Showing papers on "Zidovudine published in 2015"

Risk of Cardiovascular Events Associated with Current Exposure to HIV Antiretroviral Therapies in a US Veteran Population

Abstract: Background. To characterize the association of antiretroviral drug combinations on risk of cardiovascular events. Methods. Certain antiretroviral medications for human immunodeficiency virus (HIV) have been implicated in increasing risk of cardiovascular disease. However, antiretroviral drugs are typically prescribed in combination. We characterized the association of current exposure to antiretroviral drug combinations on risk of cardiovascular events including myocardial infarction, stroke, percutaneous coronary intervention, and coronary artery bypass surgery. We used the Veterans Health Administration Clinical Case Registry to analyze data from 24 510 patients infected with HIV from January 1996 through December 2009. We assessed the association of current exposure to 15 antiretroviral drugs and 23 prespecified combinations of agents on the risk of cardiovascular event by using marginal structural models and Cox models extended to accommodate time-dependent variables. Results. Over 164 059 person-years of follow-up, 934 patients had a cardiovascular event. Current exposure to abacavir, efavirenz, lamivudine, and zidovudine was significantly associated with increased risk of cardiovascular event, with odds ratios ranging from 1.40 to 1.53. Five combinations were significantly associated with increased risk of cardiovascular event, all of which involved lamivudine. One of these—efavirenz, lamivudine, and zidovudine—was the second most commonly used combination and was associated with a risk of cardiovascular event that is 1.60 times that of patients not currently exposed to the combination (odds ratio = 1.60, 95% confidence interval, 1.25–2.04). Conclusions. In the VA cohort, exposure to both individual drugs and drug combinations was associated with modestly increased risk of a cardiovascular event.

Improved Safety, Bioavailability and Pharmacokinetics of Zidovudine through Lactoferrin Nanoparticles during Oral Administration in Rats.

Abstract: Zidovudine (AZT) is one of the most referred antiretroviral drug. In spite of its higher bioavailability (50-75%) the most important reason of its cessation are bone marrow suppression, anemia, neutropenia and various organs related toxicities. This study aims at the improvement of oral delivery of AZT through its encapsulation in lactoferrin nanoparticles (AZT-lactonano). The nanoparticles (NPs) are of 50-60 nm in size and exhibit 67% encapsulation of the AZT. They are stable in simulated gastric and intestinal fluids. Anti-HIV-1 activity of AZT remains unaltered in nanoformulation in acute infection. The bioavailability and tissue distribution of AZT is higher in blood followed by liver and kidney. AZT-lactonano causes the improvement of pharmacokinetic profile as compared to soluble AZT; a more than 4 fold increase in AUC and AUMC in male and female rats. The serum Cmax for AZT-lactonano was increased by 30%. Similarly there was nearly 2-fold increase in Tmax and t1/2. Our in vitro study confirms that, the endosomal pH is ideal for drug release from NPs and shows constant release from up to 96h. Bone marrow micronucleus assay show that nanoformulation exhibits approximately 2fold lower toxicity than soluble form. Histopathological and biochemical analysis further confirms that less or no significant organ toxicities when nanoparticles were used. AZT-lactonano has shown its higher efficacy, low organs related toxicities, improved pharmacokinetics parameter while keeping the antiviral activity intact. Thus, the nanoformulation are safe for the target specific drug delivery.

Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design.

Abstract: OBJECTIVE To evaluate the safety of in-utero antiretroviral exposure in children born to mothers with HIV, using a trigger-based design. DESIGN The Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites to evaluate safety of in-utero antiretroviral drug exposure in HIV-uninfected children born to HIV-infected mothers. Children meeting predefined clinical or laboratory thresholds have more intensive evaluations to determine whether they meet criteria for adverse events. METHODS Adverse event "cases" were defined for the following domains: growth, hearing, language, neurology, neurodevelopment, metabolic, hematologic/clinical chemistry and blood lactate. We used adjusted log-binomial models to calculate relative risks (RR) of case status overall and within individual domains for various antiretroviral exposures during pregnancy. RESULTS Among 2680 youth enrolled between 2007 and 2012 (48% female, 66% black, 33% Hispanic), 48% met a trigger and 25% were defined as a case in at least one domain. Language (13.2%) and metabolic (11.4%) cases were most common. After adjustment for birth cohort and other factors, there was no association of any antiretroviral regimen, drug class, or individual drug with meeting overall case criteria (case in any domain). Within individual domains, zidovudine (74% exposed) was associated with increased risk of metabolic case [RR = 1.69, 95%confidence interval (CI) 1.08-2.64] and didanosine plus stavudine (<1% exposed) with increased risk of both neurodevelopmental (RR = 12.40, 95%CI 5.29-29.08) and language (RR = 4.84, 95%CI 1.14-20.51) cases. CONCLUSION Our findings support current recommendations for combination antiretroviral therapy during pregnancy, although higher risk of metabolic disorder with zidovudine exposure warrants further study.

Cardiac effects of in-utero exposure to antiretroviral therapy in HIV-uninfected children born to HIV-infected mothers.

Abstract: Prevention of mother to child HIV transmission (MTCT) has been a resounding public health success story. In the past 20 years, the rate of MTCT in the US has been reduced from 26% to under 1% using potent combination antiretroviral (cARV) regimens [1-4]. As the use of cARV regimens in pregnancy has increased, concerns have been raised regarding the potential risk of in utero cARV exposure on long-term outcomes among HIV-exposed but uninfected (HEU) children, including mitochondrial toxicity which has also been associated with cardiomyopathy in HIV-unexposed children [5-12]. Among HIV-infected children, cardiomyopathy was common prior to widespread use of cARV and was associated with high mortality [13]. However, a study of both HEU and HIV-infected children in the National Heart, Lung, and Blood Institute (NHLBI) Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (P2C2) born between 1990-1994 found no association between perinatal exposure to zidovudine (ZDV) monotherapy and abnormalities of left ventricular (LV) structure or function [14]. In another report, compared to the subset of ARV-unexposed HEU children in the P2C2 study, 136 children (96% exposed to cARV in utero) born between 2003-2006 in the NHLBI-funded Cardiovascular Status of Highly Active Antiretroviral Therapy (HAART) in HIV-Exposed Infants and Children cohort study (CHAART I) had significantly lower LV mass, septal wall thickness, and LV diameter, and higher LV contractility at age 2 years [15]. Since these prior studies were limited by their small sample size and/or they were conducted during an earlier era when there were fewer antiretroviral (ARV) options compared to the contemporary era which has more robust combination ARV combination therapy options, we evaluated the relationship between perinatal ARV drug exposure and echocardiographic measurements from the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring for ART Toxicities (SMARTT) study.

