Article

Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection a randomized trial

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Abstract

Resistance to antiretroviral agents remains a leading cause of treatment failure for patients infected with HIV-1. To describe the efficacy and safety of tenofovir disoproxil fumarate (tenofovir DF) compared with placebo in patients with detectable viral replication despite current antiretroviral therapy. Randomized, double-blind, placebo-controlled study through 24 weeks. After 24 weeks, all patients received open-label tenofovir DF for the remainder of the 48-week study. 75 North American, European, and Australian HIV clinics. 552 HIV-1-infected adults who were receiving antiretroviral therapy and had stable HIV-1 RNA levels ranging from 400 to 10,000 copies/mL. Change in HIV-1 RNA level (time-weighted average from baseline through week 24); proportion of patients with grade 3 or 4 laboratory abnormalities and adverse events; and genotypic HIV-1 resistance testing in a separate substudy at baseline, week 24, and week 48. A statistically significant decrease in HIV-1 RNA level through week 24 (the primary end point) was observed in the tenofovir DF group versus the placebo group (-0.61 log10 copies/mL vs. -0.03 log10 copies/mL, respectively [P < 0.001]; difference, -0.58 log10 copies/mL [95% CI, -0.68 to -0.49 log10 copies/mL]). In a virologic substudy, 94% of 253 patients had plasma isolates expressing reverse transcriptase mutations associated with nucleoside resistance mutations at baseline. Through week 24, the incidence of clinical adverse events was similar between patients receiving placebo and those receiving tenofovir DF (14% vs. 13%). No evidence of tenofovir DF-related toxicity was seen through week 48. In treatment-experienced patients with suboptimal viral suppression, tenofovir DF significantly reduced HIV-1 RNA level and had a safety profile similar to that of placebo.

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... Certain antiretroviral drugs -particularly tenofovir -have also been associated with kidney disease. In randomized clinical studies of generally healthy adults with limited other risk factors for kidney disease, tenovir use was generally associated with minimal nephrotoxicity [6,7]. In clinical practice, however, wherein individuals might have multiple other risk factors, the risk of tenovovir-associated CKD is likely higher [8]. ...
... Our results found a higher risk of CKD with increasing duration of tenofovir exposure, consistent with our previous findings [9] but in contrast to observations from some clinical trials [6,7]. We also found that tenofovir exposure was associated with an increased risk of CKD even when restricting our analysis to the most recent 5 years of data. ...
Article
Objective: Tenofovir disoproxil fumarate is a widely used antiretroviral for HIV infection that has been associated with an increased risk of chronic kidney disease (CKD). Our objective was to derive a scoring system to predict 5-year risk of developing CKD in HIV-infected individuals and to estimate difference in risk associated with tenofovir use. Design: We evaluated time to first occurrence of CKD (estimated glomerular filtration rate <60 ml/min per 1.73 m(2)) in 21 590 HIV-infected men from the Veterans Health Administration initiating antiretroviral therapy from 1997 to 2010. Methods: We developed a point-based score using multivariable Cox regression models. Median follow-up was 6.3 years, during which 2059 CKD events occurred. Results: Dominant contributors to the CKD risk score were traditional kidney risk factors (age, glucose, SBP, hypertension, triglycerides, proteinuria); CD4(+) cell count was also a component, but not HIV RNA. The overall 5-year event rate was 7.7% in tenofovir users and 3.8% in nonusers [overall adjusted hazard ratio 2.0, 95% confidence interval (CI) 1.8-2.2]. There was a progressive increase in 5-year CKD risk, ranging from less than 1% (zero points) to 16% (≥9 points) in nonusers of tenofovir, and from 1.4 to 21.4% among tenofovir users. The estimated number-needed-to-harm (NNH) for tenofovir use ranged from 108 for those with zero points to 20 for persons with at least nine points. Among tenofovir users with at least 1 year exposure, NNH ranged from 68 (zero points) to five (≥9 points). Conclusion: The CKD risk score can be used to predict an HIV-infected individual's absolute risk of developing CKD over 5 years and may facilitate clinical decision-making around tenofovir use.
... Tenofovir is a first-line medication for HIV or HBV infection as an acyclic nucleotide reverse-transcriptase inhibitor approved by the Food and Drug Administration [9,10]. Unlike other nucleoside analogue drugs, tenofovir has shown activity in both lymphoid cells and macrophages [11,12]. According to a previous study, viral DNA from leukocytes, lymph nodes, and plasma was eradicated after a monotherapy of inoculating tenofovir for 24 hours [11,13]. ...
... Unlike other nucleoside analogue drugs, tenofovir has shown activity in both lymphoid cells and macrophages [11,12]. According to a previous study, viral DNA from leukocytes, lymph nodes, and plasma was eradicated after a monotherapy of inoculating tenofovir for 24 hours [11,13]. Tenofovir is not a substrate, inducer or inhibitor of CYP450 [9,14], and 70 to 80% of unchanged form is eliminated by renal excretion through glomerular filtration and active tubular secretion [9]. ...
Article
Tenofovir is the representative treatment for human immunodeficiency virus and hepatitis B virus infection. This study was conducted to assess the pharmacokinetics (PKs) and safety characteristics after a single administration of tenofovir disoproxil phosphate compared to tenofovir disoproxil fumarate in healthy male subjects. An open-label, randomized, single administration, two-treatment, two-sequence crossover study was conducted in 37 healthy volunteers. Serial blood samples were collected up to 72 hours. Non-compartmental analysis was used to calculate the PK parameters. The 90% confidence intervals (90% CIs) of the geometric mean ratio (GMR) were calculated for comparing tenofovir disoproxil phosphate to tenofovir disoproxil fumarate. Safety assessments were performed including clinical laboratory tests, adverse events, etc. during the study. The GMR and 90% CIs were 1.0514 (0.9527-1.1603) for Cmax and 1.0375 (0.9516-1.1311) for AUClast, respectively, and both fell within the conventional bioequivalence range of 0.8-1.25. Both tenofovir salt forms were tolerable. This study demonstrated that tenofovir disoproxil phosphate (292 mg) was bioequivalent to tenofovir disoproxil fumarate (300 mg).
... In addition to mechanistic studies supporting a nephrotoxic potential of TDF [31][32][33], numerous other studies have investigated TDF nephrotoxicity, including case reports [25,34,35], cohort studies [1,2,[36][37][38], and randomized controlled trials [39][40][41][42][43]. Most recently, a large US study found an independent association between TDF and 3 renal outcomes ( proteinuria, CKD, and rapid eGFR decline) in treatment-naive persons [3]. ...
... Several randomized trials have also investigated adverse renal events associated with TDF use among individuals with an initially normal renal function [39][40][41][42][43]. Many of these trials were, however, of insufficient size and follow-up to detect such rare events as chronic renal impairment, as was done in this analysis. ...
Article
Background: Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)-positive persons with initially normal renal function is unknown. Methods: D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥ 90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤ 70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤ 60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥ 3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression. Results: Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤ 70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35-5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10-1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7-6.1 years). A current eGFR of 60-70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38-2.14]) but not other ARVs compared with a current eGFR of ≥ 90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12-1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09-1.32]) were independent predictors of a confirmed eGFR of ≤ 70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05-1.17] and 1.22/year [95% CI, 1.16-1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs. Conclusions: Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.
... The most frequently used NRTI in the dataset, TDF, was associated with the symptom "people unfriendly" in cluster 1, and "restless" and "effort" in cluster 2 with high probabilities. Several clinical trials have reported the associations between TDF and depression (Squires et al., 2003;Mills et al., 2016). The most frequently used NNRTI drug, EFV, was associated with nearly half of the depression items in cluster 1 and three items in cluster 2 with high probabilities. ...
Article
Access and adherence to antiretroviral therapy (ART) has transformed the face of HIV infection from a fatal to a chronic disease. However, ART is also known for its side effects. Studies have reported that ART is associated with depressive symptomatology. Large-scale HIV clinical databases with individuals' longitudinal depression records, ART medications, and clinical characteristics offer researchers unprecedented opportunities to study the effects of ART drugs on depression over time. We develop BAGEL, a Bayesian graphical model to investigate longitudinal effects of ART drugs on a range of depressive symptoms while adjusting for participants' demographic, behavior, and clinical characteristics, and taking into account the heterogeneous population through a Bayesian nonparametric prior. We evaluate BAGEL through simulation studies. Application to a dataset from the Women's Interagency HIV Study yields interpretable and clinically useful results. BAGEL not only can improve our understanding of ART drugs effects on disparate depression symptoms, but also has clinical utility in guiding informed and effective treatment selection to facilitate precision medicine in HIV.
... Previous randomized controlled trials of TDF reported very low prevalence of renal toxicity and, although small differences in glomerular filtration rate over time were noted, eGFR decline associated with TDF use was not considered to be clinically relevant. [9][10][11] Similarly, a systematic review and metaanalysis suggested that TDF-containing regimens were associated with a significantly greater loss of eGFR than regimens not containing TDF, although the magnitude of the effect was modest in clinical terms. [12] Nonetheless, several observational studies have demonstrated an association between TDF use and an increased risk of CKD, even among patients with normal renal function prior to cART initiation. ...
Article
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Background: Tenofovir (TDF) can cause kidney injury through tubular dysfunction, with or without drop of estimated glomerular filtration rate (eGFR). Whether mild eGFR reductions during treatment should be considered a reason for prompt TDF discontinuation, however, remains unclear. Methods: Patients with normal pre-TDF eGFR levels, who had developed mild renal impairment (i.e., two consecutive eGFR results between 89–60 ml/min) on TDF, were observed until onset of chronic kidney disease (CKD), defined as two eGFR<60 ml/min 3 to 6 months apart. Mul- tivariable Poisson regression analysis was used to investigate whether outcome was asso- ciated with current and cumulative use of TDF (modeled as time-varying covariates). Results: 2023 (29%) out of 6984 patients developed mild renal impairment on TDF. Among them, 191 progressed to CKD. The incidence of CKD did not significantly differ during TDF treat- ment (2.6 per 100 PYFU; 95%CI 2.2–3.2) or after its discontinuation (2.2 per 100 PYFU; 95%CI 1.8–2.6). However, the rate of CKD was significantly higher among patients continu- ing with TDF treatment compared to those who had discontinued it within 6 months of occur- rence of mild renal impairment (aIRR 4, 95%CI 2.4–6.8). In contrast, among patients who had maintained TDF >6 months despite mild renal impairment, current TDF use was not associated with a significantly higher rate of CKD. Other significant predictors of CKD were older age, intravenous drug use, diabetes, hypertension, lower pre-TDF eGFR, higher eGFR drop since TDF introduction and longer exposure to TDF. Conclusions: Prompt discontinuation of TDF among patients developing mild renal impairment may prevent further progression of renal damage.
