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Drugs 2002Stavudine administered once daily is a nucleoside analogue reverse transcriptase inhibitor. The efficacy (reduction in viral load and increase in CD4+ lymphocyte counts... (Review)
Review
Stavudine administered once daily is a nucleoside analogue reverse transcriptase inhibitor. The efficacy (reduction in viral load and increase in CD4+ lymphocyte counts from baseline) of stavudine once daily-containing triple therapy was similar to that of stavudine immediate release (IR)-containing triple therapy in the treatment of antiretroviral-naive patients with HIV infection in two 48-week, randomised, double-blind trials. In the largest trial (n = 783), 80% of patients receiving stavudine 75 or 100mg once daily in combination with lamivudine 150mg twice daily and efavirenz 600mg once daily, and 75% of patients receiving stavudine IR 30 or 40mg twice daily-containing combination therapy, had HIV RNA levels reduced to below the limit of quantification at 48 weeks (<400 copies/ml; intent-to-treat analysis). These findings are supported by those from the smaller trial in 150 patients. Stavudine once daily triple therapy was well tolerated, with the incidence of adverse events being similar to that with stavudine IR. Grades 2-4 treatment related adverse events occurring in > or =3% of patients in either group were dizziness, rash, abnormal dream, headache, insomnia, fatigue and peripheral neurological symptoms. Peripheral neurological symptoms occurred in 3% of patients receiving long-term treatment with stavudine once daily and 6% of patients receiving stavudine IR in a combined analysis.
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine
PubMed: 12466009
DOI: 10.2165/00003495-200262180-00013 -
Drugs Nov 1999Stavudine is a thymidine nucleoside analogue which is phosphorylated intracellularly to an active metabolite, stavudine 5'-triphosphate. This metabolite inhibits HIV... (Review)
Review
UNLABELLED
Stavudine is a thymidine nucleoside analogue which is phosphorylated intracellularly to an active metabolite, stavudine 5'-triphosphate. This metabolite inhibits HIV replication, either by competing with thymidine 5'-triphosphate for incorporation into viral DNA by reverse transcriptase or by causing premature termination of the viral chain after incorporation. Resistance to stavudine, either alone or as part of resistance to multiple nucleoside reverse transcriptase inhibitors, has been reported; however, high-level resistance is uncommon even after long periods of treatment. Initial treatment with stavudine-containing triple therapies reduced HIV RNA levels to below the limit of detection (LOD; 500 copies/ml) in 68 to 100% of antiretroviral-naive patients after at least 20 weeks of treatment. Effects on clinical outcomes have not yet been established, although earlier trials showed significant improvements with stavudine (alone or with 1 other drug) in patients who had previously received zidovudine. Results from 2 randomised nonblind clinical trials indicated that the efficacy of stavudine-containing triple therapy was similar to that of zidovudine-containing triple therapy (when used in combination with the same drugs), although there were no statistical comparisons. Improvements in surrogate end-points have also been seen in trials in antiretroviral-experienced patients receiving stavudine and 2 or 3 other antiretroviral agents. Stavudine-containing combination therapies have also been effective in reducing viral load and increasing CD4+ lymphocyte count in children, although data are limited. Like other nucleoside analogues, stavudine treatment can cause mitochondrial toxicity. The major adverse effect from this observed with stavudine therapy is peripheral neuropathy, which is both dosage- and treatment duration-dependent. Most cases respond to short term cessation of treatment and reintroduction of stavudine at half the previous dosage.
CONCLUSION
Stavudine-containing triple therapies are effective in the treatment of antiretroviral-naive adults with HIV infection as assessed by surrogate end-points; earlier trials involving 1 or 2-drug therapy showed that stavudine can significantly improve clinical end-points. Stavudine has also been beneficial as part of combination regimens in antiretroviral-experienced patients and children with HIV infection, although data are limited and more studies are needed. High-level resistance to stavudine is uncommon. The major adverse event associated with treatment is peripheral neuropathy, which may limit its use in some patients. Currently, stavudine has a valuable role as part of initial triple therapy in antiretroviral-naive adults with HIV/AIDS.
