Showing papers on "Zidovudine published in 2005"

Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine.

Abstract: Objective: To determine if stavudine (a4T)-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. Design: 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. Methods: 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. Results: 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. Conclusions: Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.

In Vivo, Nucleoside Reverse-Transcriptase Inhibitors Alter Expression of Both Mitochondrial and Lipid Metabolism Genes in the Absence of Depletion of Mitochondrial DNA

Abstract: Background: Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described. Methods: We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks. Results: We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator–activated receptor–g coactivator–1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues. Conclusions: Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase-g, whereas disruption of expression of lipid metabolism genes offers an explanation forNRTI-induced lipoatrophy.

Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors

Abstract: Nucleoside reverse transcriptase inhibitors (NRTIs) suppress human immunodeficiency virus (HIV) replication, but are often associated with mitochondrial toxicity. Although well studied outside of the central nervous system, no investigation has examined the effects of these drugs on brain mitochondria of individuals living with HIV. The authors used proton magnetic resonance spectroscopy to evaluate NRTI-related changes in brain mitochondria. N-acetylaspartate (NAA; sensitive to alterations in mitochondrial integrity) was measured in frontal lobe white and gray matter of 18 HIV+ individuals taking didanosine and/or stavudine (two NRTIs likely to cause mitochondrial toxicity), 14 HIV+ individuals taking zidovudine and lamivudine, 16 HIV+ individuals not currently taking antiretrovirals, and 17 HIV- controls. The HIV+ groups were comparable on demographic measures, estimates of illness severity, and estimated length of HIV infection. Those taking didanosine and/or stavudine had a significant 11.4% decrease in concentrations of frontal white matter NAA compared to HIV- controls, whereas NAA levels of the other HIV+ groups were intermediate. Group differences in metabolites were not found in frontal gray matter. Lower levels of frontal white matter NAA were associated with longer periods of didanosine and/or stavudine treatment (r = -.41, P = .06). Levels of NAA were not related to length of zidovudine/lamivudine treatment (r = -.04, P = .44). Furthermore, taking more than one of stavudine, didanosine, and abacavir increased the likelihood of having reduced NAA. The results are consistent with previous studies finding HIV-related changes in neuronal integrity. However, because NRTIs can injure mitochondria, we propose that the observed reductions in NAA in individuals taking didanosine and/or stavudine may be the result of depleted brain mitochondria and/or alterations in cellular respiration. Measurement of brain metabolites sensitive to impairments in energy metabolism, including NAA, may aid in early detection of subclinical NRTI-mediated mitochondrial toxicity.

Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Côte d'Ivoire.

Abstract: Objective: Neutropenia is the most frequent side effect of cotrimoxazole in sub-Saharan Africa. We estimated the incidence of haematological disorders during the first 6 months of a zidovudine-containing highly active antiretroviral therapy (HAART) regimen in sub-Saharan African adults receiving cotrimoxazole. Methods: Prospective cohort study in Abidjan, with blood cell count measurement at baseline (HAART initiation), month 1, month 3 and month 6. Results: A total of 498 adults [baseline: 80% currently on cotrimoxazole prophylaxis; median CD4 count 237/mm 3 [interquartile range (IQR) 181;316]; median neutrophil count 1647/mm 3 (IQR 1221;2256); median haemoglobin 113 g/l (IQR 102;122)] started zidovudine (AZT)/lamivudine/efavirenz. During follow-up, 118 patients had a grade 3-4 neutropenia [(56.3/100 person-years (PY)], 23 had a grade 3-4 anaemia (9.6/100 PY) and no cases of grade 3-4 thrombocytopenia. Of the 118 patients with grade 3-4 neutropenia, 86 (73%) had to stop cotrimoxazole because neutropenia persisted, and one (<1%) had to stop AZT because of persistent neutropenia after cotrimoxazole was stopped (neutropenia-related HAART modification: 0.4/100 PY). Of the 23 patients with grade 3-4 anaemia, 11 had to stop AZT (anaemia-related HAART modification: 4.4/100 PY). In patients who stopped cotrimoxazole but not AZT, the median gain in neutrophils at 1 month was +540/mm 3 (IQR+150;+896). Conclusions: At baseline, most patients had a normal neutrophil count and 80% of them were already receiving cotrimoxazole. An unexpectedly high rate of grade 3-4 neutropenia occurred shortly after introduction of AZT. Almost all of the persistent severe neutropenia disappeared after cotrimoxazole was stopped. This suggests an accentuated drug interaction between the two drugs in these sub-Saharan African individuals. Grade 3-4 anaemia was much less frequent, but remained the first cause of AZT discontinuation.

Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment.

Abstract: respectively) Background The magnitude of infant antiretroviral (ARV) exposure from breast milk is unknown Methods We measured concentrations of nevirapine, lamivudine, and zidovudine in serum and whole breast milk from human immunodeficiency virus type 1 (HIV-1)-infected women in Botswana receiving ARV treatment and serum from their uninfected, breast-feeding infants Results Twenty mother-infant pairs were enrolled Maternal serum concentrations of nevirapine were high (median, 9534 ng/mL at a median of 4 h after nevirapine ingestion) Median breast-milk concentrations of nevirapine, lamivudine, and zidovudine were 067, 334, and 321 times, respectively, those in maternal serum The median infant serum concentration of nevirapine was 971 ng/mL, at least 40 times the 50% inhibitory concentration and similar to peak concentrations after a single 2-mg/kg dose of nevirapine The median infant serum concentration of lamivudine was 28 ng/mL, and the median infant serum concentration of zidovudine was 123 ng/mL, but infants were also receiving zidovudine prophylaxis Conclusions HIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving these ARVs, exposing infants to the potential for beneficial and adverse effects of nevirapine ingestion Further study is needed to understand the impact of maternal ARV treatment on breast-feeding HIV-1 transmission, infant toxicity, and HIV-1 resistance mutations among infected infants

Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand

Abstract: BACKGROUND: Although zidovudine prophylaxis decreases the rate of trans mission of the human immunodeficiency virus (HIV) type 1 substantially, a large number of infants still become infected We hypothesized that the administration, in ad dition to zidovudine, of a single dose of oral nevirapine to mothers during labo r and to neonates would further reduce transmission of HIVMETHODS: We conducted a randomized, double-blind trial of three treatment regimens in Thai women who were receiving zidovudine therapy during the third trimester of pregnancy In o ne group, mothers and infants received a single dose of nevirapine (nevirapine- nevirapine regimen);in another, mothers and infants received nevirapineand place bo, respectively (nevirapine-placebo regimen); and in the last, mothers and inf ants received placebo (placebo-placebo regimen) The infants also received one week of zidovudine therapy and were formula-fedThe end point of the study was infection with HIV in the infants, established by virologic testing RESULTS:Bet ween January 15, 2001, and February 28, 2003, a total of 1844 Thai women were en rolled At the first interim analysis, the independent data monitoring committee stopped enrollment in the placebo-placebo groupAmong women who delivered befo re the interim analysis,the as-randomized Kaplan-Meier estimates of the transm ission rates were 11 percent (95 percent confidence interval, 03 to 22) in th e nevirapine-nevirapine group and 63 percent (95 percent confidence interval,3 8 to 89) in the placebo-placebo group (P 0001) The final per-protocol tra nsmission rate in the nevirapine-nevirapine group, 19 percent (95 percent conf idence interval,09 to 30), was not significantly inferior to the rate in the n evirapine-placebo group (28 percent; 95 percent confi-dence interval, 15 to 41) Nevirapine had an effect within subgroups defined by known risk factors su ch as viral load and CD4 count No serious adverse effects were associated with nevirapine therapy CONCLUSIONS: A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophyl axis starting at 28 weeks’gestation, is highly effective in reducing mother-to -child transmission of HIV

