mechanism for impaired FAO and steatosis, some research suggests that high concentrations of this compound might directly inhibit FAO in hepatocytes without necessarily causing mtDNA depletion. nih.govnih.govresearchgate.net This highlights the complexity of this compound's effects on hepatic lipid metabolism.

The combination of impaired lactate clearance and reduced fatty acid oxidation due to mitochondrial dysfunction in hepatocytes contributes significantly to the pathogenesis of lactic acidosis and hepatic steatosis observed in patients treated with this compound. natap.orgmdpi.comjwatch.org

Association with Severe Hepatomegaly

Severe hepatomegaly, often accompanied by hepatic steatosis (fatty liver), is a serious adverse event reported with the use of nucleoside analogues, including this compound. europa.eufda.gov Cases of lactic acidosis, sometimes fatal, have been reported in less than 1% of patients taking this compound in combination with other antiretrovirals, and this is usually associated with severe hepatomegaly and hepatic steatosis. europa.eu this compound can cause a dangerous enlargement of the liver accompanied by the buildup of fat in liver cells. patsnap.com The exact mechanisms leading specifically to severe hepatomegaly with this compound are intertwined with the broader picture of mitochondrial toxicity and lactic acidosis. Treatment with this compound should be discontinued if there is progressive hepatomegaly or rapidly elevating aminotransferase levels. europa.eu Caution is advised when administering this compound to patients with pre-existing hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis. europa.eu

Mitochondrial Toxicity in Adipocytes

A primary mechanism underlying this compound-associated lipoatrophy is mitochondrial toxicity. europa.euaidsmap.comhiv.gov this compound, like other NRTIs, can inhibit mitochondrial DNA polymerase gamma, an enzyme crucial for mitochondrial DNA (mtDNA) replication. hiv.govoup.comnih.gov This inhibition leads to the depletion of mtDNA in various tissues, including adipocytes (fat cells). hiv.govoup.comnatap.org Research has shown that the loss of fat may be caused when mitochondria are damaged or decline in number as a result of older medications like this compound. aidsmap.com Studies in adipocytes have demonstrated that this compound induces severe mitochondrial DNA depletion. nih.gov This mitochondrial dysfunction in adipocytes results in decreased lipogenesis (fat production) and an increase in lipoapoptotic mediators, contributing to the loss of subcutaneous fat. nih.gov

Genetic Markers Associated with Lipoatrophy (e.g., HLA-B*4001)

Genetic factors can influence an individual's susceptibility to this compound-associated lipodystrophy. The human leukocyte antigen (HLA) allele HLA-B4001 has been identified as a strong genetic risk factor for this compound-associated lipodystrophy in HIV-infected patients. oup.comnih.govoup.comnih.gov Studies have shown a significant association between the presence of HLA-B4001 and the development of moderate to severe lipodystrophy in patients receiving this compound. oup.com This genetic factor appears to be a stronger predictor than the duration of this compound treatment in some populations. oup.comnih.gov HLA-B*4001 has demonstrated high specificity and a positive predictive value for lipodystrophy. nih.govoup.comnih.gov

Genetic Association Data for HLA-B*4001 and this compound-Associated Lipodystrophy

Note: Data primarily from a study in Thailand. oup.comnih.govoup.com

Mitochondrial Impairment in Axons and Schwann Cells

Mitochondrial toxicity is considered a potential underlying mechanism for the polyneuropathy associated with this compound therapy. europa.eueuropa.eu this compound's ability to inhibit mitochondrial DNA polymerase gamma can lead to mitochondrial dysfunction in nerve cells, including axons and Schwann cells. hiv.govnih.gov Damage to the mitochondria caused by NRTIs like this compound can lead to symptoms such as damage to the peripheral nerves. aidsmap.com Studies have shown morphological changes in mitochondria, including lack of crista definition and homogenized matrix, in myelinated axons, unmyelinated axons, and Schwann's cells in cases of nucleoside analog-associated neuromyopathy, suggesting mitochondrial dysfunction as a common cause. bmj.combmj.com The pathophysiology of HIV-associated sensory neuropathy in patients on this compound may involve damage to the mitochondria of neurons and axons via damage to mitochondrial DNA. researchgate.net