Topics: Anti-HIV Agents; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; Humans; Randomized Controlled Trials as Topic; Stavudine
PubMed: 10595868
DOI: 10.2165/00003495-199958050-00012 -
Acta Crystallographica. Section C,... Dec 2005The crystal structure of the title compound (systematic name: 2',3'-didehydro-2',3'-deoxythymidine), C10H12N2O4, consists of two molecules in the asymmetric unit bound...
The crystal structure of the title compound (systematic name: 2',3'-didehydro-2',3'-deoxythymidine), C10H12N2O4, consists of two molecules in the asymmetric unit bound together by hydrogen bonds. The conformational geometry differentiates this form of stavudine from its two previously published polymorphs. In addition, a different hydrogen-bonding scheme is observed compared with the previous two structures. This polymorph is the thermodynamically most stable form of the antiviral drug, as evidenced by differential scanning calorimetry (DSC) and IR data.
Topics: Anti-HIV Agents; Crystallography, X-Ray; Drug Stability; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Stavudine; Thermodynamics
PubMed: 16330850
DOI: 10.1107/S0108270105034591 -
Drugs May 1996Stavudine is a nucleoside analogue which undergoes intracellular phosphorylation to its active metabolite, stavudine-5'-triphosphate. At clinically relevant... (Review)
Review
Stavudine is a nucleoside analogue which undergoes intracellular phosphorylation to its active metabolite, stavudine-5'-triphosphate. At clinically relevant concentrations, the active metabolite restricts HIV replication by inhibiting the inclusion of thymidine-5'-triphosphate into proviral DNA by HIV reverse transcriptase, and/or by causing DNA chain termination. Viral resistance to stavudine does not commonly develop during treatment. Where it has developed, up to a 12-fold increase in resistance has been observed in clinical isolates from patients treated with stavudine for long periods. Stavudine 40mg twice daily and zidovudine 200mg 3 times daily were compared in 822 patients at various stages of HIV infection who had previously received long term zidovudine therapy. Stavudine was superior for both primary and surrogate end-points including clinical progression, treatment failure, increase in CD4+ cell counts and bodyweight gain. In a larger study, stavudine 40mg twice daily provided greater benefit than stavudine 20mg twice daily in terms of weight gain, haematological findings and the number of hospitalisations in 11 784 patients intolerant of or resistant to, zidovudine and didanosine. Peripheral neuropathy is the major dose-limiting adverse event associated with stavudine therapy and occurred more frequently with stavudine than zidovudine. However, haematological adverse events were observed less frequently with stavudine than with zidovudine. Thus, stavudine is effective in alleviating signs and symptoms of HIV infection in patients intolerant of or no longer responding to, zidovudine or didanosine. It is also more effective than zidovudine in slowing disease progression in patients previously treated with zidovudine for long periods. The results of studies which will reveal the role of stavudine therapy in untreated patients and in combination with other anti-HIV agents are awaited with interest.
Topics: Animals; Anti-HIV Agents; HIV Infections; Humans; Stavudine
PubMed: 8861550
DOI: 10.2165/00003495-199651050-00009 -
Clinical Pharmacokinetics Oct 1997Stavudine (d4T) is a pyrimidine nucleoside analogue used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase as do... (Review)
Review
Stavudine (d4T) is a pyrimidine nucleoside analogue used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase as do zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) and lamivudine (3TC), which comprise the family of nucleoside HIV-reverse transcriptase inhibitors. Stavudine is currently approved by the US Food and Drug Administration for the treatment of patients who have become intolerant to or have failed to response to zidovudine, didanosine or zalcitabine therapy. Oral administration of stavudine results in maximal concentrations within 2 hours and increases linearly as doses increase. The absolute oral bioavailability is high, approaching 100%. There is evidence to suggest that stavudine does not accumulate in the plasma. It distributes into total body water and appears to enter cells by non-facilitated diffusion. Penetration into the cerebrospinal fluid occurs, as does the transfer of the drug across human placental tissue. Stavudine is cleared quickly by both renal and nonrenal processes. The pharmacokinetic properties of stavudine in children are similar to those of adults. The pharmacokinetic parameters of stavudine were not affected by simultaneous administration of didanosine. It appears that stavudine at doses < 2 mg/kg/day is most efficient at increasing CD4 + cell numbers. While stavudine is reported to be less cytotoxic than zidovudine, the principal toxicity in humans is peripheral neuropathy and appears to be related to daily, but not cumulative, doses.