Estimating HIV Evolutionary Pathways and the Genetic Barrier to Drug Resistance

Abstract: Background. The evolution of drug-resistant viruses challenges the management of human immunodeficiency virus (HIV) infections. Understanding this evolutionary process is important for the design of effective therapeutic strategies. Methods. We used mutagenetic trees, a family of probabilistic graphical models, to describe the accumulation of resistance-associated mutations in the viral genome. On the basis of these models, we defined the genetic barrier, a quantity that summarizes the difficulty for the virus to escape from the selective pressure of the drug by developing escape mutations. Results. From HIV reverse-transcriptase sequences that had been obtained from treated patients, we derived evolutionary models for zidovudine, zidovudine plus lamivudine, and zidovudine plus didanosine. The genetic barriers to resistance to zidovudine, stavudine, lamivudine, and didanosine, for the above 3 regimens, were computed and analyzed. We found both the mode and the rate of development of resistance to be heterogeneous. The genetic barrier to zidovudine resistance was increased if lamivudine was added to zidovudine but was decreased for didanosine. The barrier to lamivudine resistance was maintained with zidovudine plus didanosine, whereas the barrier to didanosine resistance was reduced most with zidovudine plus lamivudine. Conclusion. Mutagenetic trees provide a quantitative picture of the evolution of drug resistance. The genetic barrier is a useful tool for design of effective treatment strategies.

Highly Active Antiretroviral Therapy Started during Pregnancy or Postpartum Suppresses HIV-1 RNA, but Not DNA, in Breast Milk

Abstract: Background. The ability of highly active antiretroviral therapy (HAART) to reduce human immunodeficiency virus type 1 (HIV-1) RNA and DNA in breast milk has not been described. Methods. We compared breast-milk HIV-1 RNA and DNA loads of women in Botswana who received HAART (nevirapine lamivudine and zidovudine) and women who did not received HAART. Results. Women in the HAART group received treatment for a median of 98 days (range 67-222 days) at the time of breast- milk sampling; 23 (88%) of 26 had whole breast-milk HIV-1 RNA loads <50 copies/mL compared with 9 (36%) of 25 women who did not receive HAART (P = .0001). This finding remained significant in a multivariate logistic-regression model (P = .0006). The whole-milk HIV 1-DNA load was unaffected by HAART. Of women who received HAART 13 (50%) of 26 had HIV-1 DNA loads <10 copies/10(6) cells compared with 15 (65%) of 23 who did not received HAART (P = .39). Conclusions. HAART suppressed cell-free HIV-1 RNA in breast milk and may therefore reduce mother-to-child transmission (MTCT) of HIV-1 via breast- feeding. However HAART initiated during pregnancy or early after delivery had no apparent effect of cell-associated HIV-1 DNA loads in breast milk. Clinical trials to determine MTCT among breast-feeding women receiving HAART are needed. (authors)

Skeletal muscle involvement in human immunodeficiency virus (HIV)-infected patients in the era of highly active antiretroviral therapy (HAART).

Abstract: Skeletal muscle involvement can occur at all stages of human immunodeficiency virus (HIV) infection, and may represent the first manifestation of the disease. Myopathies in HIV-infected patients are classified as follows: (1) HIV-associated myopathies and related conditions, including HIV polymyositis, inclusion-body myositis, nemaline myopathy, diffuse infiltrative lymphocytosis syndrome (DILS), HIV-wasting syndrome, vasculitic processes, myasthenic syndromes, and chronic fatigue; (2) muscle complications of antiretroviral therapy, including zidovudine and toxic mitochondrial myopathies related to other nucleoside-analogue reverse-transcriptase inhibitors (NRTIs), HIV-associated lipodystrophy syndrome, and immune restoration syndrome related to highly active antiretroviral therapy (HAART); (3) opportunistic infections and tumor infiltrations of skeletal muscle; and (4) rhabdomyolysis. Introduction of HAART has dramatically modified the natural history of HIV disease by controlling viral replication, but, in turn, lengthening of the survival of HIV-infected individuals has been associated with an increasing prevalence of iatrogenic conditions.

Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients.