Dose-Related Mechanisms and Advanced HIV Disease Association

The incidence and severity of some this compound-associated toxicities, particularly peripheral neuropathy and lipodystrophy (specifically lipoatrophy), are dose-related. hiv.govwikipedia.orgplos.org Studies have shown that patients receiving higher doses of this compound (e.g., 40 mg twice daily) experience higher rates of toxicity and a shorter time to toxicity diagnosis compared to those receiving lower doses (e.g., 30 mg twice daily). plos.org

Advanced HIV disease is also associated with an increased frequency of peripheral neuropathy in patients treated with this compound. hiv.govwikipedia.orgfda.govfda.gov This suggests that the underlying health status and immune compromise in advanced disease may contribute to the susceptibility to this compound-induced nerve damage.

Resolution of Symptoms with Prompt Discontinuation

Prompt discontinuation of this compound therapy upon the development of symptoms can lead to the resolution or improvement of certain adverse effects, such as peripheral neuropathy and lipodystrophy. hiv.govwikipedia.orgfda.goveuropa.eu For peripheral neuropathy, symptoms may resolve after dose reduction or interruption of the drug. europa.eu In some cases of lipodystrophy, improvements or resolution have been reported after discontinuing this compound. hiv.govhiv.gov However, it's important to note that in some instances, symptoms, particularly motor weakness associated with lactic acidosis, may continue or worsen even after discontinuation. fda.govfda.govdrugs.com

Elevated Liver Enzymes and Transaminases

Elevations in liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are observed in patients taking this compound. nih.govdrugs.comajronline.org Mild and transient elevations can occur in a significant proportion of patients, while more pronounced elevations (above 5 times the upper limit of normal) are less common but still reported. nih.gov this compound's effects on mitochondrial toxicity are considered partially responsible for these elevated liver enzyme levels. omicsonline.org

Hepatitis and Liver Failure Pathophysiology

This compound can lead to severe hepatic adverse events, including hepatitis and liver failure, which can be fatal. fda.goveuropa.eu The pathophysiology involves mitochondrial injury in hepatocytes, leading to impaired metabolism of lactic acid and free fatty acids, as well as compromised hepatic synthetic and excretory functions. nih.gov Liver histology in the early stages often shows marked microvesicular steatosis (fat accumulation) with minimal hepatocyte injury. nih.gov As the injury progresses, cholestasis may develop, and the fatty change can evolve into a macrovesicular pattern. nih.gov Late-stage changes may include ballooning cell degeneration, Mallory bodies, and fibrosis. nih.gov

Risk Factors for Hepatic Decompensation (e.g., Co-infection with Hepatitis B or C)

Several risk factors increase the likelihood of hepatic decompensation and severe liver injury in patients receiving this compound. Preexisting liver dysfunction, including chronic active hepatitis, is a significant risk factor. fda.govfda.gov Co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) substantially increases the risk of liver injury and hepatic decompensation in HIV-infected patients on antiretroviral therapy, including this compound. nih.govomicsonline.orgnih.govmedscape.comoup.comscirp.org These co-infections can accelerate liver injury progression. omicsonline.org Other factors associated with increased risk include female sex, older age, obesity, alcohol use, and concurrent therapy with other potentially hepatotoxic drugs, such as didanosine, ribavirin, and tenofovir. nih.govfda.govpediatriconcall.com

In Vitro Genotoxic Effects (e.g., in human lymphocytes, mouse fibroblasts)