... There was no association between phosphate supplementation and mortality (í µí±ƒ = 0.20). While tenofovir has been linked to renal phosphate wasting and toxicity in some reports, though not in randomized trials, the initiation of a tenofovir-containing regimen in our cohort was not associated with increased mortality (í µí±ƒ = 0.12)262728. In a logistic regression model excluding participants with unknown vital status and adjusted for sex, age, and CD4 + lymphocyte count, both serum phosphate (odds ratio (OR) 1.18 per 0.1 mmol/L decrease; í µí±ƒ = 0.02) and BMI (OR 1.33 per 1.0 kg/m 2 decrease; í µí±ƒ < 0.01) were significantly associated with 12-week mortality. ...
Article
Full-text available
Background. Low body mass index (BMI) at antiretroviral therapy (ART) initiation is associated with early mortality, but the etiology is not well understood. We hypothesized that low pretreatment serum phosphate, a critical cellular metabolism intermediate primarily stored in skeletal muscle, may predict mortality within the first 12 weeks of ART. Methods. We prospectively studied 352 HIV-infected adults initiating ART in Lusaka, Zambia to estimate the odds of death for each 0.1 mmol/L decrease in baseline phosphate after adjusting for established predictors of mortality. Results. The distribution of phosphate values was similar across BMI categories (median value 1.2 mmol/L). Among the 145 participants with BMI <18.5 kg/m(2), 28 (19%) died within 12 weeks. Lower pretreatment serum phosphate was associated with increased mortality (odds ratio (OR) 1.24 per 0.1 mmol/L decrement, 95% CI: 1.05 to 1.47; P = 0.01) after adjusting for sex, age, and CD4(+) lymphocyte count. A similar relationship was not observed among participants with BMI ≥18.5 kg/m(2) (OR 0.96, 95% CI: 0.76 to 1.21; P = 0.74). Conclusions. The association of low pretreatment serum phosphate level and early ART mortality among undernourished individuals may represent a variant of the refeeding syndrome. Further studies of cellular metabolism in this population are needed.
... Además, el descenso de la CVP plasmática de VIH en el grupo de tenofovir DF se mantuvo hasta la semana 48 (-0,56 log 10 copias/ml). En este estudio, la proporción de pacientes con CVP de VIH < 400 copias/ml en la semana 24 fue del 45% en el grupo de tenofovir DF y del 12% en el grupo de placebo (datos por tratamiento recibido; p < 0,001) 319 . ...
Article
Objetivo Efectuar una puesta al día de las recomendaciones sobre el tratamiento antirretroviral (TAR) para los adultos infectados por el virus de la inmunodeficiencia humana (VIH). Métodos Estas recomendaciones se han consensuado por un comité del Grupo de Estudio de Sida (GESIDA) y del Plan Nacional sobre el Sida (PNS). Para ello se han revisado los avances en la fisiopatología del VIH, los resultados de eficacia y seguridad de ensayos clínicos, estudios de cohortes y de farmacocinética, publicados en revistas biomédicas o presentados en congresos en los últimos años. Se han definido tres niveles de evidencia según la procedencia de los datos: estudios aleatorizados (nivel A), de cohortes o de caso-control (nivel B), u opinión de expertos (nivel C). En cada una de las situaciones se ha establecido recomendar, considerar o no recomendar el TAR. Resultados En el momento actual, el TAR con combinaciones de al menos tres fármacos constituye el tratamiento de inicio de elección de la infección crónica por el VIH. Estas pautas deben incluir dos inhibidores de la transcriptasa inversa análogos de nucleósidos (ITIAN) más un no nucleósido (ITINN) o dos ITIAN más un inhibidor de la proteasa (IP). En los pacientes con una infección por VIH sintomática se recomienda iniciar TAR. En los pacientes asintomáticos el inicio de TAR se basará en la cifra de linfocitos CD4+/μl y en la carga viral plasmática (CVP): a) en pacientes con linfocitos CD4+ < 200 cél./μl se recomienda iniciar el TAR; b) en pacientes con linfocitos CD4+ entre 200 y 350 cél./μl en la mayoría de las ocasiones se debe recomendar el inicio de TAR; si bien se podría diferir cuando la cifra de linfocitos CD4+ se mantiene próxima a 350 cél./μl y la CVP es baja, y c) en los pacientes con linfocitos CD4+ > 350 cél./μl se puede diferir el inicio del TAR. El objetivo del TAR inicial es lograr una CVP indetectable. La adherencia al TAR tiene un papel fundamental en la duración de la respuesta antiviral. Las opciones terapéuticas en los fracasos del TAR son limitadas por la aparición de resistencias cruzadas. Los estudios genotípicos en estos casos son de utilidad. La toxicidad es un factor limitante del TAR, aunque los beneficios superan los posibles perjuicios. También se discuten los criterios de TAR de la infección aguda, embarazo y profilaxis postexposición, y el manejo de la coinfección por el VIH y los virus de la hepatitis C y B (VHC y VHB). Conclusiones La cifra de linfocitos CD4+ es el factor de referencia más importante para iniciar el TAR en pacientes asintomáticos. Por otra parte, el número considerable de fármacos disponibles, los métodos de monitorización más sensibles (CVP), y la posibilidad de determinar las resistencias hacen que las estrategias terapéuticas sean mucho más individualizadas.
... Tenofovir Disoproxil Fumarate is a nucleotide reverse transcriptase inhibitor that has been widely used in the United States since the initial premarketing trials in 2004 [68][69][70]. Tenofovir is excreted in the urine by glomerular filtration as well as via tubular secretion. Studies have demonstrated these nucleotide analogues including tenofovir enter tubular epithelial cells via organic anionic transporters OAT1 and OAT3 and interact with multidrug-resistance-associated protein MRP4 on the luminal membrane for tubular secretion [71]. ...
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Copyright: © 2012 Mallipattu SK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract HIV-related kidney disease has been associated with significant morbidity and mortality in the HIV population. It is clear that the epidemiology of HIV-related kidney disease has changed dramatically since the first case reports in 1984. During these early years, the predominant etiology of kidney disease in HIV was recognized as HIV-associated nephropathy (HIVAN), an aggressive form of kidney disease with a high rate of progression to end-stage renal disease (ESRD). Subsequently, with the widespread use of combination antiretroviral therapy (cART), there was a dramatic decrease in the incidence of ESRD attributed to HIV/AIDS. Although the incidence of HIV-related ESRD has plateaued in the last 15 years, the prevalence has continued to increase because of improved survival. Available prevalence estimates do not include HIV-infected individuals with comorbid ESRD, although there is growing evidence that the epidemiology of kidney disease in the HIV-infected population has changed. This article reviews the impact of risk factors such as race, diabetes mellitus, hypertension, hepatitis C virus coinfection, and the chronic use of cART on the changing epidemiology of HIV-related kidney disease. Additionally in this review, we propose potential areas of translational research that will help to further characterize HIV-related kidney disease in the 21 st century.
... Tenofovir Disoproxil Fumarate is a nucleotide reverse transcriptase inhibitor that has been widely used in the United States since the initial premarketing trials in 2004 [68][69][70]. Tenofovir is excreted in the urine by glomerular filtration as well as via tubular secretion. Studies have demonstrated these nucleotide analogues including tenofovir enter tubular epithelial cells via organic anionic transporters OAT1 and OAT3 and interact with multidrug-resistance-associated protein MRP4 on the luminal membrane for tubular secretion [71]. ...
Data
Full-text available
HIV-related kidney disease has been associated with significant morbidity and mortality in the HIV population. It is clear that the epidemiology of HIV-related kidney disease has changed dramatically since the first case reports in 1984. During these early years, the predominant etiology of kidney disease in HIV was recognized as HIV-associated nephropathy (HIVAN), an aggressive form of kidney disease with a high rate of progression to end-stage renal disease (ESRD). Subsequently, with the widespread use of combination antiretroviral therapy (cART), there was a dramatic decrease in the incidence of ESRD attributed to HIV/AIDS. Although the incidence of HIV-related ESRD has plateaued in the last 15 years, the prevalence has continued to increase because of improved survival. Available prevalence estimates do not include HIV-infected individuals with comorbid ESRD, although there is growing evidence that the epidemiology of kidney disease in the HIV-infected population has changed. This article reviews the impact of risk factors such as race, diabetes mellitus, hypertension, hepatitis C virus coinfection, and the chronic use of cART on the changing epidemiology of HIV-related kidney disease. Additionally in this review, we propose potential areas of translational research that will help to further characterize HIV-related kidney disease in the 21(st) century.
... De los INRTs, el tenofovir ocasiona menores trastornos lipídicos. 96,97 Además, la sustitución de ritonavir y liponavir por atazanavir disminuye los Tg. 98 Otro aspecto importante del cambio de la TARGA es que puede eliminarse el tratamiento hipolipidemiante con la mejoría subsecuente del metabolismo lipídico. [99][100][101] ...
Article
Full-text available
The HIV epidemic is a public health problem at worldwide. The morbidity and mortality associated with AIDS have change in a significant way with the use of anti-retroviral therapy. However, it has been affected by the changes provoked in the lipoprotein metabolism, which are characterized by a rise of the very low-density lipoprotein (VLDL) levels and triglycerides, an increase of total cholesterol, low-density lipoprotein (LDL). HIV-infection associated with other inflammatory factors, is a progression model of atherosclerosis. The proatherogenic lipid profile in HIV/AIDS persons is a high risk for the development of the coronary disease. In present paper we analyzed the contribution of both the HIV-infection and the antiretroviral therapy effect on the lipid metabolism and its therapeutical procedure.
