-
The Journal of Antimicrobial... Nov 2008We aimed to compare the steady-state pharmacokinetic parameters and tolerability of Triomune 40 (stavudine 40 mg, lamivudine 150 mg and nevirapine 200 mg) and branded... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
We aimed to compare the steady-state pharmacokinetic parameters and tolerability of Triomune 40 (stavudine 40 mg, lamivudine 150 mg and nevirapine 200 mg) and branded formulations of these drugs in HIV-infected Ugandans.
METHODS
This includes a randomized, open-label, cross-over study of HIV-infected patients stable on therapy for 1 month. Patients were randomized to generic or branded formulation. Plasma pharmacokinetics were assessed after 1 month. The following day, alternate formulation was administered, and 1 month later, drug pharmacokinetics were re-assessed. Plasma pharmacokinetics were determined using HPLC-UV detection. Similarity between steady-state pharmacokinetic parameters was assessed using the US Food and Drug Administration standards for bioequivalency testing. Tolerability was assessed using questionnaires.
RESULTS
Sixteen (10 females) patients completed the study. Median (IQR) age, weight and CD4 count were 37 (33.7-40) years, 65 (63.4-66) kg and 292 (220.7-344.5) cells/mm(3), respectively. All patients received co-trimoxazole. The geometric mean ratio (90% CI) for stavudine, lamivudine and nevirapine was 0.92 (0.78-1.08), 1.11 (0.95-1.30) and 0.84 (0.64-1.11), respectively, for C(max), and 0.83 (0.70-0.97), 1.06 (0.94-1.20) and 0.88 (0.71-1.10), respectively, for AUC. Stavudine plasma concentrations were significantly lower for the generic formulation. Pharmacokinetic parameter inter-individual variability ranged from 29% to 99%. There were no differences in tolerability for the two formulations.
CONCLUSIONS
Pharmacokinetic profiles of generic and branded drugs were similar. Differences particularly with regard to stavudine were demonstrated. Surveillance of the quality of generic antiretroviral drugs in the target populations is needed. Capacity building for pharmacokinetic research in resource-limited settings is a priority.
Topics: Adult; Anti-HIV Agents; Chromatography, High Pressure Liquid; Drugs, Generic; Female; HIV Infections; Humans; Lamivudine; Male; Nevirapine; Plasma; Spectrophotometry, Ultraviolet; Stavudine; Surveys and Questionnaires; Uganda
PubMed: 18641036
DOI: 10.1093/jac/dkn290 -
Clinical Infectious Diseases : An... Feb 2010World Health Organization guidelines for antiretroviral treatment (ART) in resource-limited settings recommend either stavudine or tenofovir as part of initial therapy.... (Comparative Study)
Comparative Study
BACKGROUND
World Health Organization guidelines for antiretroviral treatment (ART) in resource-limited settings recommend either stavudine or tenofovir as part of initial therapy. We evaluated the clinical outcomes and cost-effectiveness of first-line ART using tenofovir in India, compared with current practice using stavudine or zidovudine.
METHODS
We used a state-transition model of human immunodeficiency virus (HIV) disease to examine strategies using different nucleoside reverse-transcriptase inhibitors, combined with lamivudine and nevirapine, compared with no ART: (1) stavudine, (2) stavudine with substitution by zidovudine after 6 months, (3) zidovudine, and (4) tenofovir. Data were from the Y. R. Gaitonde Centre for AIDS Research and Education in Chennai, India, and published studies. Results. Discounted mean per person survival was 36.9 months (40.2 months undiscounted) with no ART, 115.5 months (145.3) with stavudine-containing ART, 115.7 months (145.6) with stavudine and 6-month zidovudine substitution, 115.8 months (145.6) with zidovudine-containing ART, and 125.8 months (162.0) with initial tenofovir. Discounted lifetime medical costs were $610 with no ART and ranged from $5580 with stavudine-containing ART to $5720 with zidovudine-containing ART. Initial tenofovir had an incremental cost-effectiveness ratio of $670 per year of life saved, compared with no ART, and was more economically efficient than the other regimens.
RESULTS
were most sensitive to variations in the costs of first-line tenofovir, access to additional ART after treatment failure, and quality of life adjustment.
CONCLUSIONS
Using tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for initial therapy for HIV-infected patients in India.
Topics: Adenine; Adult; Antifungal Agents; Antiretroviral Therapy, Highly Active; Cost-Benefit Analysis; Female; HIV Infections; Humans; India; Male; Organophosphonates; Stavudine; Survival Analysis; Tenofovir; Treatment Outcome; Zidovudine
PubMed: 20043752
DOI: 10.1086/649884 -
Toxicology Jun 2020Stavudine is an anti-AIDS drug widely used to prevent HIV transmission from pregnant mothers to the fetuses in underdeveloped countries for its low price. However, there...