Delayed HIV detection among infants exposed to postnatal antiretroviral prophylaxis during breastfeeding.

Abstract: OBJECTIVE The objective of this study is to determine whether detection of HIV infection was delayed in infants exposed to antiretroviral prophylaxis to prevent HIV transmission during breastfeeding. DESIGN The Breastfeeding, Antiretrovirals and Nutrition (BAN) study was a randomized trial of 2369 mother-infant pairs conducted from 2004 to 2010. In addition to an intrapartum regimen, all mother-infant pairs were randomly assigned to three antiretroviral intervention arms during 28 weeks of breastfeeding: no further antiretroviral prophylaxis (control arm); infant-daily nevirapine (nevirapine arm); and maternal zidovudine, lamivudine and either nevirapine, nelfinavir or lopinavir-ritonavir (maternal arm). After breastfeeding cessation counselling and stopping the antiretroviral interventions by 28 weeks, 28 infant HIV infections occurred. METHODS To determine whether these infections occurred during the breastfeeding and antiretroviral intervention phase but had delayed detection on the antiretroviral arms, we performed ultrasensitive (droplet digital PCR) HIV testing on infants with stored peripheral blood mononuclear cell (PBMC) specimens at 24 weeks (n = 9). RESULTS Of the nine infants, all three on the infant nevirapine arm had detectable HIV DNA at 24 weeks, compared with two of four on the maternal antiretroviral arm and one of two on the control arm. For infants with detectable HIV at 24 weeks, the median delay in detection between the ultrasensitive and standard assays was 18.3 weeks for the nevirapine arm, 15.4 weeks for the maternal arm and 9.4 weeks for the control arm. CONCLUSION The prolonged inability to detect HIV with standard assays in the context of postnatal antiretroviral prophylaxis suggests that early antiretrovirals may restrict HIV replication sufficiently to lead to missed diagnosis among infected infants. Therefore, repeat virologic testing is warranted beyond the WHO-recommended point of testing at 6 weeks after breastfeeding cessation.

Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications.

Abstract: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin’s effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) and 3 mL/kg of distilled water (group VII). Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy.

Prevalence of Lipodystrophy and Metabolic Abnormalities in HIV-infected African Children after 3 Years on First-line Antiretroviral Therapy.

Abstract: The lipodystrophy syndrome, which includes central lipohypertrophy, lipoatrophy of extremities, face and buttocks, and metabolic abnormalities, has been reported among naive and experienced HIV-infected children on antiretroviral therapy (ART) in resource-rich and resource-limited settings.1–14 Observed risk factors in children include: use of stavudine and protease inhibitors; advanced HIV disease, high viral loads and low CD4; duration of HIV infection/older age; puberty; female gender; white ethnicity; high body mass index (BMI); and rapid immunological recovery post-ART.1,2,4,6,8,13–18 Much lipodystrophy data in children come from middle-income/high-income countries, whereas >90% of HIV-infected children live in sub-Saharan Africa19 where underlying malnutrition, micronutrient deficiencies, co-infections and advanced HIV disease are more prevalent. Lipodystrophy studies specifically among sub-Sarahan African children are thus needed. Two recent cross-sectional studies in Uganda and Tanzania reported clinically ascertained lipodystrophy in 27–34% children, although most cases were mild13,14; a third cross-sectional randomized comparison of nevirapine versus lopinavir-containing ART reported lipodystrophy in 8.4%.20 Importantly, most13,14 or all20 children had substantial stavudine exposure, which was associated with lipodystrophy,13,14 similar to a cross-sectional study of skinfolds/circumferences in Ugandan/Zambian children.21 Many African ART programs are moving away from stavudine-containing regimens in children, as in adults.22–24 Children now predominantly receive zidovudine-containing regimens, as concerns remain about tenofovir’s impact on bone metabolism and renal function,25,26 and abacavir remains expensive.27 Like stavudine, zidovudine is a thymidine-analog nucleoside reverse transcriptase inhibitor (NRTI) so could potentially lead to lipodystrophy, albeit at lower rates.13,14,28 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have also been associated with lipodystrophy,1 with, if anything, higher rates in those receiving nevirapine versus efavirenz.29,30 Here, we investigate the contribution of zidovudine and efavirenz/nevirapine to body circumferences, skinfold thicknesses, metabolic parameters and clinically determined lipodystrophy, in randomized (zidovudine) and nonrandomized (efavirenz/nevirapine) comparisons 3 years after ART initiation in the ARROW trial.31

Lower Preprandial Insulin and Altered Fuel Use in HIV/Antiretroviral-Exposed Infants in Cameroon

Abstract: Context: Intrauterine HIV/antiretroviral (ARV) and postnatal ARVs are known to perturb energy metabolism and could have permanent effects on future metabolic health. Such maladaptive effects could be mediated by changes in mitochondrial function and intermediary metabolism due to fetal and early-life ARV exposure in HIV/ARV-exposed uninfected (HEU) infants. Objective: The objective of the study was to understand the relationship(s) between mitochondrial fuel use (assessed via acylcarnitines and branched chain amino acids) and preprandial insulin in infants exposed to in utero HIV/ARV plus postnatal zidovudine or nevirapine compared with HIV/ARV-unexposed uninfected (HUU) infants. Design: This was a prospective cohort study with the following three groups: 1) intrauterine HIV/ARV/postnatal zidovudine-exposed (HEU-A), 2) intrauterine HIV/ARV/postnatal nevirapine-exposed (HEU-N), and 3) HUU infants. Principal component analysis and linear regression modeling were performed to assess the association between i...