... 4 One of the strategies proposed to achieve this goal is treatment intensification, that is, the addition of one or more drugs to an already existing regimen. Intensification of regimens in the setting of moderate levels of viremia with drugs such as abacavir or tenofovir has proven to be effective, [5][6][7][8][9] but the efficacy of intensification in the setting of already successful plasma viral suppression has not been demonstrated in a randomized trial. AIDS Clinical Trials Group Study 372A was designed to answer the question of whether intensification with abacavir in this setting would delay the time to treatment failure. ...
Article
Background and objective: Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure. Methods: Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels<500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs>200 copies/mL) and treatment discontinuation. Results: At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P=.77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P=.22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms. Conclusions: The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/ mL can be further reduced and what influence this may have on latent HIV reservoirs.
... TDF is excreted through a combination of glomerular filtration and active tubular secretion, with uptake in the proximal tubule and secretion into the tubular space [20]. Initial clinical trials described a favourable renal safety profile [21,22], however there were rare postmarketing reports of Fanconi's syndrome (proximal tubulopathy) leading to glucosuria, phosphaturia, aminoaciduria and bicarbonate wasting [23,24]. Subsequent studies have found that TDF use causes a small but significant decrease in creatinine clearance (a surrogate for glomerular filtration) in both HIV positive and negative populations [25,26]. ...
Article
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Background: HIV infection is associated with increased risk of renal dysfunction, including tubular dysfunction (TD) related to antiretroviral therapy (ART). Tenofovir disoproxil fumarate (TDF) is becoming available for ART in sub-Saharan Africa, although data on its long-term safety there is limited. We aimed to study the prevalence of HIV-associated renal dysfunction in Ghana and explore associations between proteinuria or TD and potential risk factors, including TDF use. Methods: A single-centre cross-sectional observational study of patients taking ART was undertaken. Creatinine clearance (CrCl) was calculated and proteinuria detected with dipsticks. Spot urinary albumin and protein:creatinine ratios (uACR/uPCR) were measured and further evidence of TD (defined as having two or more characteristic features) sought. Logistic regression analysis identified factors associated with proteinuria or TD. Results: In 330 patients, of whom 101 were taking TDF (median 20 months), the prevalence of CrCl < 60ml/min/1.73m(2), dipstick proteinuria and TD was 7 %, 37 % and 15 %. Factors associated with proteinuria were baseline CD4-count [aOR 0.86/100 cell increment (95 % CI, 0.74-0.99)] and TDF use [aOR 2.74 (95 % CI, 1.38-5.43)]. The only factor associated with TD was TDF use [aOR 3.43 (95 % CI, 1.10-10.69)]. In a subset with uPCR measurements, uPCRs were significantly higher in patients taking TDF than those on other drugs (10.8 vs. 5.7 mg/mmol, p < 0.001), and urinary albuin:protein ratios significantly lower (0.24 vs. 0.58, p < 0.001). Conclusions: Both proteinuria and TD are common and associated with TDF use in Ghana. Further longitudinal studies to determine whether proteinuria, TD or TDF use are linked to progressive decline in renal function or other adverse outcomes are needed in Africa.
... [24][25][26][27] Similar results were observed in two placebo-controlled studies (902 and 907) which included HIV treatment-experienced individuals with detectable viral load on stable combination antiretroviral therapy. 28,29 Tenofovir + emtricitabine and abacavir + lamivudine are fixed-dose combinations commonly used along with NNRTIs or ritonavir-boosted protease inhibitors as firstline therapy, but there is conflicting evidence concerning their relative efficacy. Several trials have suggested higher efficacy for TDF + emtricitabine, 30-32 especially in the subset of patients with high viral load, whereas other studies have shown no difference in efficacy when comparing these nucleoside reverse transcriptase inhibitor backbones through 96 weeks. ...
Article
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Tenofovir is currently one of the most widely used nucleoside reverse transcriptase inhibitors in the treatment of human immunodeficiency virus (HIV) due to its good efficacy, tolerability, and convenience as a once-daily dosage. It is a drug of choice both for first-line therapy in naïve and pretreated patients, along with two other active drugs as part of a highly active antiretroviral therapy. Moreover, tenofovir can be used to treat hepatitis B virus-infected patients as well as confected patients who meet criteria to be treated for HIV or hepatitis B virus infection, and more recently some studies have supported its use as part of pre-exposure prophylaxis. Although large clinical trials and postmarketing studies have shown a gentle renal profile for tenofovir, some prospective cohort studies and case reports have raised concern about renal damage and bone disorders associated with use of tenofovir in a small proportion of patients, and apprehension lingers over its long-term usage. Renal toxicity from tenofovir seems to be linked to tubular damage, so classical markers for monitoring renal function that mainly assess glomerular function would not be advisable to detect early renal impairment. Management of toxicity associated with tenofovir should be based on assessment of optimal biomarkers for the detection and monitoring of renal disease.
... It is primarily excreted through the kidney via glomerular filtration and active tubular secretion. The 300-mg/day oral TDF regimen [3] is preferred to other anti-retrovirals such as adenofir and cidofir because of its convenience, efficacy, safety, and tolerability [4][5][6]. However recent studies show that TDF has serious side effects, especially with long-term use. ...
Article
Tenofovir disoproxil fumarate (TDF) is recommended as a first-line therapy in HIV treatment. However, TDF is nephrotoxic especially with long-term use. Early detection of nephrotoxicity and its prevention are key to avoid irreversible renal damage. This requires knowledge of the mechanism of TDF nephrotoxicity. A reliable animal model is therefore necessary to study the mechanism of TDF nephrotoxicity. To standardize a rodent model of TDF nephrotoxicity resembling humans, adult male Wistar rats were used for the studies. Initially the optimal dose and the duration of treatment required to produce nephrotoxicity in rats was established and it was found that a dose of 600 mg/kg body weight for 5 weeks p.o. was required. The histological changes (in the kidney) and biochemical changes (in the serum and urine) were recorded after treatment at different doses of TDF. At this dose the TDF treated rat kidneys showed structural and functional alterations in the proximal tubule resembling that of HIV patients on TDF therapy. The proximal convoluted tubules were distorted and their lining epithelium was absent. Biochemically, the rats exhibited Fanconi syndrome characterized by bicarbonate wasting, phosphaturia, kaluria, low serum bicarbonate and phosphate. TDF dose of 600 mg/kg body wt. which is 12 x the human dose and the treatment period of 5 weeks induces proximal tubular damage and dysfunction that is very similar to that seen in TDF treated humans. Thus, the rat model appears to be a suitable model for the study of TDF nephrotoxicity.
... However, data from controlled clinical trials and cohort studies have shown little or no toxicity clearly associated with TDF in HIV-infected patients with normal baseline renal function. In 4 manufacturersponsored controlled clinical trials, there were no significant differences in renal abnormalities between the TDF and control groups over 44 weeks, 48 weeks, 96 weeks, and 144 weeks of therapy505152535455. In the post marketing safety database and expanded access program for TDF, serious renal adverse events were observed in 0.5% of patients. ...
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... The most common side effects of nucleos(t)ide analogues (NA) reported in chronic hepatitis B (CHB) treatment include potential effects on neuromuscular function, renal function and bone mineralization. Registration studies of TDF in the treatment of human immunodeficiency virus (HIV), demonstrated a good renal safety profile (2,3). Although uncommon, Fanconi syndrome has been reported almost exclusively in HIV infected patients treated with TDF in combination with other antivirals (4). ...
Article
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Tenofovir disoproxil fumarate (TDF) is one of the first-line treatment options in chronic hepatitis B (CHB). Despite its efficacy in suppressing viral load and a high resistance barrier, long life maintenance therapy is required. Registration studies demonstrated TDF to be a safe drug. However, post-marketing experience reported cases of serious nephrotoxicity associated with hypophosphatemia, osteomalacia and, even more recently, Fanconi syndrome associated with TDF therapy in CHB monoinfected patients.Here the authors report a case of a 40 year-old male, with a CHB monoinfection, that, three years after TDF therapy, developed a progressive chronic kidney disease with a serious hypophosphatemia and a secondary osteomalacia that was manifested by bone pain and multiple bone fractures. Further investigational analyses unveiled a proximal renal tubular dysfunction, which fulfilled most of the diagnostic criteria for a Fanconi syndrome. After TDF withdrawal and oral supplementation with phosphate and calcitriol, his renal function stabilized (despite not returning to normal), proximal renal tubular dysfunction abnormalities resolved as well as osteomalacia. In conclusion, physicians should be aware that, in CHB monoinfected patients under TDF therapy, serious renal damage is possible and preventable by timely monitoring serum creatinine and phosphate.
... TDF is approved for the treatment of HIV-1 infection in adults as combination therapy with other antiretroviral drugs. Tenofovir is also commercialized in combination with emtricitabine (Truvada®) as an FDA-approved prescription drug for pre-exposure prophylaxis to reduce the risk of HIV infection [51][52][53]. ...
Article
In December 2019, a new variant of SARS-CoV emerged, the so-called acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes the new coronavirus disease (COVID-19) and has been plaguing the world owing to its unprecedented spread efficiency, which has resulted in a huge death toll. In this sense, the repositioning of approved drugs is the fastest way to an effective response to a pandemic outbreak of this scale. Considering these facts, in this review we provide a comprehensive and critical discussion on the chemical aspects surrounding the drugs currently being studied as candidates for COVID-19 therapy. We intend to provide the general chemical community with an overview on the synthetic/biosynthetic pathways related to such molecules, as well as their mechanisms of action against the evaluated viruses and some insights on the pharmacological interactions involved in each case. Overall, the review aims to present the chemical aspects of the main bioactive molecules being considered to be repositioned for effective treatment of COVID-19 in all phases, from the mildest to the most severe.