Stavudine is an anti-AIDS drug widely used to prevent HIV transmission from pregnant mothers to the fetuses in underdeveloped countries for its low price. However, there is still a controversy on whether stavudine affects embryo development. In the current study, embryotoxicity of stavudine was evaluated using cultured mouse embryos with the concentrations: 5, 10, 15 μM and vehicle control. The data indicated that the effect of stavudine was dose-dependent at early neurogenesis. Stavudine exposure reduced somite numbers, yolk sac diameter, crown-rump length, and increased the rate of embryonic degeneration compared with the control. We chose the lowest but clearly toxic concentration: 5 μM to investigate the molecular mechanisms of the damage. At the molecular level, stavudine produced DNA damage, increased the levels of the phospho-CHK1 and cleaved-caspase-3, and decreased the expression level of proliferating cell nuclear antigen. These changes indicated that stavudine caused a coordinated DNA damage response, inhibited cell proliferation, and induced apoptosis in the embryos. Collectively these results suggest that stavudine exposure disturbs the embryonic development, and its use in pregnant mothers should be re-examined.
Topics: Abnormalities, Drug-Induced; Animals; Anti-HIV Agents; Apoptosis; Caspase 3; Cell Count; Cell Proliferation; Checkpoint Kinase 1; DNA Damage; Embryonic Development; Female; Mice; Mice, Inbred C57BL; Neurogenesis; Pregnancy; Proliferating Cell Nuclear Antigen; Stavudine; Yolk Sac
PubMed: 32278789
DOI: 10.1016/j.tox.2020.152443 -
Acta Clinica Croatica Mar 2022The aim of this study was to characterize and compare changes in subcutaneous fat in the malar, brachial and crural region in a cohort of HIV-infected patients taking...
The aim of this study was to characterize and compare changes in subcutaneous fat in the malar, brachial and crural region in a cohort of HIV-infected patients taking antiretroviral therapy. This prospective longitudinal study included 77 patients who were selected from the initial cohort evaluated in 2007 and 2008. We examined reversibility of lipoatrophy measured by ultrasound over at least five-year period and factors related to its reversibility. All 46 patients who used stavudine switched from stavudine to another combination. Of 58 patients on zidovudine, 16 (28%) were on a zidovudine based regimen at the second follow up. There was evidence for subcutaneous fat increase in the malar area (p<0.001) and no increase in the brachial and crural areas. Patients who were smokers and had poor adherence to the Mediterranean diet had a thinner malar area at the follow up measurement (p=0.030) and smaller increase in subcutaneous malar fat compared to others (p=0.040). Our study suggested that modest increase of subcutaneous fat in malar area coincided with stopping stavudine and fewer usage of zidovudine. Lifestyle with non-adherence to the Mediterranean diet and smoking were associated with a smaller increase in subcutaneous malar fat.
Topics: Humans; Stavudine; Zidovudine; HIV-Associated Lipodystrophy Syndrome; Cohort Studies; Prospective Studies; Longitudinal Studies; HIV Infections
PubMed: 36398092
DOI: 10.20471/acc.2022.61.01.02 -
PloS One 2008Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune) or the corresponding brand formulations (Epivir, Zerit, and Viramune).
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC(0-12h) and C(max). Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8-1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C(max), 1.3 (0.99-1.71) and AUC(0-12h), 1.1 (0.87-1.38); lamivudine C(max), 0.8 (0.63-0.98) and AUC(0-12h), 0.8 (0.65-0.99); and nevirapine C(max), 1.1 (0.95-1.23) and AUC(0-12h), 1.1 (0.95-1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.
CONCLUSIONS/SIGNIFICANT FINDINGS
These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical.
Topics: Adult; Anti-HIV Agents; Cross-Over Studies; Drugs, Generic; Drugs, Investigational; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Patient Compliance; Stavudine; Therapeutic Equivalency; Uganda
PubMed: 19096711
DOI: 10.1371/journal.pone.0003981 -
Biomolecules Jun 2021Drugs targeting DNA and RNA in mammalian cells or viruses can also affect bacteria present in the host and thereby induce the bacterial SOS system. This has the...
