Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine
ABSTRACT To determine if stavudine (alpha4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse transcriptase inhibitor. As apoptosis and dysfunction of electron transport chain (ETC) activities may underlie mitochondrial toxicity, these parameters were also evaluated.
The 16 participants (on d4T for >3 years; with lipoatrophy and/or hyperlactatemia) substituted abacavir or zidovudine for stavudine in their antiretroviral regimen. Key parameters including dual-energy X-ray absorptiometry (DEXA) scans, fat apoptosis, mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMC), skeletal muscle and fat, as well as skeletal muscle mitochondrial ETC activities were evaluated at study entry and at 48 weeks after the substitution.
Quantitative PCR was used to evaluate mtDNA levels and the presence of deletions/rearrangements; CLIA-validated methods for ETC activities; terminal deoxynucleotidyl transferase dUTP-digoxigenin nick-end labeling assays to evaluate adipocyte apoptosis; and DEXA scans to measure changes in body fat.
MtDNA was depleted at study entry in muscle, adipose tissue and PBMC but levels rebounded with respective mean increases of 141%, 146%, and 369% at week 48. Corresponding fat improvements were noted with DEXA increases of 21%, 11%, and 16% in arm, leg, and trunk, respectively. Quantitative adipocyte apoptosis were significantly increased at baseline (P < 0.01 versus HIV-negative controls), with a significant reduction at week 48 (P < 0.05 versus baseline). Mean values for seven mitochondrial enzyme activities assays at entry indicated substantial loss of function (48% to 85% of controls) with significant improvement of complex I activity by week 48.
Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.
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ABSTRACT: Metabolic alterations and body fat changes are well-recognized limitations of protease inhibitor-based regimens. Strategies of replacing protease inhibitors with nonnucleoside reverse transcriptase inhibitors or abacavir have been shown to improve metabolic abnormalities, particularly by decreasing cholesterol and triglyceride levels, and reducing cardiovascular risk. The various therapeutic options show differences in efficacy, tolerability, and metabolic outcomes. Abacavir seems to be better tolerated, at least in the only randomized trial in which the three options were compared face-to-face, but it is associated with higher virologic failure in patients with prior suboptimal nucleoside therapy. Nonnucleoside reverse transcriptase inhibitors, particularly nevirapine, result in a better lipid profile with a greater increase in HDL cholesterol and in the HDUtotal cholesterol ratio, one of the most important parameters associated with a reduction in cardiovascular risk. Efavirenz has been associated with increased triglyceride levels in some studies. Although protease inhibitor compounds as a family have been linked to metabolic and body fat alterations, new drugs such as atazanavir seem to be associated with a more favorable lipid profile. Lipoatrophy is a stigmatizing complication in HIV-infected patients receiving HAART. There is strong evidence suggesting a prominent role of thymidine analogs, mainly stavudine, in its development. Substitution of stavudine or zidovudine for abacavir or tenofovir partially improves peripheral fat loss. In addition, the lipid profile significantly improves. Finally, although the extended use of non-thymidine nucleoside analogs and the development of new families of antiretroviral drugs will probably result in a lower impact in lipids and morphologic changes, many patients are currently under treatment with these compounds. In this setting, switching strategies may be useful to minimize clinical and psychological consequences, improving the quality of life of HIV-infected patients treated with HAART.AIDS reviews 8(4):191-203. · 4.02 Impact Factor
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ABSTRACT: Die Nukleosidischen Reverse Transkriptase Hemmer (NRTI) Zidovudin (AZT) und Stavudin (d4T) sind häufig eingesetzte Bestandteile der antiretroviralen Kombinationstherapie. Die Behandlung erstreckt sich oft über viele Jahre, sodass neben der antiviralen und immunologischen Effektivität besonders das Auftreten von Langzeitnebenwirkungen von Bedeutung ist. Im Rahmen dieser Arbeit wurden retrospektiv die Langzeit-Therapieverläufe von 213 Patienten, die zwischen 1990 und 2003 mit Zidovudin oder Stavudin behandelt wurden, verglichen. Die Kombinationsegime unterschieden sich nicht in ihrer antiretroviralen Wirksamkeit oder Einnahmedauer, jedoch in ihrem Nebenwirkungsprofil. So traten hämatologische Nebenwirkungen (Anämien, Leukopenien, Neutropenien) signifikant häufiger unter AZT auf. Die Gabe von Stavudin kann die hämatotoxische Wirkung von Zidovudin zum Teil kompensieren. Nach Therapieumstellung