... Supplementary Figure F7 plots the posterior probabilities of {R h,dq = 1} across all drugs and depression items. The most frequently used NRTI in the dataset, TDF, was associated with the symptom "people unfriendly" in cluster 1, and "restless" and "effort" in cluster 2. Several clinical trials have reported the associations between TDF and depression (Squires et al., 2003;Mills et al., 2016). The most frequently used NNRTI drug, EFV, was associated with nearly half of the depression items in cluster 1 and three items in cluster 2. This is consistent with studies demonstrating associations between EFV and depressive symptoms, such as suicidal behavior (Mollan et al., 2014;Bengtson et al., 2017;Arenas-Pinto et al., 2018). ...
Preprint
Access and adherence to antiretroviral therapy (ART) has transformed the face of HIV infection from a fatal to a chronic disease. However, ART is also known for its side effects. Studies have reported that ART is associated with depressive symptomatology. Large-scale HIV clinical databases with individuals' longitudinal depression records, ART medications, and clinical characteristics offer researchers unprecedented opportunities to study the effects of ART drugs on depression over time. We develop BAGEL, a Bayesian graphical model to investigate longitudinal effects of ART drugs on a range of depressive symptoms while adjusting for participants' demographic, behavior, and clinical characteristics, and taking into account the heterogeneous population through a Bayesian nonparametric prior. We evaluate BAGEL through simulation studies. Application to a dataset from the Women's Interagency HIV Study yields interpretable and clinically useful results. BAGEL not only can improve our understanding of ART drugs effects on disparate depression symptoms, but also has clinical utility in guiding informed and effective treatment selection to facilitate precision medicine in HIV.
... Since its approval, this drug has been included in most recommended regimens and has been the most widely used NRTI for many years based on its established high efficacy and generally good tolerance, as demonstrated in clinical trials and real-life studies. [11][12][13][14][15] Furthermore, using TDF-containing NRTI regimens has improved lipid parameters, supporting a lipid-lowering effect of TDF. [16][17][18] Despite its favourable characteristics, TDF can have clinically significant renal toxic effects and lead to a greater decline in bone mineral density (BMD) relative to some other NRTIs, attributed to high circulating plasma levels of tenofovir. ...
Article
Two elvitegravir/cobicistat‐based therapies combined with emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) or emtricitabine/tenofovir alafenamide fumarate (EVG/c/FTC/TAF) are currently available for HIV patients. This study evaluated the modifications in the lipid profile of patients who received these treatments in the last three years at our institution. A retrospective observational study in HIV‐infected patients who received EVG/c/FTC/TDF or EVG/c/FTC/TAF from January 2015 to January 2018 at a reference hospital in northwestern Spain was carried out. Epidemiological, clinical and immunovirological data were recorded. A statistical analysis was performed using SPSS software. A total of 384 EVG/c‐based therapies were initiated during the study period, 151 EVG/c/FTC/TDF and 233 EVG/c/FTC/TAF. A significantly negative influence in all the lipid profile parameters in experienced patients and total cholesterol (TC), and LDL‐C in naïve patients were observed after 48 weeks of treatment with EVG/c/FTC/TAF, while these parameters remained stable in the EVG/c/FTC/TDF group. During follow‐up, a greater proportion of patients had lipid levels above the normal range (63.1% TC, 56.2% LDL‐C) and new lipid‐modifying drugs were prescribed (11.9%) in the EVG/c/FTC/TAF group. The number of cardiovascular risk factors [OR 1.66 (95% CI 1.01–2.72);p=0.043] was recognised as an independent predictor of lipid‐lowering prescription for patients treated with both EVG/c/FTC/TDF and EVG/c/FTC/TAF. For patients treated with EVG/c/FTC/TAF, the mean total cholesterol to HDL ratio in the first 48 weeks of the study treatment was associated with a higher likelihood of lipid‐lowering prescription in multivariate analysis [OR 1.6 (95% CI 1.12–2.52);p=0.011]. Significant changes in lipid profile have been observed in patients who have received EVG/c/FTC/TAF. It was necessary to prescribe almost twice the number of lipid‐lowering drugs to patients who received EVG/c/FTC/TAF (11.9%) versus EVG/c/FTC/TDF (4.7%). This article is protected by copyright. All rights reserved.
... TFV is an acyclic nucleotide analogue of adenosine 5' monophosphate that is phosphorylated intracellularly by adenylate kinase to its active form, tenofovir diphosphate (Figure 1). TFV is effective in cases of nucleoside resistant HIV infection, making it a first line agent for treatment of this disease (Miller et al., 2001;Squires et al., 2003). Despite its efficacy, poor bioavailability was a limiting factor in development of TFV as a clinical agent. ...
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Over 1 million people in the United States are living with Human Immunodeficiency Virus (HIV) which may progress to Acquired Immunodeficiency Disease. The use of antiviral therapy has successfully controlled the rate of viral growth in patients. Antiviral agents improve the quality of life and reduce the potential for spreading HIV; HIV is currently considered a chronic disease provided patients are compliant with their antiviral medications. Tenofovir is a nucleoside transcriptase inhibitor that prevents viral replication and is approved for treatment of HIV and chronic hepatitis B infection. Tenofovir is an antiretroviral drug used alone and in combination with other nucleoside reverse transcriptase inhibitor agents to lower viral load in HIV patients. Tenofovir is administered as a prodrug in order to increase bioavailability. The prodrug forms of tenofovir are tenofovir disoproxil fumarate approved in 2001 and tenofovir alafenamide approved in 2016. Tenofovir is extensively used in controlling HIV as it is administered once daily allowing for good compliance. This minireview discusses the changes in dosing that are needed in the presence of renal impairment which is a common occurrence with HIV chronic disease progression. The impact of food, age and drug transporters on tenofovir absorption and clearance will be discussed. The potential special conditions occurring with fixed combination doses containing tenofovir will also be reviewed including the use of cobicistat, a cytochrome P450 3 inhibitor. The short review also addresses some newer preparations using niosomes to improve tenofovir absorption and delivery to the target cells.
... Since its approval by the US Food Drug and Administration in 2001, 1 tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor, has enjoyed a global acceptance as a component of both first line and second line antiretroviral regimens due to its efficacy, 2 low incidence of adverse events, 2,3 convenient pharmacokinetic profile 4 and positive clinical outcomes. 2 Despite its proven efficacy, 1 significant decline in renal function in the TDFexposed group relative to the control. 5 The incidence of TDF-related nephropathy appears to be on the increase as seen in a recent cohort study of 440 patients initiated on TDF-based regimen which reported an incidence of 12%. ...
Article
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Introduction The use of tenofovir disoproxil fumarate (TDF) in the treatment of HIV infection has been associated with renal dysfunction. In Nigeria, data on the incidence and risk factors of TDF nephrotoxicity are sparse. We determined the cumulative incidence of and risk factors for TDF-induced renal impairment in HIV-infected individuals accessing care at the antiretroviral therapy (ART) clinic of Jos University Teaching Hospital, Nigeria. Methods This retrospective cohort analysis included patients aged ≥16 years that initiated ART between January 2008 and December 2011. Renal impairment, defined as glomerular filtration rate GFR <60 mL/min/1.73 sqm using the Modification of Diet in Renal Disease (MDRD) equation was assessed at baseline and at 48 weeks on ART. Logistic regression was performed to determine factors associated with incident renal impairment. Results The mean age was 39±9 years, and 67.1% were female. The cumulative incidence of renal impairment among the TDF-exposed and TDF-unexposed groups was 4.6% and 2.3% respectively (p<0.001). TDF exposure was significantly associated with renal impairment [OR=2.0, 95%CI=(1.48-2.89), p<0.001] in bivariate analysis. In multivariate analysis, older age (aOR=1.06, 95%CI=(1.05-1.08), p<0.001), TDF exposure [aOR=1.85, 95%CI=(1.31-2.60), p<0.001] and co-morbidities [aOR=2.71, 95%CI=(1.72-4.25), p<0.001] were significantly associated with renal impairment. Conclusion TDF exposure, aging and comorbidities were predictors of renal toxicity among HIV positive patients. Regular monitoring of renal function in such high-risk individuals is recommended.
... Since its approval by the US Food Drug and Administration in 2001, 1 tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor, has enjoyed a global acceptance as a component of both first line and second line antiretroviral regimens due to its efficacy, 2 low incidence of adverse events, 2,3 convenient pharmacokinetic profile 4 and positive clinical outcomes. 2 Despite its proven efficacy, 1 significant decline in renal function in the TDFexposed group relative to the control. 5 The incidence of TDF-related nephropathy appears to be on the increase as seen in a recent cohort study of 440 patients initiated on TDF-based regimen which reported an incidence of 12%. ...
Article
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Introduction: The use of tenofovir disoproxil fumarate (TDF) in the treatment of HIV infection has been associated with renal dysfunction. In Nigeria, data on the incidence and risk factors of TDF nephrotoxicity is sparse. We determined the cumulative incidence of and risk factors for TDF-induced renal impairment in HIV-infected individuals accessing care at the antiretroviral therapy (ART) clinic of Jos University Teaching Hospital, Nigeria. Methods: This retrospective cohort analysis included patients aged ≥16 years that initiated ART between January 2008 and December 2011. Renal impairment, defined as glomerular filtration rate GFR <60 mL/min/1.73 sqm using the Modification of Diet in Renal Disease (MDRD) equation was assessed at baseline and at 48 weeks on ART. Logistic regression was performed to determine factors associated with incident renal impairment. Results: The mean age was 39±9 years, and 67.1% were female. The cumulative incidence of renal impairment among the TDF-exposed and TDF-unexposed groups was 4.6% and 2.3% respectively (p<0.001). TDF exposure was significantly associated with renal impairment [OR=2.0, 95%CI=(1.48-2.89), p<0.001] in bivariate analysis. In multivariate analysis, older age (aOR=1.06, 95%CI=(1.05-1.08), p<0.001), TDF exposure [aOR=1.85, 95%CI=(1.31-2.60), p<0.001] and co-morbidities [aOR=2.71, 95%CI=(1.72-4.25), p<0.001] were significantly associated with renal impairment. Conclusion: TDF exposure, aging and comorbidities were predictors of renal toxicity among HIV positive patients. Regular monitoring of renal function in such high-risk individuals is recommended.