Drugs targeting DNA and RNA in mammalian cells or viruses can also affect bacteria present in the host and thereby induce the bacterial SOS system. This has the potential to increase mutagenesis and the development of antimicrobial resistance (AMR). Here, we have examined nucleoside analogues (NAs) commonly used in anti-viral and anti-cancer therapies for potential effects on mutagenesis in , using the rifampicin mutagenicity assay. To further explore the mode of action of the NAs, we applied deletion mutants, a peptide inhibiting Pol V (APIM-peptide) and metabolome and proteome analyses. Five out of the thirteen NAs examined, including three nucleoside reverse transcriptase inhibitors (NRTIs) and two anti-cancer drugs, increased the mutation frequency in by more than 25-fold at doses that were within reported plasma concentration range (Pl.CR), but that did not affect bacterial growth. We show that the SOS response is induced and that the increase in mutation frequency is mediated by the TLS polymerase Pol V. Quantitative mass spectrometry-based metabolite profiling did not reveal large changes in nucleoside phosphate or other central carbon metabolite pools, which suggests that the SOS induction is an effect of increased replicative stress. Our results suggest that NAs/NRTIs can contribute to the development of AMR and that drugs inhibiting Pol V can reverse this mutagenesis.
Topics: Antineoplastic Agents; Antiviral Agents; DNA-Directed DNA Polymerase; Escherichia coli Proteins; Microbial Sensitivity Tests; Mutagenesis; Nucleosides; Stavudine
PubMed: 34198819
DOI: 10.3390/biom11060843 -
International Journal of Molecular... Jan 2020HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended...
HIV-associated sensory neuropathy (HIV-SN) is a disabling complication of HIV disease and antiretroviral therapies (ART). Since stavudine was removed from recommended treatment schedules, the prevalence of HIV-SN has declined and associated risk factors have changed. With stavudine, rs1799964*C (TNF-1031) associated with HIV-SN in Caucasians and Indonesians but not in South Africans. Here, we investigate associations between HIV-SN and rs1799964*C and 12 other polymorphisms spanning and seven neighboring genes (the -block) in Indonesians ( = 202; 34/168 cases) and South Africans ( = 75; 29/75 cases) treated without stavudine. Haplotypes were derived using fastPHASE and haplotype networks built with PopART. There were no associations with rs1799964*C in either population. However, rs9281523*C in intron 10 of (alternatively ) independently associated with HIV-SN in Indonesians after correcting for lower CD4 T-cell counts and >500 copies of HIV RNA/mL (model = 0.0011, Pseudo = 0.09). rs4947324*T (between and ) independently associated with reduced risk of HIV-SN and African haplotype 1 (containing no minor alleles) associated with increased risk of HIV-SN after correcting for greater body weight, a history of tuberculosis and nadir CD4 T-cell counts (model: = 0.0003, Pseudo = 0.23). These results confirm -block genotypes influence susceptibility of HIV-SN. However, critical genotypes differ between ethnicities and with stavudine use.
Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Asian People; Black People; Female; Genetic Predisposition to Disease; Genotype; HIV Infections; Haplotypes; Humans; Indonesia; Male; Middle Aged; Peripheral Nervous System Diseases; Polymorphism, Single Nucleotide; South Africa; Stavudine; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 31936167
DOI: 10.3390/ijms21020380 -
HIV Medicine Sep 2007The aim of the study was to describe the prevalence of and risk factors for HIV-associated sensory neuropathy (HIV-SN) in 2006 [the era of stavudine, didanosine and... (Comparative Study)
Comparative Study
OBJECTIVES
The aim of the study was to describe the prevalence of and risk factors for HIV-associated sensory neuropathy (HIV-SN) in 2006 [the era of stavudine, didanosine and zalcitabine (dNRTI)-sparing highly active antiretroviral therapy (HAART)] and to compare our findings with data obtained in the same clinic in 1993 (pre-HAART) and 2001 (frequent use of dNRTI-containing HAART).
METHODS
This was a cross-sectional comparative study using convenience sampling. HIV-positive adults attending a tertiary referral clinic over a 2-week period were screened for HIV-SN using the AIDS Clinical Trials Group screening tool. HIV-SN was defined as present if the patient had both neuropathic symptoms and abnormal signs. Demographic, clinical, laboratory and treatment data were considered as possible risk factors for HIV-SN, and results were compared with data obtained in the same clinic in 1993 and 2001.
RESULTS
One hundred patients were screened. The prevalence of HIV-SN was 42%, which was unchanged since 2001 (44%) despite a significant reduction in the use of dNRTIs. HIV-SN remained much more common than in 1993 (42% vs 13%; P<0.0001). The only independent associations with HIV-SN in 2006 were increasing patient age and a history of exposure to either stavudine or indinavir. This compares with 1993 when neuropathy was increased in those with Mycobacterium avium complex infection, and 2001 when patient age and use of stavudine and didanosine were the independent associations with HIV-SN in this clinic.