von AZT auf d4T kam es zu einem Anstieg der absoluten Leukozyten, der neutrophilen Granulozyten und des Hämoglobins. Sowohl in Zidovudin- als auch Stavudin-haltigen Regimen trat nach Beginn der antiretroviralen Therapie eine Makrozytose auf. Patienten mit Noncompliance zeigten eine anhaltende Normozytose bzw. eine Normalisierung des MCV, falls nach Beginn der ART eine Makrozytose bestand. Das MCV kann als Compliancemarker genutzt werden. Unter d4T-haltigen Regimen traten häufiger metabolische Nebenwirkungen wie Hypercholesterinämien, Hypertriglyceridämien und Hepatotoxizität auf, v.a. in Kombination mit Proteaseinhibitoren. Lipodystrophien wurden unter Proteasehemmer-haltigen und freien Regimen beobachtet. Unter Stavudin traten Veränderungen der Körperfettverteilung signifikant häufiger auf als unter Zidovudin. Zidovudine and stavudine, both NRTI, are frequently used drugs in antiretroviral therapies (ART). The ART will be given for many years, so long-term toxicities are an important limitating factor. In this study the antiretroviral therapies of 213 patients, who have been treated with zidovudine or stavudine between 1990 and 2003, were compared retrospectively. The regimens dont differ from antiviral efficacy or time on ART but from adverse reactions. Hematologic complications (anemia, leucopenia, neutropenia) are common effects of zidovudine. Macrocytosis has been observed in zidovudine- and stavudine-containing regimens. Persons with noncompliance showed a normal mean corpuscular volume (MCV). It can be used to assess noncompliance. Under d4T-containing therapies metabolic complications like hypertriglyceridemia, hypercholesterolemia and hepatotoxicity occurred more often than under zidovudine, especially in combination with PI. Lipodystrophy has been observed in PI-containing and sparing regimens. It occurred more often under stavudine than zidovudine.
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ABSTRACT: This thesis addresses two important topics in HIV-1 medicine; (i) the clinical relevance of pre-treatment G-A hypermutation and the contribution of host and viral genetics to its development and; (ii) the influence of genetic variation in host enzymes responsible for antiretroviral drug metabolism on response to therapy. These themes are outlined below. HIV-1 Hypermutation At present, limited data exists regarding the relative roles of host encoded cytidine deaminases APOBEC3G and APOBEC3F in promoting G-A hypermutation of HIV-1 proviral DNA in vivo, nor the clinical relevance of hypermutation or the influence of genetic diversity of the APOBEC3G locus and of the viral encoded vif protein that counteracts the action of APOBEC3G. The analyses contained within this thesis demonstrate that within the WA HIV cohort, clinically relevant hypermutation is restricted to a minority of individuals and is mediated predominantly by APOBEC3G. In this study, the presence of HIV-1 hypermutation had a substantially greater effect on plasma viremia than other known host antiviral factors such as CCR5D32 or specific HLA-B alleles. Furthermore, the considerable genetic diversity of the vif gene is likely to make a greater contribution to the development of hypermutation than the limited genetic diversity of the APOBEC3G gene in Caucasians. These data indicate that G-A hypermutation is a clinically relevant phenomenon and may provide a fresh perspective to the area of HIV/AIDS therapies. Genetic Determinant of HIV-1 Treatment Response Thymidine kinase 2 (TK2) and thymidylate kinase (dTMPK) are rate limiting enzymes for the metabolism of the antiretrovirals d4T and AZT, respectively, and are thus central to the antiviral efficacy and toxicity of these agents. However, the genetic diversity of TK2 and dTMPK and their influence on toxicities associated with their use is largely unknown. The results discussed in this thesis indicate that in contrast to the highly conserved TK2 locus, the dTMPK locus of Caucasian individuals, including regulatory regions potentially influencing transcription and translation, is considerably polymorphic and organised into five common haplotypes. The results regarding the contribution of dTMPK genetic variation to toxicities associated with AZT therapy are encouraging. A common dTMPK haplotype had significant, albeit modest, effect on haematological parameters (haemoglobin and mean corpuscular volume) in HIV-infected patients, although no AZT-specific treatment effect was observed in this relatively haematologically stable cohort. In addition, another common dTMPK haplotype provided significant protection against AZT-induced adipocyte mtDNA depletion in a pilot study of AZT- and d4T-treated individuals. The dTMPK haplotypes characterised in this thesis should facilitate further studies regarding dTMPK genetic variation in HIV-1 infection and response to treatment, which are warranted from the clinical results presented herein.