Article
Objective: Describe the efficacy and safety of tenofovir. Methods: Observational, descriptive study. Data were analyzed for the intention-to-treat sample. The primary efficacy end-point included the proportion of patients with HIV-1 RNA level of 50 copies/ml or less. Secondary efficacy end points was the increase of the CD4 cell count at week 48. The primary safety end-point was the number of patients with abnormalities (clinical adverse events and laboratory toxicities). The causality of the adverse effects was measured by the Naranjo algorithm Results: 154 subjects were enrolled; 12 were excluded from all analyses. Efficacy end points: Plasma HIV-1 RNA response: -1.29 ± 0.97 log10 copies/ml; Patients with HIV-1 RNA levels of 50 copies/ml or less: 28.16%; CD4 cell count response: 40.27 ± 141.50 cel/mm³. Safety profile was similar to showed at prescribing information, 3 Fanconi Syndrome were detected. Conclusion: Tenofovir supposes an antiretroviral of high effectiveness in our hospital, with an optimum safety profile.
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Tenofovir disoproxil fumarate (TDF) is an oral prodrug of tenofovir, a novel, acyclic nucleotide analogue with in vitro activity against HIV-1 and HIV-2. TDF is licensed by American Food and Drug Administration (FDA) in 2001 for the treat- ment of HIV infection. TDF is currently one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infec- tion. Its efficacy, favorable toxicity profile, and convenient dosing have made this drug one of the most popular first-line treatment. Numerous stud - ies have demonstrated the use of TDF in the treat- ment of HIV infection. It also has been shown to be effective in HIV/HBV coinfected patients and in patients with wild-type and lamivudine-resistant strains. Accumulating evidence suggests that TDF is more potent in suppressing HBV replication. In this review, we summarize the study progress of TDF in treating HBV infection.
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Objective To determine the frequency and causes for discontinuing treatment with tenofovir and analyse possible predictive factors for changing this therapy in pretreated HIV patients. Method A multi-centre, observational and retrospective study of all HIV patients undergoing treatment with tenofovir between July 2002 and December 2005. Data were obtained from databases for outpatients attending the three pharmacy departments participating in the study, and by reviewing clinical histories. The main sociodemographic, clinical and analytical variables at the start of treatment with tenofovir were collected. The causes for discontinuing treatment were classified as follows: adverse effects, virological failure, death and “other causes”. A survival analysis was performed using the Kaplan-Meier method to analyse the possible predictive factors for discontinuing treatment. Results A total of 733 patients were included in the study and the median treatment period was 34.7 months. A total of 23.8% of patients discontinued treatment for the following reasons: adverse effects (43.2%), death (17.7%), virological failure (14.8%) and “other causes” (24.4%). There were 99 cases of lost to follow-up. In the survival analysis an association was found between normal serum creatinine values (p = 0.0042) at the start of treatment and the statistically significant probability of discontinuing treatment. Conclusions Almost a quarter of the patients discontinued treatment with tenofovir during the study. The main cause for this was adverse effects. No association was found between any abnormal basal analytical parameter and a greater probability of discontinuing treatment.
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Nephrotoxicity due to tenofovir treatment of HIV patients has been reported. However, the mechanism of tenofovir nephrotoxicity is not clear. NFκB is an important proinflammatory transcription factor that plays a pivotal role in oxidative stress-induced inflammation. We hypothesised that NFκB proinflammatory signalling pathway may play a role in tenofovir induced renal damage. Renal damage was induced in adult male Wistar rats by the oral administration of 600 mg/kg body wt. daily for 5 consecutive weeks. Kidneys were removed and used for histological and biochemical analysis. The protein and mRNA expressions of NFκB and its target genes namely iNOS, COX-2 and TNFα, and its inhibitor IκB-alpha were analysed by immunohistochemical methods, western blot and quantitative RT PCR. NFκBp65 activity was determined by ELISA. The protein and mRNA expressions of NFκB p65, iNOS, COX-2 and TNFα were increased in the kidneys of TDF treated rats. The activity of NFκBp65 was increased by 28 fold in the nuclear fractions of the TDF treated rat kidneys. Pretreatment with melatonin, a NFκB inhibitor attenuated TDF induced renal damage. It is concluded that the activation of NFκB and its downstream proinflammatory target genes iNOS, COX-2, and TNF-α may contribute to the pathophysiology of TDF induced renal damage.
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Export Date: 17 July 2013, Source: Scopus, CODEN: CRBMB, :doi 10.1007/s12018-012-9133-y, Language of Original Document: English, Correspondence Address: Borderi, M.; Department of Internal Medicine, Aging and Nephrology, Infectious Diseases Section, University of Bologna, Bologna, Italy; email: marco.borderi@aosp.bo.it, : Chemicals/CAScolony stimulating factor 1, 81627-83-0; didanosine, 69655-05-6; efavirenz, 154598-52-4; indinavir, 150378-17-9, 157810-81-6, 180683-37-8; lamivudine, 134678-17-4, 134680-32-3; lopinavir, 192725-17-0; nelfinavir, 159989-64-7, 159989-65-8; osteoclast differentiation factor, 200145-93-3; ritonavir, 155213-67-5; saquinavir, 127779-20-8, 149845-06-7; stavudine, 3056-17-5; tenofovir, 147127-19-3, 147127-20-6; zalcitabine, 7481-89-2; zidovudine, 30516-87-1, References: Lohse, N., Hansen, A.-B.E., Pedersen, G., Kronborg, G., Gerstoft, J., Sorensen, H.T., Vaeth, M., Obel, N., Survival of persons with and without HIV infection in Denmark, 1995-2005 (2007) Annals of Internal Medicine, 146 (2), pp. 87-95. , http://www.annals.org/cgi/reprint/146/2/87.pdf;
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Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome affect millions of children worldwide. The development of antiretroviral therapy has significantly improved the morbidity and mortality of pediatric patients infected with HIV. Currently, 4 classes of antiretroviral agents exist: nucleoside / nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and entry inhibitors. A total of 21 single-entity antiretroviral agents and 4 co-formulated antiretroviral products hold Food and Drug Administration (FDA) approval for treatment of HIV-1 infection. However, not all of these agents are indicated for use in patients less than 18 years of age. Since the year 2000, 7 new antiretroviral agents (atazanavir, emtricitabine, enfuvirtide, fosamprenavir, lopinavir/ritonavir, tenofovir, and tipranavir) have been approved by the FDA for use in adult patients as part of combination therapy for the treatment of HIV-1 infection. Although only 3 of these newer agents (emtricitabine, enfuvirtide, and lopinavir/ritonavir) are currently FDA approved for use in pediatric patients, pediatric clinical studies of the other 4 new agents are currently underway. The purpose of this article is to review these 7 new antiretroviral agents and describe their roles in the treatment of pediatric HIV infection. For each drug, the following information will be addressed: FDA-approved indication and age groups, clinical efficacy, pharmacokinetics, adverse drug reactions, clinically relevant drug interactions, pediatric and adult dosing, dosage forms, administration, and place in the treatment of pediatric HIV infection.
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Renal disease is becoming an increasingly prevalent comorbidity in patients with human immunodeficiency virus (HIV) infection. The increase in life expectancy following the introduction of highly active antiretroviral therapy (HAART) and the long-term development of metabolic complications (such as diabetes and dyslipidaemia), hypertension, and vascular diseases can contribute to the increasing frequency in the recognition of renal impairment in HIV-infected patients. Some antiretroviral agents, and particularly tenofovir, have been associated with nephrotoxic drug effects, including decline in glomerular filtration rate, proximal tubular damage, and acute kidney injury. The occurrence of clinically evident renal toxicity in patients treated with HAART seems to be very low, but glomerular or tubular subclinical dysfunction may occur more frequently. Therefore, careful clinical and laboratory monitoring for the early recognition of renal abnormalities is recommended for all subjects receiving antiretroviral treatment. In this article, the current knowledge about the nephrotoxic effects of antiretroviral agents has been reviewed, and an algorithm for screening and management of HAART-related kidney disease is proposed in the light of the most recent clinical studies and international guidelines.
Chapter
The nucleotide analogs are agents with proven in vitro and in vivo efficacy against a wide variety of DNA viruses and retroviruses. Structurally, nucleotide analogs are acyclic nucleoside phosphonates (nucleoside monophosphates) that are designed to circumvent the first phosphorylation step necessary for the activation of nucleoside analogs, such as zidovudine, stavudine, didanosine, lamivudine, and abacavir (1.
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The appropriate use of antiretrovirals reduces morbidity and mortality caused by HIV infection. The present article provides health care professionals with a practical guide for the use of antiretrovirals. Therapy should be initiated based predominantly on clinical presentation and CD4 count, and should consist of three active drugs or at least two active drugs when this is not possible, as in cases of some treatment-experienced patients. This is the most effective way to achieve long-term suppression of viral replication. Selection of individual drugs in the regimen should consider the weight of the evidence supporting these choices, as well as their tolerability profiles and ease of use, the patients' comorbidities and treatment history. Treatment interruption is not recommended, either in aviremic patients or in those who have experienced virological failure. Instead, the therapeutic regimen should be adjusted to minimize side effects, promote adherence and suppress viral replication.