Development of Severe Anemia and Changes in Hemoglobin in a Cohort of HIV-Infected Ugandan Adults Receiving Zidovudine-, Stavudine-, and Tenofovir-Containing Antiretroviral Regimens

Abstract: Introduction:Anemia is a common problem in HIV in sub-Saharan Africa. We describe the contribution of antiretroviral therapy (ART) regimen to the incidence of anemia and changes in hemoglobin (Hb) in HIV-infected patients in Uganda.Methods:This study was nested in a prevention of cryptococcal disease trial (CRYPTOPRO; ISCRTN7648152). Patients received 3 different backbones of nucleoside reverse transcriptase inhibitor in a nonrandomized manner.Results:Of the 852 patients (161 on zidovudine [ZDV], 628 on stavudine [d4T], and 63 on tenofovir [TDF]; all received lamuvidine), the risk of developing grade 4 anemia was higher (adjusted hazard ratio 2.7) for those receiving ZDV than those receiving d4T. Those receivingd4T had a higher average increase in Hb than those receiving ZDV (P = .024) or TDF (P = .014).Conclusion:In this observational study, ZDV was associated with severe anemia compared to d4T or TDF; those receiving ZDV and TDF had smaller increases in Hb after ART initiation. We encourage publication ...

Highly active antiretroviral therapy and dyslipidemia in people living with HIV/AIDS in Fako Division, South West Region of Cameroon

Abstract: The advent of HAART has been associated with a profound reduction in morbidity and mortality from HIV/AIDS. However, side effects and toxicities associated with HAART may lead to an increased risk for cardiovascular diseases. The aim of this study was to determine the prevalence of dyslipidemia and determining factors of derangements in lipid profile associated with the use of HAART regimens in people living with HIV/AIDS in Fako Division of the South West Region of Cameroon. This cross-sectional study was conducted between March and August 2014. Lipid profile was determined after overnight fast and dyslipidemia diagnosed according to the US National Cholesterol Education Program III criteria. Socio-demographic characteristics were also collected using a questionnaire. Data was analyzed using STATA; chi-square test, student’s t-test, ANOVA and logistic regressions were computed. Two hundred and nine participants were recruited including 157 (75.1 %) on HAART and 52 (24.9 %) HAART-naive. Antiretrovirals were drugs containing two nucleoside backbones (zidovudine/ /lamivudine/tenofovir) with either a non-nucleoside (nevirapine/efavirenz) or a protease inhibitor (lopinavir). No patient was treated with statins. Their mean age was 43.4 (±11.0) years. The mean CD4+ T cell count was 425 (±281) cells/μl after mean duration of HIV infection of 54.8 (±43.9) months and mean duration on ART of 63.7 (±41.4) months. The prevalence of total cholesterol (≥ 200 mg/dL) was 51.0 % in patients on HAART and 9.6 % pre-HAART patients (p < 0.0001), whereas LDL-cholesterol ≥ 130 mg/dL occurred in 36.9 % and in 7.7 % respectively, (p = 0.0001). Receiving HAART (adjusted odds ratio =6.24, 95 % CI: 2.33–17.45, p < 0.0001) and HIV duration of 42 months and more (aOR = 2.26, 95 % CI: 1.16–4.42, p = 0.017) were independently associated with total cholesterol ≥ 200 mg/dL. Receiving HAART (aOR = 5.28, 95 % CI: 1.17–16.32, p = 0.004) was independently associated with raised LDL-cholesterol values. The adjusted odds ratio (95 % CI) of BMI ≥ 25.0 kg/m2 versus BMI < 25.0 kg/m2 was 3.25 (1.44–7.34) for triglycerides ≥ 150 mg/dL. HAART regimens were significantly associated with atherogenic lipid profile. Lipid profile should be monitored in HIV/AIDS patients on therapy so that any negative effects of HAART are optimally managed.

Decreased Mitochondrial Function Among Healthy Infants Exposed to Antiretrovirals During Gestation, Delivery and the Neonatal Period.

Abstract: BACKGROUND Antiretroviral (ARV)-associated mitochondrial toxicity in HIV/ARV-exposed healthy infants is a concern. Clinically relevant toxicity is rare. Hyperlactatemia is common but nonspecific, both increased and decreased mitochondrial DNA (mtDNA) level has been reported. Mitochondrial function has scarcely been investigated. METHODS In a prospective observational study of 133 HIV/ARV-exposed infants, mtDNA content was measured with quantitative real-time polymerase chain reaction, and mitochondrial respiratory chain enzymatic activity of complex IV (CIV) and mitochondrial mass (MM) were assessed spectrophotometrically from cryopreserved peripheral blood mononuclear cells obtained at 6 weeks and 3, 6 and 12 months of age and compared with a control group. RESULTS Most mothers (88%) received combined ARV therapy during pregnancy, and 92% of infants received zidovudine monotherapy. No infant had clinical evidence of mitochondrial disease during follow-up. Nonsignificant higher MM and lower mtDNA levels (normalized by MM) were observed over time in HIV/ARV-exposed infants. MM-normalized CIV activity was consistently lower in HIV/ARV-exposed children than in controls over time (0.09 vs. 0.35, 0.12 vs. 0.38, 0.13 vs. 0.24 and 0.14 vs. 0.24 nmol/min/mg at 6 weeks and 3, 6 and 12 months; P = 0.014, P < 0.0001, P = 0.065 and P = 0.011, respectively) and showed a linear trend toward normalization with age (P < 0.01). In HIV/ARV-exposed infants, an inverse correlation between CIV activity and mtDNA levels was observed until 6 months of age (r = -0.327, P = 0.016; r = -0.311, P = 0.040 and r = -0.275, P = 0.046). CONCLUSIONS Mitochondrial-encoded CIV activity was consistently lower among HIV/ARV-exposed healthy infants and inversely correlated with mtDNA levels, suggesting upregulation of the latter.

Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease

Abstract: Background & Aims The NOD.c3c4 mouse model develops autoimmune biliary disease characterized by spontaneous granulomatous cholangitis, antimitochondrial antibodies and liver failure. This model for primary biliary cirrhosis (PBC) has evidence of biliary infection with mouse mammary tumour virus (MMTV), suggesting that the virus may have a role in cholangitis development and progression of liver disease in this mouse model. We tested the hypothesis that MMTV infection is associated with cholangitis in the NOD.c3c4 mouse model by investigating whether antiretroviral therapy impacts on viral levels and liver disease. Methods NOD.c3c4 mice were treated with combination antiretroviral therapy. Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score. Results Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice. Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model. Conclusions The attenuation of cholangitis with regimens containing the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the protease inhibitors, lopinavir and ritonavir, suggests that retroviral infection may play a role in the development of cholangitis in this model.

Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection

Abstract: Nucleoside reverse transcriptase inhibitors (NRTIs) are an integral part of the current antiretroviral therapy (ART), which dramatically reduced the mortality from AIDS and turned the disease from lethal to chronic. The further steps in curing the HIV-1 infection must include more effective targeting of infected cells and virus sanctuaries inside the body and modification of drugs and treatment schedules to reduce common complications of the long-term treatment and increase patient compliancy. Here, we describe novel NRTI prodrugs synthesized from cholesteryl-e-polylysine (CEPL) nanogels by conjugation with NRTI 5'-succinate derivatives (sNRTI). Biodegradability, small particle size, and high NRTI loading (30% by weight) of these conjugates; extended drug release, which would allow a weekly administration schedule; high therapeutic index (>1000) with a lower toxicity compared to NRTIs; and efficient accumulation in macrophages known as carriers for HIV-1 infection are among the most attractive properties of new nanodrugs. Nanogel conjugates of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) have been investigated individually and in formulations similar to clinical NRTI cocktails. Nanodrug formulations demonstrated 10-fold suppression of reverse transcriptase activity (EC90) in HIV-infected macrophages at 2-10, 2-4, and 1-2 μM drug levels, respectively, for single nanodrugs and dual and triple nanodrug cocktails. Nanogel conjugate of lamivudine was the most effective single nanodrug (EC90 2 μM). Nanodrugs showed a more favorable pharmacokinetics compared to free NRTIs. Infrequent iv injections of PEGylated CEPL-sAZT alone could efficiently suppress HIV-1 RT activity to background level in humanized mouse (hu-PBL) HIV model.

Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter.

Abstract: The SLC22A1 influx transporter is expressed on the basolateral membrane of hepatocytes and is involved in the excretion of numerous cations. Inhibition of SLC22A1 by several antiretrovirals, such as the protease inhibitor darunavir, has not previously been determined. In order to better understand and predict drug-SLC22A1 interactions, a range of antiretrovirals were screened for SLC22A1-associated inhibition and transport. Stable SLC22A1-expressing KCL22 cells were produced previously by nucleofection. Control KCL22 cells were transfected with the empty vector pcDNA3.1. Accumulation of tetraethylammonium (5.5 μM, 30 min) was determined in SLC22A1-expressing and mock-transfected cells with and without 50 μM of SLC22A1 inhibitor prazosin, or 50 μM of each antiretroviral drug. SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were determined. Cellular accumulation of efavirenz and darunavir was also assessed in SLC22A1-expressing KCL22 cells and reversibility of this accumulation was assessed using prazosin. Tetraethylammonium accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (10.6 ± 0.8 μM vs. 0.3 ± 0.004 μM, p = 0.009) and was significantly reduced in SLC22A1-expressing cells when co-incubated with all antiretrovirals tested except atazanavir, lamivudine, tenofovir, zidovudine, and raltegravir. Particularly noticeable was the predominance of SLC22A1 inhibitors in the protease inhibitor and non-nucleoside reverse transcriptase inhibitor classes. Absolute SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were 21.8, 46.2, and 2.8 μM, respectively. Efavirenz accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (17% higher, p = 0.009) which was reversed using prazosin, whereas no difference was observed for darunavir (p = 0.86). These data inform the mechanistic basis for disposition, drug-drug interactions and pharmacogenetic candidate gene selection for antiretroviral drugs.

Is zidovudine first-line therapy virologically comparable to tenofovir in resource-limited settings?

Abstract: To compare virologic success between adult patients on tenofovir (TDF) and zidovudine (AZT)-containing first-line antiretroviral (ART) regimens in 10 rural clinics in Lesotho, Southern Africa.; Multicentre cross-sectional study, patients ≥16 years, on first-line ART ≥6 months, receiving AZT/lamivudine (3TC) or TDF/3TC combined with efavirenz (EFV) or nevirapine (NVP). Patient characteristics and clinical/therapeutic history were collected on the day of blood draw for viral load (VL). Analysis was stratified for non-nucleoside reverse transcriptase inhibitor (EFV or NVP). A logistic regression model weighted for patients' baseline characteristics was used to assess the likelihood of virologic success (>80 copies/ml) in patients with TDF- as compared to AZT-backbones.; In total 1539 patients were included in the analysis. Most were clinically and immunologically stable (clinical failure: 2.7% (AZT) and 2.8% (TDF); immunological failure: 4.6% (AZT) and 4.8% (TDF)). In EFV-based regimens (n = 1162), TDF was significantly associated with higher rates of virologic suppression than AZT (93.8% vs. 88.1%; weighted odds ratio: 2.15 (95% CI: 1.29-3.58; P = 0.003)). In NVP-based regimens, a similar trend was observed, but not significant (89.4% vs. 86.7%; 1.99 (0.83-4.75, P = 0.121)).; These findings support the WHO recommendation to use TDF/3TC/EFV as first-line regimen. They do, however, not support the recommendation that patients who are clinically stable on AZT should continue on this first-line regimen.