Abstract: Previous investigational data using abacavir (ABC), lamuvidine (3TC), and zidovudine has suggested the possibility of triple nucleoside analogue reverse transcriptase inhibitors (NRTI) therapy as an option in the treatment of HIV infection. We performed a pilot study to assess the potency of once daily ABC+ 3TC+ tenofovir (TDF) in the treatment of HIV-infected naive patients. CD4 and HIV-viral load (VL) were followed monthly. Patients were considered to be nonresponder/failing if there was no reduction in VL by ≥ 2 log10 by week 8 and/or a rebound in VL after initial suppression. Resistance testing was then obtained. Nineteen patients naive to antiretroviral therapy (3 women and 16 men) were enrolled, of whom, 2 did not return (withdrew from study at week 2). Median VL and CD4 count at baseline were 147,167 copies per milliliter (5.16 log10; [range, 7650–>750,000]) and 277 cells/mm3 (range, 59–598). Eight patients had VL > 100000 at baseline. Of 17 patients eligible for follow-up, 5 (27%) were responders ...

Is there a difference in the efficacy of peripartum antiretroviral regimens in reducing mother-to-child transmission of HIV in Africa?

Abstract: Background: Peripartum antiretroviral regimens have been shown to prevent mother-to-child transmission of HIV (MTCT) in randomized clinical trials; however direct comparison of published results is impossible given methodological and population differences. Objective: To directly compare the efficacy of different antiretroviral regimens in reducing the risk of 6-week MTCT rate in African breastfeeding populations. Methods: Pooled analysis including all mother–infant pairs from any relevant trial: West African ZDV- placebo trials Petra ZDV+3TC [two regimens A (pre/intra/postpartum) and B (intra/post-partum) placebo from Uganda and Tanzania] SAINT (NVP and Petra arm B) HIVNET012 (NVP ultra short ZDV pp) and the Vitamin A trial (as placebo arm in South Africa). Peripartum HIV infection was any positive RNA or DNA polymerase chain reaction test < day 60. The MTCT risk was estimated at 6 weeks for each treatment arm and compared with placebo or single-dose NVP using logistic regression adjusting for maternal CD4 cell count breastfeeding and birthweight. Results: Overall 4125 singleton live-births were included; 3629 (88%) were assessed for HIV status at 6 weeks of age. In comparison with placebo zidovudine + lamivudine (ZDV+3TC) arm A [adjusted odds ratio (AOR) 0.23; P < 0.0001] ZDV+3TC arm B (AOR 0.49; P < 0.001) antenatal ZDV short (AOR 0.55; P = 0.006) and nevirapine (NVP) (AOR 0.60; P = 0.0007) significantly reduced MTCT. In comparison with NVP only the longest regimen of ZDV+3TC (AOR 0.39 P < 0.0005) was significantly more effective. Conclusion: These results are in line with current World Health Organisation guidelines suggesting equivalence of choice between single-dose NVP and short-course ZDV and confirm the greater efficacy of ZDV+3TC than with any single antiretroviral drug. (authors)

Zidovudine induces S-phase arrest and cell cycle gene expression changes in human cells

Abstract: Antiretroviral therapy for the human immunodeficiency virus-1 (HIV-1) typically includes two nucleoside reverse transcriptase inhibitors (NRTIs). 3'-Azido-3'-deoxythymidine (AZT, Zidovudine) plus 2'-deoxy-3'-thiacytidine (3TC, Lamivudine) is a combination that is used frequently. The NRTIs are mutagenic nucleoside analogs that become incorporated into DNA and terminate replication. We therefore hypothesized that exposure to this class of drug may alter cell cycle parameters. We used flow cytometry to examine the cell cycle in human epithelioid carcinoma (HeLa) cells exposed to AZT and 3TC alone, as well as a series of AZT/3TC dose combinations: (A) 125.0 microM AZT/12.5 microM 3TC; (B) 250.0 microM AZT/25.0 microM 3TC; and (C) 500 microM AZT/50 microM 3TC. At 24 h, at all doses, there was a good cell viability (>/=68%), and incorporation of AZT into nuclear DNA. Using flow cytometry, a dose-related increase in the percentage of cells in S phase, from 9.5% with no drug, to 36.0% with dose C, was observed in cells exposed for 24 h (P = 0.001, ANOVA). A concomitant decrease in the percentage of cells in G(1) phase, from 82.6% with no drug to 58.5% with dose C, was observed in cells exposed for 24 h (P = 0.017, ANOVA). A similar S phase arrest was seen in cells exposed to 125, 250 and 500 microM AZT alone, but there was no S phase alteration with 50 microM 3TC alone, suggesting that AZT is responsible for the accumulation of cells in S phase. To elucidate the accumulation of cells in S phase and explore the cell cycle gene expression changes induced by AZT and 3TC, we used c-DNA microarray, Cell Cycle Super Array and real-time PCR. There was a strong upregulation of the DNA damage-inducible transcript 3 (DDIT3 or GADD153) in NRTI-exposed cells. In addition, AZT induced an upregulation of cyclin D1 accompanied by a downregulation of the cyclin D1-associated inhibitors P18 and P57, and the G(1)-S check point gene P21, the net effect of which would be to foster a cell progression into S phase. Cyclin A2 was down-regulated in cells exposed to AZT, suggesting a block in S-G(2)-M progression that would also be consistent with the accumulation of cells in S phase. Overall, the study demonstrates that AZT, but not 3TC, causes an arrest of cells in S phase with a consistent alteration in the expression of several cell cycle genes.