Topics: Adult; Anti-HIV Agents; Child; HIV Infections; Humans; Infant; Peripheral Nervous System Diseases; Reverse Transcriptase Inhibitors; Stavudine
PubMed: 9342503
DOI: 10.2165/00003088-199733040-00003 -
The Journal of Organic Chemistry Oct 2021Herein, we demonstrate an elegant multistep continuous flow synthesis for stavudine (d4T), a potent nucleoside chemotherapeutic agent for human immunodeficiency virus,...
Herein, we demonstrate an elegant multistep continuous flow synthesis for stavudine (d4T), a potent nucleoside chemotherapeutic agent for human immunodeficiency virus, acquired immunodeficiency syndrome (AIDS) and AIDS-related conditions. This was accomplished via six chemical transformations in five sequential continuous flow reactors from an affordable starting material, 5-methyluridine. In the first instance, single step continuous flow synthesis was demonstrated with an average of 97% yield, 21.4 g/h throughput per step, and a total of 15.5 min residence time. Finally, multistep continuous flow synthesis of d4T in 87% total yield with a total residence time of 19.9 min and 117 mg/h throughput without intermediate purification was demonstrated.
Topics: Humans; Stavudine
PubMed: 34060836
DOI: 10.1021/acs.joc.1c01013 -
Expert Opinion on Pharmacotherapy Jun 2013Stavudine extended release (d4T XR) was a formulation which tried to solve the two main problems associated with the use of stavudine immediate release (d4T IR). These... (Review)
Review
INTRODUCTION
Stavudine extended release (d4T XR) was a formulation which tried to solve the two main problems associated with the use of stavudine immediate release (d4T IR). These were twice daily dosing schema at a time when most formulations were long-life allowing once daily dosing; and that the use of d4T IR was associated with long-term toxicity through mitochondrial toxicity clinically expressed as peripheral neuropathy, pancreatitis and above all, lipodystrophy. The link between stavudine exposure and lipodystrophy had a great negative impact on its use in clinical practice.
AREAS COVERED
The authors cover the most relevant papers related to the efficacy and safety of d4T XR-based antiretroviral therapy.
EXPERT OPINION
The development of d4T XR has only been partially successful with regard to its objectives. Improved pharmacokinetic properties allow its once daily dosing, and although it exhibits less mitochondrial toxicity it is still hampered by its development in a significant proportion of patients. This has caused its use to be almost residual in industrialised countries. As of now, d4T XR has not been made available in developing countries, despite the extended use of the immediate-release formulation. Currently, if there is no other chance of starting combination antiretroviral therapy, d4T XR could play a role in the treatment of HIV infection.
Topics: Anti-HIV Agents; Delayed-Action Preparations; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome
PubMed: 23510448
DOI: 10.1517/14656566.2013.782285 -
Advances in Experimental Medicine and... 1996
Review
Topics: Antiviral Agents; Drug Resistance, Microbial; HIV Infections; HIV-1; Humans; Stavudine
PubMed: 8815691
DOI: No ID Found -
The Cochrane Database of Systematic... Jan 2015Stavudine remains a component of combination antiretroviral therapy (ART) in resource-constrained countries due to its relatively low cost despite the WHO recommendation... (Review)
Review
BACKGROUND
Stavudine remains a component of combination antiretroviral therapy (ART) in resource-constrained countries due to its relatively low cost despite the WHO recommendation for its phasing out as a strategy to reduce stavudine associated toxicities. Where stavudine is still in use, it is recommended at a dose lower than the standard dose in order to reduce stavudine related toxicity.
OBJECTIVES
To compare the safety and virologic efficacy of low dose versus high dose stavudine for treating HIV-1 infection.