In vitro studies have shown this compound to produce positive results in assays assessing clastogenesis and cell transformation. This compound elevated the frequency of chromosome aberrations in human lymphocytes at concentrations ranging from 25 to 250 µg/mL, without metabolic activation. fda.govnih.govfda.gov It also increased the frequency of transformed foci in mouse fibroblast cells at concentrations from 25 to 2500 µg/mL, both with and without metabolic activation. fda.govnih.govfda.gov Oxidative stress mediated DNA damage has been suggested as a mechanism for its mutagenic and clastogenic effects in human lymphocytes and mouse fibroblast cells. cabidigitallibrary.org

In Vivo Genotoxic Effects (e.g., chromosomal aberrations)

In addition to in vitro findings, this compound has demonstrated genotoxic effects in vivo. It produced positive results in the in vivo mouse micronucleus test, indicating it is clastogenic. fda.govnih.govfda.gov Clastogenicity refers to the induction of structural chromosomal aberrations. who.int Studies have shown that this compound, like other NRTIs, can induce chromosomal aberrations in vivo. researchgate.net

Carcinogenicity in Animal Models (e.g., liver tumors, urinary bladder tumors)

Carcinogenicity studies in animal models have investigated the potential of this compound to cause tumors. In 2-year carcinogenicity studies in mice and rats, this compound was not found to be carcinogenic at doses producing exposures significantly higher than human exposure at the recommended clinical dose. fda.gov However, benign and malignant liver tumors in mice and rats, as well as malignant urinary bladder tumors in male rats, were observed at much higher exposure levels. fda.gov Carcinogenesis can occur through various mechanisms, including DNA damage and chronic inflammation. mdpi.comoaepublish.com Animal models, particularly rodents, are commonly used to study chemical carcinogenesis, including bladder cancer induced by various compounds. oaepublish.comnih.gov

Genomic Instability and Mutation Rates

The incorporation of NRTIs into nuclear DNA is proposed to result in genotoxic and mutagenic effects, including the induction of genomic instability and increased mutation rates. researchgate.net Compromised integrity of both nuclear and mitochondrial DNA is linked to genomic instability. researchgate.net While some studies focus on mutation rates in pathogens like Mycobacterium tuberculosis or the impact of viral proteins on mutation rates oup.comunipd.it, the mechanism by which this compound directly influences host genomic instability and mutation rates involves its incorporation into host DNA due to its structural similarity to natural nucleosides. fda.govresearchgate.net

Myopathy

Myopathy, or muscle weakness and pain, is a known adverse effect associated with this compound use, similar to other NRTIs like zidovudine. mdpi.com The mechanism underlying this compound-induced myopathy is strongly linked to mitochondrial toxicity. nih.govwww.gov.uk this compound triphosphate inhibits cellular DNA polymerases, including DNA polymerase gamma (DNA pol γ), which is responsible for the replication of mitochondrial DNA (mtDNA). nih.govfda.gov Inhibition of DNA pol γ leads to depletion or dysfunction of mitochondria, impairing their ability to carry out essential functions like energy production and fatty acid metabolism. nih.govpharmgkb.org This mitochondrial failure in muscle tissue contributes to the development of myopathy. nih.gov Studies on zidovudine, which shares a similar mechanism of mitochondrial toxicity, have shown damage to mitochondria through both short-term effects on the respiratory chain and long-term alterations of mtDNA. nih.gov

Table: Summary of this compound Genotoxicity Findings

Table: Summary of this compound Carcinogenicity Findings in Animal Models

Immune Reconstitution Inflammatory Syndrome (IRIS) Mechanisms

Immune Reconstitution Inflammatory Syndrome (IRIS) is a paradoxical clinical worsening that occurs in some HIV-infected patients after initiating effective antiretroviral therapy, including regimens containing this compound. wikipedia.orgsketchfab.commims.comguidetoimmunopharmacology.orgnih.gov This phenomenon is attributed to the recovery of the immune system, particularly the increase in CD4+ T cell counts, which mounts an inflammatory response to pre-existing opportunistic infections or antigens that were present before the initiation of HAART. wikipedia.orgmims.comguidetoimmunopharmacology.orgnih.govmims.com

The exact mechanisms driving IRIS are not yet fully understood, but several hypotheses exist. One central concept is that the restored immune system, previously suppressed by HIV, begins to recognize and react vigorously to pathogens or microbial antigens that were present at subclinical levels or were poorly contained during the period of immunodeficiency. wikipedia.orgnih.govmims.com This leads to an exaggerated inflammatory response at the site of the infection or antigen presence.