Sex differences in antiretroviral therapy-associated intolerance and adverse events

Abstract: Although women account for a substantial proportion of the global population infected with HIV, most clinical trials evaluating the safety and efficacy of specific antiretroviral therapy regimens have been preformed in predominantly male cohorts. Our knowledge of the sex differences associated with responses to these treatments is therefore limited. Potentially sex-specific influences, such as endogenous or exogenous hormones, could impact antiretroviral tolerance. Women also have different pharmacokinetic profiles for selected antiretrovirals compared with men. These factors could influence how women respond and react to antiretrovirals. Several observational studies have described a higher frequency of antiretroviral-related adverse effects among women compared with men. Women appear to be at an especially high risk for lactic acidosis, nevirapine-associated rashes and hepatotoxicity, and fat redistribution after highly active antiretroviral therapy exposure. Although a statistical association between antiretroviral toxicity and pregnancy has not been described, pregnancy may provide an additional influence on the toxicity of several antiretrovirals or antiretroviral combinations. Potential tolerability should be an important component in discussions of antiretroviral options among women.

The L74V mutation in human immunodeficiency virus type 1 reverse transcriptase counteracts enhanced excision of zidovudine monophosphate associated with thymidine analog resistance mutations.

Abstract: Thymidine analog mutations (TAMs) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) confer resistance to zidovudine (AZT) by increasing the rate of ATP-dependent phosphorolysis of the terminal nucleotide monophosphate (primer unblocking). By contrast, the L74V mutation, which confers resistance to didanosine, sensitizes HIV-1 to AZT and partially restores AZT susceptibility when present together with one or more TAMs. To compare rates of primer unblocking in RTs carrying different clusters of TAMs and to explore the biochemical mechanism by which L74V affects AZT susceptibility, ATP-mediated rescue of AZT-blocked DNA synthesis was assayed using a series of purified recombinant RTs. Rates of primer unblocking were higher in the 67N/70R/219Q RT than in the 41L/210W/215Y enzyme and were similar to rates observed with an RT carrying six TAMs (41L/67N/70R/210W/215Y/219Q). The presence of 74V in an otherwise wild-type RT reduced the rate of primer unblocking to a degree similar to that observed with the M184V mutation for lamivudine resistance, which also sensitizes HIV-1 to AZT. Introduction of 74V into RTs carrying TAMs partially counteracted the effect of TAMs on the rate of primer unblocking. The effect of 74V was less marked than that of the 184V mutation in the 67N/70R/219Q and 41L/210W/215Y RTs but similar in the RT carrying six TAMs. These results demonstrate that L74V enhances AZT susceptibility by reducing the extent of its removal by ATP-dependent phosphorolysis and provides further evidence for a common mechanism by which mutations conferring resistance to didanosine and lamivudine sensitize HIV-1 to AZT.

Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients.

