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Mitochondrial toxicity induced by nucleoside-analogue reserve-transcriptase inhibitors is a key in the pathogenesis of antiretroviral therapy-related lipodystrophy.

01 Jan 1999-Vol. 354, pp 1112-1115
Abstract: Highly active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome of peripheral fat wasting and central adiposity. HIV-1 protease inhibitors are generally believed to be the causal agents, although the syndrome has also been observed with protease-inhibitor-sparing regimens. Here, we postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy, similar to the role of mitochondrial defects in the development of multiple symmetrical lipomatosis.
Citations
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01 Jan 2005
TL;DR: Lipodystrophy following treatment with NRTI-containing HAART is associated with a decrease in adipose tissue mtRNAs, andND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients.
Abstract: Background Damage to mitochondria (mt) is a major side effect of highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI). Such damage is associated with the onset of lipodystrophy in HAART-treated HIV+ patients. To further investigate mt changes during this syndrome, we analysed the expression of mtRNA in adipocytes from lipodystrophic HIV+ patients taking NRTI-containing HAART and compared it with similar cells from healthy individuals. Materials and methods Total RNA was extracted from adipocytes collected from different anatomical locations of 11 HIV+ lipodystrophic patients and seven healthy control individuals. RNA was reverse transcribed and Taqman-based real-time PCR was used to quantify three different mt transcripts (ND1, CYTB and ND6 gene products). mtRNA content was normalized versus the housekeeping transcript L13. Results ND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients. HIV+ men and women did not differ in a statistically significant way regarding the levels of ND1 and ND6, whereas the opposite occurred for CYTB. Conclusions Lipodystrophy following treatment with NRTI-containing HAART is associated with a decrease in adipose tissue mtRNAs.

27 citations

Journal Article
TL;DR: The predictive value of resistance testing is currently being examined in patients who have failed their first therapy, and further developments include vaccine, cytokine-, and gene therapy-based treatment strategies.

22 citations

01 Jan 2016
TL;DR: An integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data is developed and can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors.
Abstract: The human immunodeficiency virus (HIV) has resisted nearly three decades of efforts targeting a cure. Sustained suppression of the virus has remained a challenge, mainly due to the remarkable evolutionary adaptation that the virus exhibits by the accumulation of drug-resistant mutations in its genome. Current therapeutic strategies aim at achieving and maintaining a low viral burden and typically involve multiple drugs. The choice of optimal combinations of these drugs is crucial, particularly in the background of treatment failure having occurred previously with certain other drugs. An understanding of the dynamics of viral mutant genotypes aids in the assessment of treatment failure with a certain drug combination, and exploring potential salvage treatment regimens. Mathematical models of viral dynamics have proved invaluable in understanding the viral life cycle and the impact of antiretroviral drugs. However, such models typically use simplified and coarse-grained mutation schemes, that curbs the extent of their application to drug-specific clinical mutation data, in order to assess potential next-line therapies. Statistical models of mutation accumulation have served well in dissecting mechanisms of resistance evolution by reconstructing mutation pathways under different drug-environments. While these models perform well in predicting treatment outcomes by statistical learning, they do not incorporate drug effect mechanistically. Additionally, due to an inherent lack of temporal features in such models, they are less informative on aspects such as predicting mutational abundance at treatment failure. This limits their application in analyzing the pharmacology of antiretroviral drugs, in particular, time-dependent characteristics of HIV therapy such as pharmacokinetics and pharmacodynamics, and also in understanding the impact of drug efficacy on mutation dynamics. In this thesis, we develop an integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data. Our combined modelling approach enables us to study the dynamics of different mutant genotypes and assess mutational abundance at virological failure. As an application of our model, we estimate in vivo fitness characteristics of viral mutants under different drug environments. Our approach also extends naturally to multiple-drug therapies. Further, we demonstrate the versatility of our model by showing how it can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors. Additionally, we address another important aspect in the clinical management of HIV disease, namely drug pharmacokinetics. It is clear that time-dependent changes in in vivo drug concentration could have an impact on the antiviral effect, and also influence decisions on dosing intervals. We present a framework that provides an integrated understanding of key characteristics of multiple-dosing regimens including drug accumulation ratios and half-lifes, and then explore the impact of drug pharmacokinetics on viral suppression. Finally, parameter identifiability in such nonlinear models of viral dynamics is always a concern, and we investigate techniques that alleviate this issue in our setting.

10 citations

DissertationDOI
01 Apr 2014
TL;DR: This chapter discusses changes of cART Regimens and Guidelines and its impact on HIV Survival, as well as background, disease progression, and progress in HIV Treatment.
Abstract: .................................................................................................................................................. 4 Dedication ............................................................................................................................................... 5 Acknowledgement .................................................................................................................................. 6 List of Figures ....................................................................................................................................... 13 List of Tables ........................................................................................................................................ 16 Abbreviations and Acronyms ............................................................................................................. 18 Chapter 1 Introduction ..................................................................................................................... 20 1.1 Background ............................................................................................................................ 21 1.2 Natural History and Disease Progression of HIV .................................................................. 22 1.3 HIV Treatment ............................................................................................................................. 24 1.3.1 HIV Life Cycle ..................................................................................................................... 24 1.3.2 Antiretroviral Drugs ....................................................................................................... 27 1.3.2.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) .............................................. 28 1.3.2.2 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ................................... 28 1.3.2.3 Protease Inhibitors (PIs) ............................................................................................. 28 1.3.2.4 Fusion Inhibitors ........................................................................................................ 28 1.3.2.5 Entry Inhibitors .......................................................................................................... 30 1.3.2.6 Integrase Strand Transfer Inhibitors........................................................................... 30 1.4 Progress in HIV Treatment .......................................................................................................... 30 1.4.1 From Monoto Triple Therapy and its Impact on HIV Survival .......................................... 30 1.4.2 Changes of cART Regimens and Guidelines ........................................................................ 32