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Background. Several antiretrovirals (ARVs) are associated with chronic renal impairment, but the extent of such adverse events in HIV-positive persons with initially normal renal function is unknown.Methods. D:A:D participants with estimated glomerular filtration rates (eGFR) >90&emsp14;ml/min >1/1/2004 were followed to confirmed (>3 months) eGFR<70 (possible intervention threshold), confirmed eGFR<60 (moderate chronic kidney disease, CKD) or last eGFR. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression.Results. Of 22,603 persons, 468(2.1%) experienced eGFR<70 (IR 4.78/1000 PY [95%CI 4.35-5.22]) and 131(0.6%) CKD (1.33/1000 PY [1.10-1.56]) during median 4.5 (IQR 2.7-6.1) years. Latest eGFR 60-70 caused significantly higher tenofovir (TDF) discontinuation rates (aIRR 1.72 [1.38-2.14]), but not of other ARVs, compared with eGFR≥90. Cumulative TDF (1.18 [1.12-1.25]/year) and boosted atazanavir (ATV/r, 1.19 [1.09-1.32]/year) use were independent eGFR≤70 predictors, but not significant for CKD, whilst boosted lopinavir (LPV/r) use was significant for both endpoints (1.11 [1.05-1.17]/year and 1.22 [1.16-1.28]/year). Associations were unaffected by censoring for concomitant ARV use, but diminished after ARV discontinuation.Conclusions. TDF, ATV/r, and LPV/r use were independent predictors of chronic renal impairment in HIV-positive persons without pre-existing renal impairment. Increased TDF discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation the drug estimate decreased.
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Tenofovir disoproxil fumarate (TDF) effectively suppresses viral replication in chronic hepatitis B (CHB), but occasionally leads to renal impairment. We evaluated the prevalence of viral and biochemical breakthrough and renal function kinetics in renally impaired CHB patients on reduced and on full dose TDF.This clinic-based longitudinal cohort study included patients receiving full and reduced dose TDF (due to eGFR (Cockcroft-Gault) <60mL/min/1.73m2 ). Viral and biochemical breakthroughs were assessed 1 month after starting full and reduced TDF dose until the end of follow-up. Breakthroughs were studied in full and reduced dose TDF, and renal function (MDRD) longitudinally before and after dose reduction within patients starting on full dose TDF. Of 750 patients on TDF, 78 (10%) had reduced dose and 672 (90%) full dose. At the time of dose reduction, 36 (46%) patients had chronic kidney disease stage G3B. A viral breakthrough occurred in one cirrhotic dialysis-dependent patient (dosed 300 mg weekly) which resolved without signs of decompensation, and in one patient on full dose which resolved spontaneously. One biochemical breakthrough occurred during dose reduction and resolved naturally without viral breakthrough. The MDRD improved within the first year of dose reduction (+3.0 (2.5) mL/min per year; p<0.005) and remained stable thereafter. Fifty-three (79%) patients reached an MDRD >50mL/min during dose reduction.Low dose TDF maintains renal function and viral suppression in most renally impaired CHB patients, even in those with advanced liver disease. This useful, yet simple strategy could be particularly viable in resource-constrained settings.
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By providing valuable information about the human immunodeficiency virus (HIV), basic research is one of the cornerstones of the Division of AIDS (DAIDS) therapeutic clinical research efforts. Research supported by DAIDS has defined treatment guidelines for HIV infection and associated opportunistic infections, prophylactic regimens for secondary infections, and biological markers for predicting the effectiveness of therapeutics and disease progression.
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Introducción: Los avances en la terapia antirretroviral han convertido la infección por VIH en una enfermedad crónica, en consecuencia, se han tornado relevantes patologías relacionadas con el virus, el tratamiento y el envejecimiento, una de ellas es la Enfermedad Renal Crónica (ERC), cuya prevalencia se ha incrementado. Objetivo: Establecer factores de riesgo asociados al desarrollo de ERC, en pacientes infectados por VIH, en terapia antirretroviral de gran actividad, en la ciudad de Cartagena.Métodos: Se realizó un estudio de corte transversal, con pacientes asistentes a terapia antirretroviral, entre enero y diciembre de 2017. La función renal fue determinada por Tasa de Filtración Glomerular Estimada (TFGe) mediante ecuación CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) y determinación de albuminuria por cuantificación de relación albumina y creatinina en orina aislada. La ERC se definió como una TFGe menor o igual a 60 ml/min/1,73m2, por un período de, al menos, tres meses. Se utilizó un modelo de regresión logística para estimar los efectos de diversas variables en el desarrollo de ERC.Resultados: Fueron incluidos 267 pacientes, mediana de edad 41 años, mediana del tiempo desde el diagnóstico de VIH, y duración de la TARGA de 4,8 y 4,5 años, respectivamente. Prevalencia de HTA de 8.2% y Diabetes mellitus de 2.9%. La ERC fue diagnosticada en 3.7% de la población y luego del ajuste, el factor de riesgo asociado fue la edad ≥52 años (OR=14,04 (IC 95% 2,90 – 67,95)).Conclusiones: La prevalencia de ERC en pacientes infectados con VIH es alta, con respecto a la población general. La edad se encontró relacionada al desarrollo de ERC.
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T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1.4%; 47 of 3367 integrase sequences); most often among non-B (5.3%) than B (0.9%) HIV-1 subtypes. During INSTI-based therapy, few patients experienced virologic failure with emergent INSTI RAMs (3%; 122 of 3881 patients), among whom T97A emerged infrequently in the presence (n = 6) or absence (n = 8) of primary INSTI RAMs. A comparison between pre-existing and emergent T97A patient populations (i.e., in the absence of primary INSTI RAMs) showed no significant differences in EVG or RAL susceptibility in vitro. Furthermore, among all T97A-containing viruses tested, only 38–44% exhibited reduced susceptibility to EVG and/or RAL (all of low magnitude; <11-fold), while all maintained susceptibility to dolutegravir. Of the patients with pre-existing T97A, 17 had available clinical follow-up: 16 achieved virologic suppression and 1 maintained T97A and INSTI sensitivity without further resistance development. Overall, T97A is an infrequent integrase polymorphism that is enriched among non-B HIV-1 subtypes and can confer low-level reduced susceptibility to EVG and/or RAL. However, detection of T97A does not affect response to INSTI-based therapy with EVG or RAL. These results suggest a very low risk of initiating INSTI-based therapy in patients with pre-existing T97A.
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Background: Toxicities that led to antiretroviral substitution in a multi-country treatment program were described. Methods: First line regimens included stavudine, lamivudine and nevirapine or efavirenz. Alternative therapy included zidovudine, tenofovir, efavirenz and lopinavir/ritonavir. Clinicians were trained to diagnose common antiretroviral side effects. Facilities had access to safety laboratory assays. Toxicity was detected clinically, and confirmed or monitored using specific laboratory assays where indicated. Results: Between 2004 and 2006, among 6,520 patients in Uganda, Kenya and Zambia, initiating antiretroviral therapy, toxicity-related substitutions were observed for stavudine 24.6%, zidovudine 13%, nevirapine 6.6%, efavirenz 3.4%, lopinavir/ritonavir 2% and tenofovir 0.7%. Mean time to switch ranged from 25 days for Lopinavir/ ritonavir, to 141 days for stavudine. Most common toxicities included neuropathy (stavudine), anemia (zidovudine), rash and liver toxicity (nevirapine). Conclusions: Toxicity rates in the study were comparable to reports in Food and Drug Administration (FDA) label package inserts and other smaller published reports in Africa and Asia. These toxicity rates could be used to inform drug forecasting for resource-limited settings. Comparably high tolerability of tenofovir and efavirenz may support their preferential use.
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Tenofovir disoproxil fumarate (tenofovir DF; Viread®), an ester prodrug of the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir, is indicated in combination with other antiretroviral agents in the treatment of HIV infection. As a component of an antiretroviral regimen, oral tenofovir DF 300mg once daily effectively reduces viral load in patients with HIV infection who are treatment-experienced with baseline NRTI resistance mutations or treatment-naive. Tenofovir DF provides a simple and convenient once-daily dosage regimen, and is generally well tolerated and able to produce sustained suppression of viral replication. Pharmacological Properties Tenofovir DF is metabolised to tenofovir diphosphate, which inhibits the activity of HIV reverse transcriptase and terminates the DNA chain. In vitro, the drug demonstrates good inhibitory activity against HIV strains, synergistic or additive activity when combined with certain other antiretroviral drugs, minimal cytotoxicity and no evidence of reduced mitochondrial DNA synthesis. Reduced susceptibility to tenofovir is associated with the reverse transcriptase mutation K65R. In patients with baseline resistance mutations in clinical trials, the greatest response to tenofovir DF was associated with the M184V mutation and no thymidine analogue-associated mutations. Reduced responses were associated with the L210W or M41L mutations, and a lack of response with the K65R mutation. The emergence of the K65R mutation during clinical trials using more than one class of antiretroviral therapy was specifically associated with tenofovir DF; however, the K65R mutation developed infrequently and was not associated with viral rebound. The oral bioavailability of tenofovir DF administered without food is 25%. After multiple doses of tenofovir DF 300mg once daily, the median maximum serum concentration of 326 ng/mL at steady state is reached after a median of 2.3 hours. Tenofovir has a median serum terminal elimination half-life of 14.4 hours, and undergoes primarily renal elimination as the unchanged drug. Exposure to tenofovir is increased in patients with moderate-to-severe renal impairment. Tenofovir does not inhibit cytochrome P450 enzymes, so few drug interactions are expected with drugs metabolised via this route. Coadministration of tenofovir DF with didanosine substantially increases didanosine exposure, coadministration with lopinavir/ritonavir increases tenofovir exposure and coadministration with atazanavir decreases atazanavir exposure. Therapeutic Efficacy In two well designed clinical trials in antiretroviral treatment-experienced patients with HIV infection, oral tenofovir DF 300mg once daily in combination with other antiretroviral drugs produced significantly greater time-weighted reductions from baseline in HIV RNA levels than placebo at week 4 and/or 24; these reductions were maintained at week 48 in the placebo cross-over phase of the trials. In the dose-ranging trial, tenofovir DF 75, 150 or 300mg once daily were all more effective than placebo; however, the greatest reduction in viral load at weeks 4, 24 and 48 was produced by tenofovir DF 300mg once daily, which is the approved dosage in patients with HIV infection. The proportion of antiretroviral therapy-naive patients with HIV infection achieving HIV RNA levels <400 copies/mL was similar with tenofovir DF 300mg once daily and stavudine 40mg twice daily at weeks 48, 96 and 144 in a well designed trial. All patients also received lamivudine 150mg twice daily and efavirenz 600mg once daily. For the primary endpoint, the stratum-weighted lower 95% confidence interval of the difference between tenofovir DF and stavudine at week 48 slightly exceeded (by 0.4) the predefined equivalence criteria (−10.4 vs −10). In nonblind clinical trials, tenofovir DF 300mg once daily was effective in treating HIV infection when used in a regimen containing antiretroviral therapies from more than one class and as part of a simplified dosage regimen. However, as with other triple NRTI regimens, tenofovir DF with lamivudine plus either didanosine or abacavir showed high rates of suboptimal response and/or early failure. Tolerability Oral tenofovir DF 300mg once daily, as part of combination therapy, was generally well tolerated in controlled clinical trials. The tolerability profiles of tenofovir-containing regimens were similar to those of regimens containing placebo or stavudine in controlled clinical trials. Mild-to-moderate gastrointestinal disorders (e.g. nausea, diarrhoea, vomiting and flatulence) were the most commonly reported adverse events. The frequency of laboratory abnormalities with tenofovir DF was similar to that with placebo and stavudine. However, tenofovir DF was associated with a more favourable serum lipid profile than stavudine. The risk of adverse events potentially associated with mitochondrial dysfunction with tenofovir DF appears similar to that with placebo and lower than that with stavudine. In clinical trials, the incidence of tenofovir DF-related renal abnormalities was low and similar in frequency between tenofovir DF- and stavudine-containing regimens.