Comparing genotoxic signatures in cord blood cells from neonates exposed in utero to zidovudine or tenofovir.

Abstract: OBJECTIVES Zidovudine and tenofovir are the two main nucleos(t)ide analogs used to prevent mother-to-child transmission of HIV. In vitro, both drugs bind to and integrate into human DNA and inhibit telomerase. The objective of the present study was to assess the genotoxic effects of either zidovudine or tenofovir-based combination therapies on cord blood cells in newborns exposed in utero. DESIGN We compared the aneuploid rate and the gene expression profiles in cord blood samples from newborns exposed either to zidovudine or tenofovir-based combination therapies during pregnancy and from unexposed controls (n = 8, 9, and 8, respectively). METHODS The aneuploidy rate was measured on the cord blood T-cell karyotype. Gene expression profiles of cord blood T cells and hematopoietic stem and progenitor cells were determined with microarrays, analyzed in a gene set enrichment analysis and confirmed by real-time quantitative PCRs. RESULTS Aneuploidy was more frequent in the zidovudine-exposed group (26.3%) than in the tenofovir-exposed group (14.2%) or in controls (13.3%; P < 0.05 for both). The transcription of genes involved in DNA repair, telomere maintenance, nucleotide metabolism, DNA/RNA synthesis, and the cell cycle was deregulated in samples from both the zidovudine and the tenofovir-exposed groups. CONCLUSION Although tenofovir has a lower clastogenic impact than zidovudine, gene expression profiling showed that both drugs alter the transcription of DNA repair and telomere maintenance genes.

Superior Effectiveness of Zidovudine Compared with Tenofovir When Combined with Nevirapine-based Antiretroviral Therapy in a Large Nigerian Cohort

Abstract: (See the Editorial Commentary by Manasa and Katzenstein on pages 519–20.) Based on relative safety, efficacy, and convenience, the World Health Organization (WHO) recommends efavirenz, tenofovir, plus either emtricitabine or lamivudine as the sole, preferred first-line antiretroviral therapy (ART) regimen for human immunodeficiency virus (HIV)–infected adults living in resource-constrained settings [1]. When efavirenz cannot be used, nevirapine remains the alternate nonnucleoside reverse transcriptase inhibitor (NNRTI) option, given with the following 2 nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine plus lamivudine or tenofovir plus either emtricitabine or lamivudine [1]. When combined with efavirenz, tenofovir is superior to zidovudine. Specifically, higher rates of virologic suppression were reported among patients on efavirenz-based ART who received tenofovir–emtricitabine vs zidovudine–lamivudine (81% vs 70%; P = .005) in addition to lower rates of ART discontinuation due to adverse events (4% vs 9%, respectively, P = .02) [2]. In clinical practice, the strength of tenofovir was extrapolated from these data to nevirapine-based regimens, despite the lack of associated outcome data. Simultaneously, there was a global focus on increasing access to tenofovir to avoid zidovudine-related toxicities. Consistent with WHO guidelines in 2008, approximately 20% of patients on first-line ART in our clinical program were receiving a tenofovir plus nevirapine-containing regimen; only nevirapine plus zidovudine and lamivudine was more commonly used. Since then, the efficacy of ART containing tenofovir and nevirapine has been questioned by results from small prospective [3–6] and larger retrospective studies [7–10], suggesting that higher rates of virologic failure or worse clinical outcomes occur with nevirapine plus tenofovir vs comparator regimens. Existing data are limited by the use of more potent comparator groups, small sample size, cross-sectional study design, or lack of virologic outcomes. To address this gap, data from a large observational clinical cohort were used to conduct a robust comparison of virologic outcomes among HIV-infected patients on first-line, nevirapine-based ART. This study addresses the important question of which commonly used NRTI combination (zidovudine- vs tenofovir-containing) performs best with nevirapine; this is a question of great clinical significance for patients unable to take efavirenz. Accordingly, the primary objective was to evaluate the influence of the NRTI combination on time to virologic failure in our cohort.

Pharmacoepidemiology of antiretroviral drugs in a teaching hospital in Lagos, Nigeria.

Abstract: Objective : Prescribing, adherence, and adverse drug events to HAART in a large antiretroviral programme in Lagos was evaluated. Design : A retrospective 5 year open cohort study Setting : The AIDS Prevention Initiative in Nigeria (APIN) clinic at LUTH is one of the United States Presidential Emergency Plan for AIDS Relief (PEPFAR) funded centers for HIV relief program in Nigeria Participants The case files of 390 patients on HAART and attending the APIN clinic were reviewed sequel to random selection. Main outcome measures : Demographics of the patients and pattern of antiretroviral (ARV) combination drugs prescribed were extracted from their case files. The details of the adverse drug events (ADEs) were extracted from drug toxicity forms regularly filled for each patient. A Chi-square test with Yates correction was used to determine the association between adherence and therapeutic outcome Results : A total of 2944 prescriptions were assessed. Zidovudine + lamivudine + nevirapine (35.87%) and stavudine + lamivudine + nevirapine (35.63%) were the most frequently prescribed combinations. Over 2000 ADEs were reported with cough (13.3%), fever (8.75%) and skin rashes (8.01%) being the most frequently reported. Drug adherence was associated with good therapeutic outcome (÷2 = 115.60, p<0.0001). Conclusions : Zidovudine + lamivudine + nevirapine was the most frequently prescribed ARV combination. Cough was the most frequently reported ADE. Interventions aimed at rational prescribing of ARV drugs and improving adherence to antiretroviral drugs is essential for good therapeutic outcome in the treatment of HIV infection. Keywords : Pharmacoepidemiology, antiretroviral drugs, drug adherence, adverse events