CONCLUSIONS
HIV-SN remained common among ambulatory patients in 2006 (42% prevalence) despite a significant reduction in the use of dNRTIs. In addition to patient age and stavudine exposure, indinavir use may be a risk factor for HIV-SN.
Topics: Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; Australia; Cross-Sectional Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Polyneuropathies; Prevalence; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine
PubMed: 17661844
DOI: 10.1111/j.1468-1293.2007.00478.x -
Neurology Jan 2009The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which... (Clinical Trial)
Clinical Trial
BACKGROUND
The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which include stavudine, are the most common regimens to treat HIV infection in Uganda and many other parts of Africa.
OBJECTIVE
To evaluate the benefits and risks of stavudine-based highly active antiretroviral therapy (HAART) for HIV-associated cognitive impairment and distal sensory neuropathy. The study compared neuropsychological performance changes in HIV+ individuals initiating HAART for 6 months and HIV- individuals receiving no treatment for 6 months. The risk of antiretroviral toxic neuropathy as a result of the initiation of stavudine-based HAART was also examined.
METHODS
At baseline, 102 HIV+ individuals in Uganda received neurologic, neuropsychological, and functional assessments; began HAART; and were followed up for 6 months. Twenty-five HIV- individuals received identical clinical assessments and were followed up for 6 months.
RESULTS
In HIV+ individuals, there was improvement in verbal memory, motor and psychomotor speed, executive thinking, and verbal fluency. After adjusting for differences in sex, HIV+ individuals demonstrated significant improvement in the Color Trails 2 test (p = 0.025) compared with HIV- individuals. Symptoms of neuropathy developed in 38% of previously asymptomatic HIV+ patients after initiation of the stavudine-based HAART.
CONCLUSIONS
After the initiation of highly active antiretroviral therapy (HAART) including stavudine, HIV+ individuals with cognitive impairment improve significantly as demonstrated by improved performance on a test of executive function. However, peripheral neurotoxicity occurred in 30 patients, presumably because of stavudine-based HAART, suggesting the need for less toxic therapy.
Topics: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cognition Disorders; Developing Countries; Disability Evaluation; Female; Humans; Male; Neuropsychological Tests; Outcome Assessment, Health Care; Risk Assessment; Stavudine; Treatment Outcome; Uganda
PubMed: 19139369
DOI: 10.1212/01.wnl.0000339042.96109.86 -
BioMed Research International 2017Protease inhibitor (PI) may cause abnormal glucose metabolism, abnormal lipid metabolism, and metabolic syndrome in HIV-infected adults but less well studied in Asian...
Protease inhibitor (PI) may cause abnormal glucose metabolism, abnormal lipid metabolism, and metabolic syndrome in HIV-infected adults but less well studied in Asian adolescents. This cross-sectional study evaluated anthropometric factors, oral glucose tolerance test, and lipid profiles of perinatally HIV-infected Thai adolescents who had received PI-based antiretroviral therapy for at least 6 months. Eighty adolescents were enrolled [median (IQR) age 16.7 (14.6-18.0) years, 42 males]. Metabolic syndrome, prediabetes, and type 2 diabetes mellitus (T2DM) were found in 8 (10%), 17 (22.1%), and 3 (3.8%) adolescents, respectively. Dyslipidemia was found in 56 (70%) adolescents, with hypertriglyceridemia being the most common type. In multivariate analysis, presence of lipohypertrophy (OR: 25.7, 95% CI: 3.2-202.8; = 0.002) and longer duration of PI use (OR: 1.04, 95% CI: 1.00-1.08; = 0.023) were associated with metabolic syndrome. Obesity (OR: 7.71, 95% CI: 1.36-43.7; = 0.021), presence of lipohypertrophy (OR: 62.9, 95% CI: 4.97-795.6; = 0.001), and exposure to stavudine for ≥6 months (OR: 8.18, 95% CI: 1.37-48.7; = 0.021) were associated with prediabetes/T2DM, while exposure to tenofovir for ≥6 months reduced the risk (OR: 0.17, 95% CI: 0.04-0.78; = 0.022). Metabolic disorders were commonly found in adolescents receiving PI. Careful monitoring and early intervention to modify cardiovascular risk should be systematically implemented in this population particularly those with exposure to stavudine.
Topics: Adolescent; Anthropometry; Anti-HIV Agents; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; HIV Infections; Humans; Lipid Metabolism; Lipids; Male; Metabolic Diseases; Metabolic Syndrome; Multivariate Analysis; Obesity; Prediabetic State; Prognosis; Protease Inhibitors; Stavudine; Tertiary Care Centers
PubMed: 28293638
DOI: 10.1155/2017/7481597