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Background: The renal safety of tenofovir in HIV-infected children has not been well studied. In paediatrics, prediction of glomerular filtration rate (GFR) is usually obtained by the Schwartz equation; the Cockcroft-Gault equation is considered more appropriate in children aged >12 years, but can be misleading in younger children. The aims of this study were to assess renal safety and GFR changes as estimated by the Schwartz and Cockcroft-Gault equations in HIV-infected children treated with tenofovir for 96 weeks. Methods: Several parameters of glomerular and tubular function were prospectively assessed (at baseline and at weeks 24, 48, 72 and 96) in 27 HIV-infected children (aged 4.9–18.0 years) receiving a tenofovir-containing antiretroviral regimen. GFR was estimated using Schwartz and Cockcroft-Gault equations in children younger and older than 12 years, respectively. Results: No child experienced a grade 1 (≥44 μmol/L) or higher increase in serum creatinine or a grade 1 (≤0.71 mmol/L) or higher hypophosphataemia. Serum bicarbonate values were in the normal range for age at baseline. Mean serum creatinine, serum phosphorus and serum bicarbonate values remained unchanged. No child showed proteinuria, microalbuminuria or glycosuria at baseline or during the study period. The mean urinary protein/creatinine, albumin/creatinine, α1-microglobulin/creatinine and maximal tubular phosphate reabsorption (TmPC4/GFR) ratios remained unchanged. Up to week 96, no patient experienced a significant decrease in GFR, as estimated by the more appropriate formula for age. Conclusion: Through 96 weeks, we found no evidence of impaired glomerular or tubular renal function in tenofovir-treated HIV-infected children.
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The human immunodeficiency virus (HIV) is responsible for acquired immune deficiency syndrome (AIDS), one of the major pandemic diseases. Highly active antiretroviral therapy (HAART) is the standard HIV-treatment regimen that usually comprises a combination of three or more antiretroviral drugs. HIV reverse transcriptase inhibitors are the main HAART target, which involves the use of both nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, compounds affecting other aspects of HIV replication, such as virus entry and fusion or important viral enzymes, such as integrases and proteases, have also been developed. Natural compounds from different sources, like plants, microbial and marine organisms, showed promising anti-HIV activities to the point of establishing the basis for developing new drugs. Indeed, natural compounds-based therapies have the potential to become more efficient than conventional HAART, with less or no side effects. This review aims to gather and discuss the current information about the anti-HIV activity of natural and synthetic compounds, their history and mechanism of action as well as the role of plants and their bioactive compounds as a source of new anti-HIV drugs.
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IntroductionNucleoside Phosphonate Strategy for AntiviralsAcyclic Nucleoside PhosphonatesCyclic Nucleoside PhosphonatesProdrugs of Nucleoside PhosphonatesClinical Applications of Antiviral Nucleoside PhosphonatesConclusions References
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Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, is a nucleotide reverse transcriptase inhibitor. It is administered orally at 300 mg once daily in combination with an additional nucleoside reverse transcriptase inhibitor (NRTI), typically emtricitabine, and an additional antiretroviral such as a non-nucleoside reverse transcriptase inhibitor (NNRTI), an integrase inhibitor or a protease inhibitor (PI). After hydrolysis in the lumen of the gastrointestinal tract, tenofovir is taken up by cells and subsequently phosphorylated to the active tenofovir-diphosphate (TFV-DP) moiety. TFV-DP is incorporated into viral DNA and terminates DNA elongation. Tenofovir is excreted by the kidneys through glomerular filtration and tubular secretion. Although few drug-drug interactions occur, tenofovir plasma concentrations may increase in the presence of other renally eliminated drugs. Safety and efficacy of TDF have been demonstrated in treatment-naïve and treatment-experienced patients. Although generally well tolerated, some studies suggest an increased risk for adverse events, such as bone toxicity and/or nephrotoxicity with long term TDF use. Patient adherence to TDF-containing regimens is improved over other antiretrovirals due to its once daily administration and low toxicity profile. Its use as pre-exposure prophylaxis against HIV is currently being investigated. © the author(s), publisher and licensee Libertas Academica Ltd.
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HIV-infected patients may present with a variety of patterns of renal involvement Acute kidney failure (AKF) is common and is often the result of acute tubular necrosis (ATN), acute interstitial nephritis, and thrombotic microangiopathy The most common precipitating factors of ATN include medications and dehydration superimposed on sepsis, hypotension, and respiratory failure It is potentially avoidable, and support through the period of renal failure may lead to resolution of the renal dysfunction Although it is potentially reversible with dialysis support, AKF nonetheless carries a high mortality
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Among the recently introduced antiviral drugs for chronic hepatitis B some have demonstrated renal side effects. Nephrotoxicity seems to be rare but requires careful handling of these drugs. Tenofovir, primarily used as an antiretroviral molecule in HIV patients, can be associated with tubulopathy, presenting as Fanconi syndrome with phosphaturia and glucosuria, or as acute renal failure due to acute tubular necrosis. Kidney toxicity is probably enhanced by concomittant antiprotease (HAART) therapy and has been described, in most cases among patients with previous chronic renal disease. The renal side effects of adefovir are very similar but are probably less frequent when this drug is used at the usual 10 mg daily dose. These two antiviral drugs have to be adapted to the renal function of the patient and the daily dose must be reduced when estimated GFR is below 60 ml/min. Monitoring of the patients receiving these drugs must include regular dosing of serum creatinin, phosphatemia and proteinuria. Nephrotoxicity has not been reported with Lamivudine and Entecavir, two other analogues that can be used for treating chronic HBV infection.
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Objectives: HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis. Patients and methods: We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs. Results: Subtype B patients ( n = 3410) were mostly MSM (78%) and those with subtype C ( n = 810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P < 0.001). Conclusions: Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.
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Despite widespread HAART use, HIV disease remains associated with increased risk of kidney disease. Whether tenofovir use is associated with higher risk of kidney disease is controversial. We evaluated the association of cumulative and ever exposure to tenofovir on kidney outcomes in 10,841 HIV-infected patients from the Veterans Health Administration who initiated antiretroviral therapy from 1997 to 2007. Cox proportional hazards and marginal structural models evaluated associations between tenofovir and time to first occurrence of proteinuria (two consecutive urine dipstick measurements ≥30 mg/dl), rapid decline in kidney function (≥3 ml/min per 1.73 m annual decline), and chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min per 1.73 m). Median follow-up ranged from 3.9 years (proteinuria) to 5.5 years (CKD), during which 3400 proteinuria, 3078 rapid decline, and 533 CKD events occurred. After multivariable adjustment, each year of exposure to tenofovir was associated with 34% increased risk of proteinuria [95% confidence interval (CI) 25-45, P < 0.0001], 11% increased risk of rapid decline (3-18, P = 0.0033), and 33% increased risk of CKD (18-51, P < 0.0001). Preexisting renal risk factors did not appear to worsen the effects of tenofovir. Other antiretroviral drugs showed weaker or inconsistent associations with kidney disease events. Among those who discontinued tenofovir use, risk of kidney disease events did not appear to decrease during follow-up. Tenofovir exposure was independently associated with increased risk for three types of kidney disease events, and did not appear to be reversible. Because subtle kidney function decline affects long-term morbidity and mortality, the balance between efficacy and probable adverse effects requires further study.
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Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration. To determine if adefovir confers antiretroviral or immunologic benefit when added to stable antiretroviral therapy. Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997. Thirty-three US HIV treatment centers. Of 1171 patients screened, 442 patients infected with HIV receiving stable antiretroviral therapy for at least 8 weeks with plasma HIV RNA greater than 2500 copies/mL and CD4+ cell count above 0.20 x 10(9)/L were randomized. Patients were randomized to receive either a single 120-mg/d dose of adefovir dipivoxil (n = 219) or an indistinguishable placebo (n = 223). All patients received L-carnitine, 500 mg/d. Open-label adefovir was offered after 24 weeks and was continued until the end of the study. Changes in HIV RNA from baseline, based on area under the curve and CD4+ cell levels, adverse events, and effect of baseline genotypic resistance on response to adefovir. Patients assigned to adefovir demonstrated a 0.4-log10 decline from baseline in HIV RNA compared with no change in the placebo group (P<.001), which continued through 48 weeks. CD4+ cell counts did not change. During the initial 24 weeks, elevated hepatic enzyme levels (P<.001), gastrointestinal tract complaints (P<.001), and weight loss (P<.001) were associated with use of adefovir. Between 24 weeks and 48 weeks elevations in serum creatinine occurred in 60% of patients, usually returning to baseline after discontinuation of adefovir. Patients with lamivudine or lamivudine and zidovudine resistance mutations demonstrated anti-HIV effects with adefovir (P< or =.01 vs placebo group). This study suggests that once-daily adefovir therapy reduces HIV RNA and is active against isolates resistant to lamivudine or lamivudine and zidovudine. Nephrotoxicity occurred when treatment extended beyond 24 weeks but was reversible.