Key factors contributing to the development of IRIS include a low baseline CD4+ T cell count and a high viral load before starting HAART, as well as a rapid increase in CD4+ T cell counts and a significant drop in viral load after therapy initiation. wikipedia.org The rapid proliferation and activation of CD4+ T cells, particularly memory cells, upon viral suppression are thought to play a significant role. wikipedia.orgguidetoimmunopharmacology.org

While IRIS can be triggered by various opportunistic pathogens, including mycobacteria (such as Mycobacterium tuberculosis and Mycobacterium avium complex), viruses (like cytomegalovirus and varicella zoster virus), fungi (Cryptococcus neoformans), and protozoa, the underlying mechanism involves a dysregulation of the immune response. nih.gov This dysregulation may involve an imbalance between pro-inflammatory and anti-inflammatory cytokines. wikipedia.org Some research suggests that hyper-responsiveness of the innate immune system to T cell help might also contribute to the inflammatory cascade observed in IRIS. mims.com

This compound, as a component of HAART that effectively reduces viral load and allows for immune recovery, can therefore be associated with the development of IRIS in susceptible individuals, similar to other antiretroviral drugs that lead to robust immune reconstitution. wikipedia.orgsketchfab.commims.comguidetoimmunopharmacology.org The occurrence of IRIS highlights the complex interplay between viral suppression, immune recovery, and the host's response to residual or unmasked pathogens.

Bone Marrow Suppression (less common than zidovudine)

Bone marrow suppression, characterized by a decrease in the production of blood cells, is a known adverse effect of some NRTIs. While this compound can cause hematological abnormalities, it is generally considered less myelosuppressive compared to zidovudine. uni.lumims.com

The mechanism of bone marrow suppression by NRTIs like this compound and zidovudine is linked to their interference with cellular DNA polymerases, particularly mitochondrial DNA polymerase gamma (DNA pol γ). mims.comwikipedia.orgwikidata.orguni.lu DNA pol γ is essential for the replication of mitochondrial DNA (mtDNA). Inhibition of this enzyme can lead to mtDNA depletion and mitochondrial dysfunction in various tissues, including bone marrow progenitor cells. mims.comwikipedia.orgwikidata.org

However, the differential myelosuppression between this compound and zidovudine is not solely explained by mitochondrial toxicity, as both drugs can affect mitochondrial function. A key distinction lies in their impact on nuclear DNA synthesis in bone marrow cells. Studies have shown that this compound is incorporated into nuclear DNA of bone marrow cells at significantly lower levels (50- to 100-fold less) compared to zidovudine when cells are exposed to similar drug concentrations. mims.com This lower incorporation into nuclear DNA in hematopoietic precursor cells is a proposed mechanism for the reduced myelotoxicity of this compound relative to zidovudine. mims.com

Zidovudine's myelosuppressive effects, particularly anemia and neutropenia, are thought to involve the suppression of erythropoiesis and inhibition of erythroid stem cells, in addition to mitochondrial toxicity. nih.govnih.gov While this compound can also cause mitochondrial toxicity leading to other adverse effects like peripheral neuropathy and lactic acidosis, its lesser impact on bone marrow appears to be related to this reduced interference with nuclear DNA synthesis in these rapidly dividing cells compared to zidovudine. mims.commims.comwikipedia.orgwikidata.orguni.lu

The relative myelosuppression of this compound compared to zidovudine is a significant clinical difference that influenced treatment decisions, particularly in patients with pre-existing hematological issues or those receiving concomitant medications that could exacerbate myelosuppression. wikipedia.org