8 citations

References
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Journal ArticleDOI
TL;DR: These Guidelines were developed by the Panel* on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation.
Abstract: SUMMARY The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV-infected persons. In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for the clinical management of HIV-infected adults and adolescents. This report recommends that care should be supervised by an expert, and makes recommendations for laboratory monitoring including plasma HIV RNA, CD4 cell counts and HIV drug resistance testing. The report also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special considerations are provided for adolescents and pregnant women. As with treatment of other chronic conditions, therapeutic decisions require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Antiretroviral regimens are complex, have major side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance due to non-adherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic

4,321 citations

Journal ArticleDOI
07 May 1998-AIDS
TL;DR: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors and diabetes mellitus is relatively uncommon.
Abstract: Objective: To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy. Design: Cross-sectional study. Setting: Outpatient clinic of a university teaching hospital. Patients: HlV-infected patients either receiving at least one protease inhibitor (n = 116) or protease inhibitor-naive (n = 32), and healthy men (n = 47). Interventions and main outcome measures: Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholesterol, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed. Results: HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P = 0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1(3%) protease inhibitor-naive patient (P = 0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus. Conclusion: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

2,358 citations

Journal ArticleDOI
TL;DR: Weight before therapy, fasting triglyceride, and C-peptide concentrations early in therapy, and therapy duration seem to predict lipodystrophy severity, but hyperlipidaemia and impaired glucose tolerance were also common.

1,578 citations

Journal ArticleDOI
14 Jul 2004-JAMA
TL;DR: Through 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine for antiretroviral-naive patients and appeared to be associated with better lipid profiles and less lipodystrophy.
Abstract: ContextTenofovir disoproxil fumarate (DF) is a once-daily nucleotide analogue reverse transcriptase inhibitor.ObjectiveTo evaluate the efficacy and safety of tenofovir DF compared with stavudine in antiretroviral-naive patients.Design, Setting, and ParticipantsA prospective, randomized, double-blind study conducted at 81 centers in the United States, South America, and Europe from June 9, 2000, to January 30, 2004. A total of 753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study.InterventionPatients were randomized to receive either tenofovir DF (n = 299) or stavudine (n = 303), with placebo, in combination with lamivudine and efavirenz.Main Outcome MeasureProportion of patients with HIV RNA levels of less than 400 copies/mL at week 48.ResultsIn the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures, the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval, −10.4% to 1.5%), exceeding the predefined −10% limit for equivalence. However, equivalence was demonstrated in the secondary analyses (HIV RNA <50 copies/mL) at week 48 and through 144 weeks. Virologic failure was associated most frequently with efavirenz and lamivudine resistance. Through 144 weeks, the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups, respectively (P = .06). A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n = 170] vs +134 mg/dL for stavudine [n = 162], P<.001), total cholesterol (+30 mg/dL [n = 170] vs +58 mg/dL [n = 162], P<.001), direct low-density lipoprotein cholesterol (+14 mg/dL [n = 169] vs +26 mg/dL [n = 161], P<.001), and high-density lipoprotein cholesterol (+9 mg/dL [n = 168] vs +6 mg/dL [n = 154], P = .003). Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58 [19%] of 301, P<.001). The number of bone fractures and the renal safety profile were similar between the 2 groups.ConclusionsThrough 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine, lamivudine, and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy.

1,394 citations

Journal ArticleDOI
TL;DR: A strong association between immunodeficiency and risk of liver-related death was found and long-term follow-up is required to investigate whether clinically significant treatment-associated liver- related mortality will develop.
Abstract: Background An increasing proportion of deaths among human immunodeficiency virus (HIV)-infected persons with access to combination antiretroviral therapy (cART) are due to complications of liver diseases. Methods We investigated the frequency of and risk factors associated with liver-related deaths in the Data Collection on Adverse Events of Anti-HIV Drugs study, which prospectively evaluated 76 893 person-years of follow-up in 23 441 HIV-infected persons. Multivariable Poisson regression analyses identified factors associated with liver-related, AIDS-related, and other causes of death. Results There were 1246 deaths (5.3%; 1.6 per 100 person-years); 14.5% were from liver-related causes. Of these, 16.9% had active hepatitis B virus (HBV), 66.1% had hepatitis C virus (HCV), and 7.1% had dual viral hepatitis co-infections. Predictors of liver-related deaths were latest CD4 cell count (adjusted relative rate [RR], 16.1; 95% confidence interval [CI], 8.1-31.7 for or =500/microL), age (RR, 1.3; 95% CI, 1.2-1.4 per 5 years older), intravenous drug use (RR, 2.0; 95% CI, 1.2-3.4), HCV infection (RR, 6.7; 95% CI, 4.0-11.2), and active HBV infection (RR, 3.7; 95% CI, 2.4-5.9). Univariable analyses showed no relationship between cumulative years patients were receiving cART and liver-related death (RR, 1.00; 95% CI, 0.93-1.07). Adjustment for the most recent CD4 cell count and patient characteristics resulted in an increased risk of liver-related mortality per year of mono or dual antiretroviral therapy before cART (RR, 1.09; 95% CI, 1.02-1.16; P = .008) and per year of cART (RR, 1.11; 95% CI, 1.02-1.21; P = .02). Conclusions Liver-related death was the most frequent cause of non-AIDS-related death. We found a strong association between immunodeficiency and risk of liver-related death. Longer follow-up is required to investigate whether clinically significant treatment-associated liver-related mortality will develop.

1,141 citations