Abstract: Background: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen. Methods: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV + EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase. Results: The baseline median HIV RNA level and CD4 cell count were 5.08 logic copies/mL (56% ≥ 100,000 copies/mL) and 210 cells/mm 3 (48% <200 cells/mm 3 ), respectively. No significant differences were noted between ABC/3TC/ZDV + EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing = failure]; P = 0.697) or time to treatment failure (P = 0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV + EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV + EFV group; P = 0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV + EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P = 0.057). Conclusions: After induction with ABC/3TC/ZDV + EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.

Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens.

Abstract: Objectives: Despite evidence for the role of adipokines such as adiponectin in the metabolic toxicities of protease inhibitor (PI)-treated patients, little is known about their role in nucleoside reverse transcriptase inhibitor (NRTI)-induced lipoatrophy (LA). We analyzed the relations between mitochondrial toxicity, adipokine expression, and clinical LA in peripheral blood mononuclear cells (PBMCs) and adipose samples from individuals treated with stavudine (d4T) or zidovudine (ZDV) in comparison to patients undergoing highly active antiretroviral therapy (HAART) as well as HIV-negative individuals. Methods: In this cross-sectional analysis, we studied 18 PI-naive HIV-infected patients with LA treated with d4T (d4T + LA + [n = 12]) or zidovudine (ZDV + LA + [n = 6]) in comparison to HAART-treated patients with (HAART + LA + [n = 8]) and without (HAART + LA - [n = 8]) LA as well as HIV-negative controls (n = 12). Adipose samples were assessed for protein and/or messenger RNA (mRNA) levels of adiponectin, tumor necrosis factor-a (TNFa), interleukin (IL)-6, and sterol regulatory element-binding protein (SREBP) 1a/c in all groups, whereas adipose and PBMC samples from the d4T + LA + , ZDV + LA + , and HIV-negative subgroups were assessed for mitochondrial DNA (mtDNA) depletion and cytochrome c-oxidase (COX) II/COX IV ratios. Results: There was no change in mtDNA levels in adipose or PBMC samples in NRTI-treated patients with LA, although patients treated with d4T had reduced COX II/COX IV ratios in adipose and PBMC samples. Adipose tissue adiponectin mRNA and plasma levels were reduced in the d4T- and ZDV-treated patients regardless of the use of PIs. Tissue SREBP 1 mRNA levels were also significantly reduced in both NRTI groups when compared with the HIV-negative controls. Significant reductions in SREBP1c levels were also evident with the HAART + LA + group when compared with HAART + LA - controls. Conclusions: Patients with LA on d4T-based regimens show evidence of mitochondrial respiratory chain dysfunction, whereas the d4T- and ZDV-based regimens also demonstrated reduced SREBP 1 c and adiponectin levels, findings that have previously been shown with PIs.

Emtricitabine: a review of its use in the management of HIV infection.

Abstract: Emtricitabine (Emtriva) is an orally administered nucleoside reverse transcriptase inhibitor (NRTI) that is indicated in combination with other antiretroviral agents in the treatment of HIV infection in adults. As a component of antiretroviral therapy (ART), emtricitabine effectively reduces and/or maintains suppression of viral load in ART-naive adults or ART-experienced adults switching from stable combination regimens, and is generally well tolerated. Emtricitabine is a component of preferred initial HIV combination therapy regimens; it can be used in place of lamivudine as part of the dual NRTI backbone in non-nucleoside reverse transcriptase inhibitor (NNRTI)- and protease inhibitor (PI)-based regimens. Moreover, preliminary data from a randomised, open-label study suggest that emtricitabine plus tenofovir DF, a preferred dual-NRTI combination, is better tolerated than co-formulated lamivudine/zidovudine, another preferred dual-NRTI combination, resulting in a higher persistent virological response rate, as analysed using the US FDA time to loss of virological response (TLOVR) algorithm. With the convenience of once-daily (single pill) administration, no dietary restrictions and a favourable drug interaction and tolerability profile, emtricitabine should facilitate patient adherence to treatment, which, in turn, is central to the success of antiretroviral therapy. Similarly, emtricitabine is attractive as an option for ART-experienced stable adults requiring regimen simplification.

Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity.