SEARCH METHODS
The comprehensive search strategy developed by the Cochrane HIV/AIDS Review Group was used to identify randomised controlled trials that compared the use of low dose versus high dose stavudine. The last search was conducted in February 2014 and the searches covered the period 1996 to 2014.
SELECTION CRITERIA
Randomised controlled trials comparing the use of low dose and high dose stavudine as part of ART combination therapy for treating adults.
DATA COLLECTION AND ANALYSIS
Two reviewers independently selected eligible trials, assessed methodological quality of the included studies and completed data extraction and analysis.
MAIN RESULTS
The search identified 3952 abstracts which were scanned for relevance. Three trials met the inclusion criteria (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005). All three trials were conducted in developed countries, participants were ART experienced and all had sustained virologic suppression at baseline. A total of 157 participants were recruited to the trials. Sample sizes ranged from 24 to 92 and more than 79% of participants were male.The studies were at a high risk of selection, performance/detection and selective outcome reporting biases. Some baseline characteristics differed among the groups, including triglyceride levels in two studies and body mass index in one study. In light of variation in the design and follow-up of the study results, no meta-analysis was performed and the results of single studies are presented. There was no significant difference in virologic suppression in the included studies (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005); Risk Ratio (RR) 1.09 (95% CI: 0.93 to 1.28), 0.94 (95% CI:0.59 to 1.50) and 1.03 (95% CI: 0.90 to 1.18) respectively. Symptomatic hyperlactatemia was seen in the high dose arm of the Milinkovic 2007 study; RR 0.21 (95% CI: 0.01 to 4.66), in no participants in the McComsey 2008 trial and not reported on in the Sanchez-Conde 2005 trial. McComsey 2008 and Milinkovic 2007 demonstrated a reduction in bone mineral density (BMD), reduction in limb fat and an increase in triglycerides in the high dose arms. The studies did not indicate that any participants discontinued treatment due to adverse events.
AUTHORS' CONCLUSIONS
This systematic review identified only three small trials that evaluated virologic efficacy and safety of high dose versus low dose stavudine. All three trials were conducted in developed countries and none reported from developing countries yet stavudine remains a component of ART combination therapy in many developing countries. It was not possible to perform a meta-analysis on these trails. Individual results from the trials were imprecise and have not identified a clear advantage in virologic efficacy or safety between low and high dose stavudine. Furthermore, enrolled participants were treatment experienced with sustained virologic suppression and so existing data cannot be generalized to settings where stavudine is currently used in ART naive patients with high viral loads. Stavudine dose reduction trials in ART naive patients, in developing countries where stavudine is still being used are warranted as the phasing out of stavudine that is recommended by WHO may not be immediately universally feasible.
Topics: Anti-HIV Agents; Developing Countries; Female; HIV Infections; HIV-1; Humans; Male; Randomized Controlled Trials as Topic; Stavudine; Viral Load
PubMed: 25627012
DOI: 10.1002/14651858.CD007497.pub2 -
Expert Opinion on Drug Safety May 2008Western randomized trials and prospective cohorts in resource-limited settings have proven virological success with stavudine-based highly active antiretroviral therapy.... (Review)
Review
BACKGROUND
Western randomized trials and prospective cohorts in resource-limited settings have proven virological success with stavudine-based highly active antiretroviral therapy. However, stavudine is no longer recommended in first-line treatments in these two settings due to its intrinsic toxicities and side effects. Yet it remains a cornerstone of treatment in resource-limited settings, due to lack of alternatives and its availability in generic fixed-dose combinations.
OBJECTIVE
To review the toxic effects of stavudine and their prevention and management strategies, especially in resource-limited settings.
METHODS
Data from clinical and pharmacological trials in Western countries, as well as prospective cohorts in resource-limited settings, were reviewed.
CONCLUSION
Initiating or switching to less toxic nucleoside analogues whenever possible, or lowering stavudine doses to 30 mg b.i.d., is strongly recommended.
Topics: Acidosis, Lactic; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Health Resources; Humans; Male; Peripheral Nervous System Diseases; Reverse Transcriptase Inhibitors; Sex Factors; Stavudine
PubMed: 18462186
DOI: 10.1517/14740338.7.3.283