Modeling of In-Utero and Intra-Partum Transmissions to Evaluate the Efficacy of Interventions for the Prevention of Perinatal HIV

Abstract: Background Antiretroviral treatments decrease HIV mother-to-child transmission through pre/post exposure prophylaxis and reduction of maternal viral load. We modeled in-utero and intra-partum HIV transmissions to investigate the preventive role of various antiretroviral treatments interventions. Methods We analysed data from 3,759 women-infant pairs enrolled in 3 randomized clinical trials evaluating (1) zidovudine monotherapy, (2) zidovudine plus perinatal single-dose nevirapine or (3) zidovudine plus lopinavir/ritonavir for the prevention of mother-to-child transmission of HIV in Thailand. All infants were formula-fed. Non-linear mixed effect modeling was used to express the viral load evolution under antiretroviral treatments and the probability of transmission. Results Median viral load was 4 log10 copies/mL (Interquartile range: 3.36–4.56) before antiretroviral treatments initiation. An Emax model described the viral load time-course during pregnancy. Half of the maximum effect of zidovudine (28% decrease) and lopinavir/ritonavir (72% decrease) were achieved after 98 and 12 days, respectively. Adjusted on viral load at baseline (Odds ratio = 1.50 [95% confidence interval: 1.34, 1.68] per log10 copies/mL increment), antiretroviral treatments duration (OR = 0.80 [0.75, 0.84] per week increment) but not the nature of antiretroviral treatments were associated with in-utero transmission. Adjusted on gestational age at delivery (<37 weeks, OR = 2.37 [1.37, 4.10]), baseline CD4 (Odds ratio = 0.79 [0.72, 0.88] per 100 cells/mm3 increment) and predicted viral load at delivery (OR = 1.47 [1.25, 1.64] per log10 copies/mL increment), single-dose nevirapine considerably reduced intra-partum transmission (OR = 0.32 [0.2, 0.51]). Conclusion These models determined the respective contributions of various antiretroviral strategies on prevention of mother-to-child transmission. This can help predict the efficacy of new antiretroviral treatments and/or prevention of mother-to-child transmission strategies particularly for women with no or late antenatal care who are at high risk of transmitting HIV to their offspring. Trial Registration This analysis is based on secondary data obtained from three clinical trials. ClinicalTrials.gov. NCT00386230, NCT00398684, NCT00409591.

High Incidence of Zidovudine Induced Anaemia in HIV Infected Patients in Southern Odisha.

Abstract: Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor was the first breakthrough in AIDS therapy in 1990.This study was conducted with an aim to determine prevalence of AZT induced anaemia in HIV infected patients initiated on AZT containing anti retroviral therapy(ART) regimen and also to find out any risk factor for causing AZT induced anaemia. Study was carried out in ART centre, M.K.C.G, MCH, Berhampur between Jan 2009 and Dec 2011. HIV infected patients registered at ART centre were treated according to National AIDS Control Organisation (NACO) guidelines. Patients (n = 1221) with Hb >8 gm/dl were prescribed AZT based ART regimen. Patients having anaemia (<8 gm/dl) were excluded from the study. Correlation of baseline characteristics (age, sex, weight, Hb level, CD4 count, World Health Organization (WHO) clinical stage) with risk of developing anaemia was also calculated. 178 (14.6 %) patients on AZT regimen developed anaemia. Patients with low CD4 count were more prone to develop severe anaemia. Age, sex, weight, WHO clinical stage had no relation with development of anaemia. Incidence of AZT induced anaemia was very high and patients having low CD4 count were more susceptible to develop anaemia.

Antiretroviral therapy, CD4, viral load, and disease stage in HIV patients in Saudi Arabia: a 2001–2013 cross-sectional study

Abstract: Introduction: The incidence of HIV/AIDS is increasing worldwide and in the Middle East. In this study, we analyzed the use of antiretroviral therapy (ART), the patterns of CD4 and viral load (VL), and stage of presentation. Methodology: Laboratory variables, ART use, and CD4 count were obtained and analyzed retrospectively. Results: A total of 997 cases from eight HIV/AIDS care providers were included. Of the total cases, 274 (28.3%) had a CD4 count of 5 log 10 . Of the total cases, 50% were on highly active antiretroviral therapy (HAART), and the majority of cases were asymptomatic (70%). Of those patients on ART, 247 (39.5%) took tenofovir/emtricitabine combined with either efavirenz (147; 14.7%) or lopinavir/ritonavir (100; 10%), and 158 (15.8%) were on lamivudine and zidovudine with either efavirenz (32; 3.2%) or lopinavir/ritonavir (126; 12.6%). Other combinations were used in 70 (7%) patients. The mean (± standard deviation) of baseline CD4 and viral load were 401 cells/mm 3 (322 cells/mm 3 ) and 4.6 log10 10 (1.3 log 10 ), respectively. At diagnosis, 72% of patients were asymptomatic; 50% had AIDS and 20% had CD4 count < 350. Conclusions: ART use was in line with international guidelines, but the number of patients receiving ART was lower than expected. Large proportions of cases presented late with AIDS at diagnosis or had CD4 < 350. Further data is needed to evaluate the medical care of patients with HIV/AIDS in the Kingdom of Saudi Arabia.