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A set of mutations [Ala-62-->Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain of reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides and has been seen in HIV-1 variants isolated from patients receiving combination chemotherapy with 3'-azido-3'-deoxythymidine (AZT) plus 2',3'-dideoxycytidine (ddC) or 2',3'-dideoxyinosine (ddI). The IC50 values of AZT, ddC, ddI, 2',3'-dideoxyguanosine, and 2',3'-didehydro-3'-deoxythymidine against an infectious clone constructed to include the five mutations were significantly higher than those of a wild-type infectious clone. The K1 value for AZT 5'-triphosphate determined for the virus-associated RT from a posttherapy strain was 35-fold higher than that of RT from a pretherapy strain. Detailed analysis of HIV-1 strains isolated at various times during therapy showed that the Q151M mutation developed first in vivo, at the time when the viremia level suddenly increased, followed by the F116Y and F77L mutations. All five mutations ultimately developed, and the viremia level rose even further. Analyses based on the three-dimensional structure of HIV-1 RT suggest that the positions where at least several of the five mutations occur are located in close proximity to the proposed dNTP-binding site of RT and the first nucleotide position of the single-stranded template.
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The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus–type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 106 cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
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Although highly active antiretroviral therapy (HAART) in the form of triple combinations of drugs including protease inhibitors can reduce the plasma viral load of some HIV-1-infected individuals to undetectable levels, it is unclear what the effects of these regimens are on latently infected CD4+ T cells and what role these cells play in the persistence of HIV-1 infection in individuals receiving such treatment. The present study demonstrates that highly purified CD4+ T cells from 13 of 13 patients receiving HAART with an average treatment time of 10 months and with undetectable (<500 copies HIV RNA/ml) plasma viremia by a commonly used bDNA assay carried integrated proviral DNA and were capable of producing infectious virus upon cellular activation in vitro. Phenotypic analysis of HIV-1 produced by activation of latently infected CD4+ T cells revealed the presence in some patients of syncytium-inducing virus. In addition, the presence of unintegrated HIV-1 DNA in infected resting CD4+ T cells from patients receiving HAART, even those with undetectable plasma viremia, suggests persistent active virus replication in vivo.
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Data from 1330 human immunodeficiency virus type 1 (HIV-1)-infected patients enrolled in seven antiretroviral treatment trials were analyzed to characterize the clinical benefit of treatment-mediated reductions in plasma HIV-1 RNA levels. The risk of a new AIDS-defining event or death was reduced proportionally to the magnitude of the reduction of the HIV-1 RNA level during the first 6 months of therapy. Pretherapy HIV-1 RNA levels were prognostic independently of ontherapy levels. In addition, the reduction in risk associated with any given reduction of the level of HIV-1 RNA did not vary by pretherapy level. Having either a reduction in HIV-1 RNA level or an increase in CD4+ lymphocyte count, or both, was associated with a delay in clinical disease progression. This indicates that patient prognosis should be assessed using both HIV-1 RNA and CD4+ lymphocyte responses to therapy.
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Context The availability of new antiretroviral drugs and formulations, including drugs in new classes, and recent data on treatment choices for antiretroviral-naive and -ex- perienced patients warrant an update of the International AIDS Society-USA guide- lines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV) infection. Objectives To summarize new data in the field and to provide current recommen- dations for the antiretroviral management and laboratory monitoring of HIV infec- tion. This report provides guidelines in key areas of antiretroviral management: when toinitiatetherapy,choiceofinitialregimens,patientmonitoring,whentochangetherapy, and how best to approach treatment options, including optimal use of recently ap- proved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced pa- tients.
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Objective: To compare the antiviral activity of abacavir (ABC) with stable background therapy (SBG) and SBG alone in antiretroviral therapy-experienced subjects as demonstrated by the proportion of subjects with plasma HIV-1 RNA ≤ 400 copies/ml, plasma HIV-1 RNA and CD4 cell count profiles, and safety and tolerance of the two regimens over 16 weeks. Design: One-hundred and eighty-five HIV-1 infected adults, with CD4 cell counts ≥ 100 × 106/l and plasma HIV-1 RNA of 400-50 000 copies/ml and who had received SBG therapy for at least 12 weeks, were randomized to receive ABC (300 mg twice daily) or placebo in a double blind, multi-centre study. Methods: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4 cell counts. Genotypic and phenotypic resistance was determined at baseline and week 16. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. Results: At week 16 significantly more subjects receiving ABC + SBG had plasma HIV-1 RNA ≤ 400 copies/ml (36/92, 39%) than subjects receiving SBG alone (7/93, 8%;P  < 0.001). A similar response was observed in both the lamivudine naïve and lamivudine-experienced subjects. The presence of the M184V mutation did not preclude an antiviral response to ABC; 73% of subjects with the M184V mutation alone experienced a ≥ 1.0 log10 copies/ml reduction in plasma HIV-1 RNA or had a value of ≤ 400 copies/ml by week 16. Conclusions: ABC was generally well tolerated and exerted significant antiviral effect when added to combination antiretroviral therapy over 16 weeks.
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Objective: To correlate self-reported antiretroviral adherence with virologic suppression. Design: Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. Setting: Five university-affiliated HIV clinics. Patients: A group of 173 HIV-infected patients with a mean baseline CD4 count of 142¥106 cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. Intervention: Individualized, unrestricted antiretroviral therapy. Measurements: Patients were classified into four groups by adherence to therapy in the previous 4 weeks (<80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. Results: Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P=0.009 for linear trend). Patients reporting <80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19¥106 CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72¥106 CD4 cells/l in those reporting 100% adherence (P=0.02). Conclusion: Self-reported poor adherence (<80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.
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National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid. The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.
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The efficacy of pre- and postexposure treatment with the antiviral compound (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) was tested against simian immunodeficiency virus (SIV) in macaques as a model for human immunodeficiency virus (HIV). PMPA was administered subcutaneously once daily beginning either 48 hours before, 4 hours after, or 24 hours after virus inoculation. Treatment continued for 4 weeks and the virologic, immunologic, and clinical status of the macaques was monitored for up to 56 weeks. PMPA prevented SIV infection in all macaques without toxicity, whereas all control macaques became infected. These results suggest a potential role for PMPA prophylaxis against early HIV infection in cases of known exposure.
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The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.
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Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9–12 months, HIV-1 remained detectable in latently infected CD4+ T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS
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To evaluate the safety and efficacy of once daily doses of tenofovir DF (TDF) administered in combination with other antiretroviral therapy (ART) in treatment-experienced HIV-1-infected patients with incomplete virological suppression. One-hundred and eighty-nine subjects with plasma HIV-1 RNA levels between 400 and 100,000 copies/ml and stable ART (> or = 8 weeks) were randomized (2 : 2 : 2 : 1 ratio) to add TDF 75 mg, 150 mg, or 300 mg or placebo to existing ART in a double-blinded manner. After 24 weeks, patients initially randomized to placebo received blinded TDF 300 mg. Efficacy was analyzed by the mean changes HIV-1 RNA levels (log10 copies/ml plasma; DAVG(xx)) from week 0 to weeks 4, 24, and 48. Safety was analyzed by incidence of grade 3 or 4 clinical and laboratory adverse events. At baseline, patients had mean 4.6 years prior ART use with 94% having HIV-1 with nucleoside-associated resistance mutations. There were statistically significant decreases in DAVG(4) and DAVG(24) for all doses of TDF compared with placebo, with the greatest effect seen with TDF 300 mg (DAVG(4), -0.62, P < 0.001; DAVG(24), -0.58; P < 0.001; DAVG(48), -0.62). The incidence of adverse events was similar among the TDF groups and placebo through week 24. Throughout the 48-week study, no significant changes in renal function were observed. In treatment-experienced patients with baseline nucleoside resistance mutations, TDF provided dose-related, durable reductions in HIV-1 RNA. Through 24 weeks, the safety profile of TDF was similar to that of placebo.
Article
To evaluate the virologic responses and mutational profiles in antiretroviral-experienced patients adding tenofovir DF once-daily to their existing regimens. Resistance analyses were performed for patients in a phase II placebo-controlled clinical trial of tenofovir DF. HIV-1 reverse transcriptase and protease genes from plasma samples were analyzed genotypically and phenotypically at baseline, week 24, and week 48. Of 184 patients, 173 (94%) had baseline HIV-1 expressing one or more nucleoside reverse transcriptase inhibitor-associated resistance mutation. Protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations were observed in 57% and 32% of patients, respectively. Compared to placebo, significant reductions in HIV-1 RNA were observed for tenofovir DF-treated patients who had thymidine analog- (TAM), lamivudine- (M184V), NNRTI- or protease inhibitor-associated mutations. Patients with phenotypic susceptibility to tenofovir within 4-fold of wild-type responded durably to tenofovir DF 300 mg therapy with a decline in plasma HIV-1 RNA of > or = 0.5 log10 copies/ml; few patients had a more than 4-fold reduced susceptibility to tenofovir at baseline. Four patients (2%) developed the K65R mutation (selected by tenofovir in vitro) and showed 3- to 4-fold reductions in tenofovir susceptibility but no evidence of rebound viremia. Thirty-four percent of patients developed additional TAMs, coincident with concurrent zidovudine or stavudine therapy, but also showed durable HIV-1 reductions. There was no evidence of novel resistance to tenofovir. Adding tenofovir DF 300 mg to an existing regimen in patients with ongoing viral replication and a wide range of genotypic resistance patterns resulted in significant and durable HIV-1 RNA reductions. In addition, there was a low incidence of genotypic or phenotypic resistance to tenofovir DF arising during 48 weeks of therapy.