Abstract: Long-term side effects of antiretroviral therapy are attributed to the mitochondrial (mt) toxicity of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their ability to deplete mtDNA. Studies in hepatocytes suggest that uridine is able to prevent and treat mtDNA depletion by pyrimidine NRTls [zalcitabine (ddC) and stavudine (d4T)] and to fully abrogate hepatocyte death, elevated lactate production and intracellular steatosis. Uridine was also found to improve the liver and haematopoietic toxicities of zidovudine (AZT), which are unrelated to mtDNA depletion, and to prevent neuronal cell death induced by ddC. Most recently, uridine was found to prevent the onset of a lipoatrophic phenotype (reduced intracellular lipids, increased apoptosis, mtDNA depletion and mt depolarization) in adipocytes incubated long-term with d4T and AZT. Various steps of mt nucleoside utilization may be involved in the protective effect, but competition of uridine metabolites with NRTIs at polymerase y or other enzymes is a plausible explanation. Pharmacokinetic studies suggest that uridine serum levels can be safely increased in humans to achieve concentrations which are protective in vitro (50-200 microM). Uridine was not found to interfere with the antiretroviral activity of NRTIs. Mitocnol, a sugar cane extract which effectively increases uridine in human serum, was beneficial in individual HIV patients with mt toxicity and is now being tested in placebo-controlled randomized trials. Until these data become available, the risk-benefit calculation of using uridine should be individualized. The current safety data justify the closely monitored use of uridine in individuals who suffer from mt toxicity but who cannot be switched to less toxic NRTIs.

Impaired Rescue of Chain-Terminated DNA Synthesis Associated with the L74V Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Abstract: The L74V and M184V mutations in the reverse transcriptase (RT) gene of human immunodeficiency virus type 1 (HIV-1) are frequently associated with resistance to the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and lamivudine. Yet viruses containing any of these mutations often display hypersusceptibility to zidovudine (ZDV). Two distinct mechanisms have been described to explain HIV-1 drug resistance. One of these involves diminished rates of incorporation of the nucleotide analogue by mutated RT, while the other mechanism involves increased rates of phosphorolytic excision of the drug-terminated primer. To understand the biochemical mechanisms responsible for the hypersensitization of L74V-containing viruses to ZDV, we studied the efficiency of excision of ZDV-monophosphate (ZDV-MP)-terminated primers by recombinant wild-type and mutated HIV-1 RTs in cell-free assays. We observed that the L74V mutation in RT caused reductions in ATP-dependent removal of ZDV-MP from newly synthesized viral DNA. In addition, we determined that the L74V and M184V mutations did not affect the ratio between the populations of RT-DNA/DNA complexes found at pre- and posttranslocational stages; however, they might have affected proper alignment between incorporated chain terminator and pyrophosphate donor, substrate orientation, affinity for ATP, and/or primer-template substrate. Finally, we confirmed previous findings that L74V-containing viruses display diminished replication capacity and that this is associated with reduced levels of synthesis of early reverse-transcribed viral DNA molecules.

Breast milk HIV-1 suppression and decreased transmission: a randomized trial comparing HIVNET 012 nevirapine versus short-course zidovudine

Abstract: Objective:To compare the effect of perinatal regimens of short-course nevirapine (HIVNET 012) and zidovudine [Thai-Centers for Disease Control and Prevention (CDC) regimen] on breast milk viral shedding and perinatal transmission during the first 6 weeks postpartum in a randomized clinical trial.Des

Pharmacokinetics and tissue distribution of zidovudine in rats following intravenous administration of zidovudine myristate loaded liposomes.

Abstract: Liposomes accumulating in the reticuloendothelial system (RES) appear to be a promising vehicle to improve the therapeutic index of anti-HIV drugs such as zidovudine (AZT). Since the entrapment efficiency of AZT in liposomes was found to be low and AZT leakage from liposomes is fast, zidovudine myristate (AZT-M) was synthesized as a prodrug, and AZT-M incorporated liposomes in a lyophilized form were prepared with an average diameter of 90 nm and an encapsulation efficiency of 98% after reconstitution. The pharmacokinetic profiles and tissue distribution of AZT after i.v. administration of AZT-M liposomes in rats were investigated, and the results were compared with those after i.v. administration of AZT solution. AZT levels in plasma were significantly higher following application of AZT-M liposomes compared with AZT solution, and AUC0_infinity increased from 5.0 +/- 0.7 micromol x min x ml(-1) to 8.2 +/- 1.7 micromol x min x ml(-1) accordingly. Tissue distribution studies also confirmed higher concentrations of AZT in organs of RES and brain, suggesting that AZT-M liposomes might be promising candidates for therapy of HIV infections.

Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS therapy.

Abstract: NRTIs are cornerstones of antiretroviral therapy and perhaps the most important drugs developed for AIDS treatment. Judicious use of NRTIs in the fight against HIV infection has afforded significant clinical advances in AIDS treatment. Nonetheless, it is axiomatic to expect side effects from NRTIs as well. A principal toxicity of NRTIs relates to chronic and cumulative MT in various tissues. The long-term impact of this toxicity on affected patients is not clear except in extreme cases where morbidity was severe and mortality occurred. Because of chronicity and potential for severity, NRTI MT remains an important clinical problem. Further studies will help us unravel mechanisms of NRTI MT and the natural history of mitochondrial biogenesis in humans and other mammalian systems.

Effect of Ribavirin on Intracellular and Plasma Pharmacokinetics of Nucleoside Reverse Transcriptase Inhibitors in Patients with Human Immunodeficiency Virus-Hepatitis C Virus Coinfection: Results of a Randomized Clinical Study

Abstract: The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.

Cardiac mitochondrial compromise in 1-yr-old Erythrocebus patas monkeys perinatally- exposed to nucleoside reverse transcriptase inhibitors

Abstract: Hearts from 1-yr-old Erythrocebus patas monkeys were examined after in utero and 6-wk-postbirth exposure to antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs). Protocols were modeled on those given to human immunodeficiency virus (HIV)-1-infected pregnant women. NRTIs were administered daily to the dams for the last 20% or 50% of gestation, and to the infants for 6 wk after birth. Exposures included: no drug (n=4); Zidovudine, 3′-azido-3′-deoxythymidine (AZT; n=4); AZT/Lamivudine, (−)-β-l-2′, 3′-Dideoxy-3′-thiacytidine (Epivir, 3TC) (n=4); AZT/Didanosine (Videx, ddl) (n=4); and Stavudine (Zerit, d4T)/3TC (n=4). Echocardiograms and clinical chemistry showed no drug-related changes, but the d4T/3TC-exposed fetuses at 6 and 12 mo had increased white cell counts (p<0.05). At 1 yr of age, oxidative phosphorylation (OXPHOS) enzyme activities were similar in heart mitochondria from all groups. Mitochondrial pathology, that included clones of damaged mitochondria (p<0.05), was found in hearts of all 1-yr drug-exposed infants. Levels of mtDNA were elevated (p<0.05) in hearts of all NRTI-exposed monkeys in the following order: control < d4T/3TC

Highly active antiretroviral therapy and human immunodeficiency virus encephalitis.

Abstract: The ability of highly active antiretroviral therapy (HAART) to prevent the onset of HIV-associated dementia and to prevent or reduce the neuropathological features of HIV encephalitis (HIVE) remains unclear. Using a severe combined immunodeficient (SCID) mouse model of HIVE, we determined the effects of regular HAART treatment on HIVE. Before studying HAART in infected SCID mice, nonmanipulated SCID mice were treated with a single injection of the HAART cocktail (consisting of zidovudine, lamivudine, and indinavir) to determine optimum dosage and sampling time and to measure antiretroviral levels in the brain. After these preliminary studies, SCID mice that were inoculated with either HIV-infected or uninfected human monocytes were given intraperitoneal (IP) injections of HAART three times daily over a 1- and 2-week period. All three drugs were detected in the brain using a novel drug extraction technique and a modified high-performance liquid chromatography method. HAART significantly decreased the amount of astrogliosis and viral load in treated mice compared with mice that received vehicle injections. These studies offer insight into the ability of HAART to treat HIV infection of the brain.