Cardiomyocytes are Protected from Antiretroviral Nucleoside Analog-Induced Mitochondrial Toxicity by Overexpression of PGC-1α

Abstract: The nucleoside reverse transcriptase inhibitors (NRTIs), used for treatment of the human immunodeficiency virus-1, compromise mitochondria in cardiomyocytes and other host cells, limiting the clinical use of these drugs. To explore underlying mechanisms, we overexpressed PGC-1α, a master regulator of mitochondrial biogenesis, twofold in H9c2 rat cardiomyocyte cultures, hypothesizing that this might protect the mitochondria from damage induced by the NRTI combination zidovudine (AZT) and didanosine (ddI). The experimental groups, evaluated during 16 passages (P) of drug exposure, included: PGC-1α-overexpressing cells with no exposure, or exposure to 50 µM AZT plus 50 µM ddI; and control cells with no exposure or exposure to the same doses of AZT and ddI. The AZT/ddI combination caused a growth inhibition of 15-20% in control cells, but none in PGC-1α cells. Apoptosis was highest in AZT/ddI-exposed control cells, and PGC-1α overexpression protected cells from AZT/ddI-induced apoptosis. At P3, P6, P8, and P12, uncoupled mitochondrial oxygen consumption rate, determined by Seahorse 24 XF Analyzer, as higher in AZT/ddI-exposed PGC-1α cells, compared to AZT/ddI-exposed control cells (p < 0.05 at all P). Complex I activity was higher in AZT/ddI-exposed PGC-1α overexpressing cells than that in AZT/ddI-exposed control cells (p < 0.05), and reactive oxygen species levels were lower in PGC-1α overexpressing cells than that in control cells (p < 0.05) when both were exposed to AZT/ddI. Taken together, these experiments show proof of concept that overexpression of PGC-1α protects cardiomyocytes from NRTI-induced toxicity, and suggest that a pharmaceutical agent with similar activity may protect against NRTI-induced mitochondrial toxicity.

HIV-1 subtype B/B' and baseline drug resistance mutation are associated with virologic failure: a multicenter cohort study in China.

Abstract: Background Distribution of HIV-1 subtypes, transmitted drug resistance (TDR)/drug resistance mutation (DRM), and their impact on response to combination antiretroviral therapy remain poorly understood in China. Methods We analyzed data from our multicenter cohort study with 444 antiretroviral-naive participants recruited between 2008 and 2010. HIV-1 subtype and tropism were determined by V3 sequencing, and TDR/DRM was determined by Pol sequencing. Virologic and immunologic responses were monitored over 96 weeks of follow-up. The initial combination antiretroviral therapy regimen for all patients was nevirapine + lamivudine + zidovudine or stavudine. Analysis 1 included patients who finished 96 weeks of follow-up (n = 379), and analysis 2 included all 444 patients. Results Subtype B/B' was associated with higher prevalence of TDR/DRM to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. Median time to HIV-1 suppression was 18 weeks in all 3 subtype groups. In Cox proportional models for viral suppression, neither viral tropism nor HIV-1 subtypes had any impact on viral suppression; however, subtypes CRF01_AE and C/CRF07_BC/CRF08_BC were associated with lower risk of virologic failure compared with subtype B/B', with adjusted hazard ratio of 0.11 (P = 0.032) and 0.06 (P = 0.036), respectively in analysis 1, 0.42 (P = 0.047) and 0.22 (P = 0.008), respectively in analysis 2. This association was attenuated by adding DRM profiles to multivariate regression models. Neither subtype nor HIV-1 tropism affected immunologic response. Conclusions HIV-1 subtype tended to be associated with virologic but not immunologic response; this effect could be ascribed to baseline DRM.

Toxicity and clinical outcomes in patients with HIV on zidovudine and tenofovir based regimens: a retrospective cohort study.

Abstract: Background Adverse drug reactions are a major concern with zidovudine/stavudine treatment regimens. The less toxic tenofovir regimen is an alternative, but is seldom considered due to the higher costs. This study compared adverse drug reactions and other clinical outcomes resulting from the use of these two treatment regimens in India. Methods Baseline, clinical characteristics and follow-up outcomes were collected by chart reviews of HIV-positive adults and compared using univariate/multivariate analysis, with and without propensity score adjustments. Results Data were collected from 129 and 92 patients on zidovudine (with lamivudine and nevirapine) and tenofovir (with emtricitabine and efavirenz) regimens, respectively. Compared to patients receiving the zidovudine regimen, patients receiving the tenofovir regimen had fewer adverse drug reactions (47%, 61/129 vs 11%, 10/92; p 95%) was similar across regimens. Conclusions Patients on a tenofovir regimen have better clinical outcomes and improved general health than patients on the zidovudine regimen.

Infection with the frequently transmitted HIV-1 M41L variant has no influence on selection of tenofovir resistance

Abstract: Objectives: In similar to 10% of newly diagnosed HIV-1 patients, drug-resistant viral variants are detected. In such transmitted HIV-1 variants, the thymidine analogue mutation (TAM) M41L is frequently observed as a single resistance mutation and these viral variants often belong to phylogenetic transmission clusters. The presence of at least three TAMs, in particular patterns with M41L/L210W, impairs the efficacy of the extensively used drug tenofovir. We investigated whether the presence of a single M41L mutation at baseline influences the selection of resistance to tenofovir and emtricitabine in vitro and in vivo. Methods: The impact of M41L on the development of drug resistance to tenofovir and emtricitabine was determined by extensive in vitro selection experiments and investigation of the virological outcome of patients on a first-line regimen. Results: The presence of a single M41L mutation did not influence the selected mutational profile or the genetic barrier to resistance to tenofovir and/or emtricitabine during long-term in vitro selection experiments. In vivo, virological outcome of first-line regimens containing tenofovir and emtricitabine was comparable between patients diagnosed with HIV-1 harbouring M41L (n = 17, 16 were part of one transmission cluster) and WT virus (n = 248). Conclusions: Detection of a single M41L reverse transcriptase mutation at baseline did not influence the development of resistance in vitro or virological outcome on tenofovir-containing regimens in patients belonging to a large transmission cluster. Our results indicate that a high genetic barrier regimen may not be required when patients are diagnosed with HIV variants containing a single M41L mutation in reverse transcriptase.

Choice of Antiretroviral Drugs for Postexposure Prophylaxis for Children: A Systematic Review

Abstract: Background. This systematic review aimed to assess the safety and efficacy of antiretroviral options for postexposure prophylaxis (PEP). Recognizing the limited data on the safety and efficacy of antiretroviral drugs for PEP in children, this review was extended to include consideration of data on the use of antiretroviral drugs for treatment of infants and children living with human immunodeficiency virus. Methods. The PEP literature was assessed to identify studies reporting safety and completion rates for children given PEP, and this information was complemented by safety and efficacy data for drugs used in antiretroviral therapy. The proportion of patients experiencing each outcome was calculated and data were pooled using randomeffects meta-analysis. Results. Three prospective cohort studies reported outcomes of children given zidovudine (ZDV) plus lamivudine (3TC) as a 2-drug PEP regimen. The proportion of children completing the full 28-day course of PEP was 64.0% (95% confidence interval [CI], 41.2%–86.8%), whereas the proportion discontinuing due to adverse events was 4.5% (95% CI, .4%–8.6%). One randomized trial compared abacavir (ABC) plus lamivudine (3TC) and ZDV+3TC as part of a dual or triple first-line antiretroviral therapy regimen; this study showed better efficacy in the ABC-containing combinations and no difference in the time to first serious adverse event. Three randomized trials compared lopinavir/ritonavir (LPV/r) to nevirapine (NVP) for antiretroviral therapy and showed a lower risk of treatment discontinuations associated with LPV/r vs NVP (hazard ratio, 0.56 [95% CI, .41–.75]) but no difference in drug-related adverse events. The overall quality of the evidence was rated as very low. Conclusions. This review supports ZDV+3TC+LPV/r as the preferred 3-drug regimen for PEP in children.

Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study

Abstract: BACKGROUND The most recommended NRTI combinations as first-line antiretroviral treatment for HIV-1 infection in resource-rich settings are tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine. Efficacy studies of these combinations also considering pill numbers, dosing frequencies and ethnicities are rare. METHODS We included patients starting first-line combination ART (cART) with or switching from first-line cART without treatment failure to tenofovir/emtricitabine, abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine plus efavirenz or nevirapine. Cox proportional hazards regression was used to investigate the effect of the different NRTI combinations on two primary outcomes: virological failure (VF) and emergence of NRTI resistance. Additionally, we performed a pill burden analysis and adjusted the model for pill number and dosing frequency. RESULTS Failure events per treated patient for the four NRTI combinations were as follows: 19/1858 (tenofovir/emtricitabine), 9/387 (abacavir/lamivudine), 11/344 (tenofovir/lamivudine) and 45/1244 (zidovudine/lamivudine). Compared with tenofovir/emtricitabine, abacavir/lamivudine had an adjusted HR for having VF of 2.01 (95% CI 0.86-4.55), tenofovir/lamivudine 2.89 (1.22-6.88) and zidovudine/lamivudine 2.28 (1.01-5.14), whereas for the emergence of NRTI resistance abacavir/lamivudine had an HR of 1.17 (0.11-12.2), tenofovir/lamivudine 11.3 (2.34-55.3) and zidovudine/lamivudine 4.02 (0.78-20.7). Differences among regimens disappeared when models were additionally adjusted for pill burden. However, non-white patients compared with white patients and higher pill number per day were associated with increased risks of VF and emergence of NRTI resistance: HR of non-white ethnicity for VF was 2.85 (1.64-4.96) and for NRTI resistance 3.54 (1.20-10.4); HR of pill burden for VF was 1.41 (1.01-1.96) and for NRTI resistance 1.72 (0.97-3.02). CONCLUSIONS Although VF and emergence of resistance was very low in the population studied, tenofovir/emtricitabine appears to be superior to abacavir/lamivudine, tenofovir/lamivudine and zidovudine/lamivudine. However, it is unclear whether these differences are due to the substances as such or to an association of tenofovir/emtricitabine regimens with lower pill burden.

A Time to Event Analysis of Adverse Drug Reactions Due to Tenofovir, Zidovudine and Stavudine in a Cohort of Patients Receiving Antiretroviral Treatment at an Outpatient Clinic in Zimbabwe

Abstract: Background: Achieving the long terms goals of antiretroviral treatment (ART) requires a careful approach during treatment initiation that takes into account patient’s psychosocial state, availability and accessibility of treatment combinations, and adherence support. Adverse drug reactions that occur during the initial phases have a bearing on treatment outcomes and thus need to be monitored and treated. Objective: This study was done to assess length of time (survival time) it took for clinically significant adverse drug reactions to occur in patients taking Nucleoside Reverse Transcriptase Inhibitors (N(t)RTI) available for treatment of Human Immunodeficiency Virus (HIV) infection in Zimbabwe. Methods: A retrospective cohort of patient data collected from January 2009 to December 2012 was extracted from an Electronic Health Record database. Data from patients who were initiated on antiretroviral (ARV) drug regimens containing N(t)RTI drugs were analysed for survival time. A sample of 205 patient files was extracted for the time period for survival analysis using adverse drug reactions due to N(t)RTI drugs. Results: After data extraction, a total of 205 patient records were used in determining the time to event analysis of ADR’s in the cohort. The age range for the patients included in the study was 9 - 76 with a mean of 41 years (s.d = 14.8). Patients initiated on stavudine had a lower survival time before a clinically significant ADR compared to tenofovir (-365 days, p-value < 0.0005). Patients on zidovudine also had a less time before a significant reaction compared to those on tenofovir (-230 days; p-value = 0.008). Patients on zidovudine fared better compared to those on stavudine (-134 days; p-value < 0.0005). The mean survival time was highest for tenofovir (618 days), followed by zidovudine (388 days), and then stavudine (254 days).Conclusion: Patients on tenofovir have a longer survival time before a clinically significant adverse reaction. Treatment programmes need to continue commencing patients on tenofovir containing regimens as patients can be maintained for longer periods on this regimen.