Zidovudine/Lamivudine for HIV-1 Infection Contributes to Limb Fat Loss

Lipoatrophy is known to be associated with stavudine as part of the treatment for HIV infection, but it is less clear if this serious side effect is also related to other nucleoside reverse transcriptase inhibitors like zidovudine. We aimed to determine whether zidovudine-sparing first-line antiretroviral therapy would lead to less lipoatrophy and other metabolic changes than zidovudine-containing therapy.Fifty antiretroviral therapy-naïve HIV-1 infected men with an indication to start antiretroviral therapy were included in a randomized single blinded clinical trial. Randomisation was between zidovudine-containing therapy (zidovudine/lamivudine+lopinavir/ritonavir) and zidovudine-sparing therapy (nevirapine+lopinavir/ritonavir). Main outcome measures were body composition assessed by computed tomography and dual-energy X-ray absorptiometry scan and lipid profile before and after 3, 12, 24 months of antiretroviral therapy. In the zidovudine/lamivudine+lopinavir/ritonavir group, from 3 months onward limb fat decreased progressively by 684+/-293 grams (estimated mean+/-standard error of the mean)(p = 0.02) up to 24 months whereas abdominal fat increased, but exclusively in the visceral compartment (+21.9+/-8.1 cm(2), p = 0.008)). In contrast, in the nevirapine+lopinavir/ritonavir group, a generalized increase in fat mass was observed. After 24 months no significant differences in high density lipoprotein and total/high density lipoprotein cholesterol ratio were found between both treatment groups, but total and low density lipoprotein cholesterol levels were higher in the nevirapine+lopinavir/ritonavir group (6.1+/-0.2 versus 5.3+/-0.2 and 3.6+/-0.1 versus 2.8+/-0.1 mmol/l respectively, p<0.05). Virologic response and safety were comparable in both groups.Zidovudine/lamivudine+lopinavir/ritonavir, but not nevirapine+lopinavir/ritonavir in antiretroviral therapy-naïve patients, is associated with lipoatrophy and greater relative intraabdominal lipohypertrophy, suggesting that zidovudine/lamivudine contributes to both these features of lipodystrophy. These findings support to no longer consider zidovudine/lamivudine as one of the preferred possible components of first-line antiretroviral therapy where alternative treatments are available.ClinicalTrials.gov NCT 00122226

Stavudine but not didanosine as part of HAART contributes to peripheral lipoatrophy: a substudy from the Antiretroviral Regimen Evaluation Study (ARES)

PURPOSE: To objectively assess changes in body fat distribution in a subgroup of antiretroviral therapy-naïve participants in a randomized comparative trial of regimens including a nucleoside analogue backbone of didanosine with either lamivudine or stavudine. METHOD: Whole body dual-energy X-ray absorptiometry (DEXA) scans were performed at baseline and weeks 48 and 96 of therapy in all 19 patients from one of the sites participating in the Antiretroviral Regimen Evaluation Study (ARES). Patients had been randomized to receive nelfinavir/didanosine/stavudine (n = 8), nevirapine/didanosine/lamivudine (n = 7), or ritonavir-boosted saquinavir/didanosine/lamivudine (n = 4). RESULTS: In an intent-to-treat analysis, patients allocated to didanosine plus stavudine-containing treatment after 96 weeks had lost a median of 1,825 g (-26%) of total limb fat, as compared to a median gain of 1,639 (48%) and 403 (6%) g in those randomized to the didanosine/lamivudine plus nevirapine or saquinavir-containing regimens, respectively. These changes in limb fat were statistically significantly different when comparing patients allocated to stavudine-containing treatment with both of the other two treatment arms combined (p = .01). CONCLUSION: This study suggests that didanosine/lamivudine, when combined with either nevirapine or ritonavir-boosted saquinavir over 96 weeks of therapy, is possibly not associated with limb fat atrophy, in contrast to when treatment contained didanosine, stavudine, and nelfinavir combine

Increase in Carotid Artery Intima-Media Thickness and Arterial Stiffness but Improvement in Several Markers of Endothelial Function after Initiation of Antiretroviral Therapy

Background. The risk of cardiovascular disease in human immunodeficiency virus (HIV)-infected patients is an increasing concern. We studied the changes in vascular properties after the initiation of combination antiretroviral therapy (cART) as well as the contribution of different drug classes. Methods. cART-naive men were randomized to receive either lopinavir/ritonavir (LPV/r) plus zidovudine/lamivudine (ZDV/3TC) (n = 19) or LPV/r plus nevirapine (NVP) (n = 18). Carotid artery intima-media thickness (C-IMT), arterial stiffness (distensibility coefficients [DCs] and compliance coefficients [CCs] of the carotid, femoral, and brachial arteries; carotid elastic modulus; and augmentation index), and markers of endothelial function (soluble vascular cell adhesion molecule [sVCAM]-1, intercellular adhesion molecule [sICAM]-1, plasma von Willebrand factor (vWF) antigen, and plasminogen activator inhibitor-1 antigen) and inflammation (high-sensitivity C-reactive protein) were measured before the initiation of cART and after 3, 12, and 24 months of cART. Results. C-IMT increased by 0.061 +/- 0.016mm (P <.001) in the ZDV/3TC/LPV/r arm and by 0.044 +/- 0.018 mm (P = .012) in the NVP/LPV/r arm ( data are estimated means +/- SEs). Femoral artery DC( -1.66 +/- 0.78 x 10(-3)/kPa [P = .035]) and CC (-0.11 +/- 0.053 mm(2)/kPa [P = .043]) decreased in the ZDV/3TC/LPV/r arm and femoral DC decreased in the NVP/LPV/r arm (-1.72 +/- 0.85 x 10(-3)/kPa [P = .046]), with no significant difference in C-IMT or arterial stiffness between arms. sVCAM-1, sICAM-1, and vWF levels decreased significantly in both groups. Conclusion. C-IMT and femoral artery stiffness increased after the initiation of cART, whereas several markers of endothelial function improved, regardless of the composition of cAR

Boosted versus unboosted indinavir with zidovudine and lamivudine in nucleoside pre-treated patients: a randomized, open-label trial with 112 weeks of follow-up (HIV-NAT 005)

INTRODUCTION: The use of HIV protease inhibitors (PIs) in a ritonavir (RTV)-boosted form is now common. However, randomized data comparing boosted with unboosted PI strategies are scarce. METHODS: This randomized, open-label trial compared indinavir (IDV) 800 mg three times daily with IDV/RTV 800/100 mg twice daily, both given with zidovudine (AZT)/lamivudine (3TC) twice daily in individuals with at least 3 months previous AZT experience. The primary endpoint was the time-weighted average change in HIV RNA from baseline. Designed as a 48-week study, follow-up continued until week 112. Primary analysis is by intention to treat. RESULTS: One hundred and three patients commenced therapy and are included in the analysis. Patients had a median of 29 months past nucleoside reverse transcriptase inhibitor (NRTI) exposure. Baseline median (interquartile range) log10 HIV RNA was 4.0 (3.3-4.5) and CD4+ T-cell count 166 (40-323) cells/microl. After 112-weeks of study there was no significant difference observed between arms in the mean (SD) change in time-weighted average HIV RNA from baseline (-1.6 [1.1] HIV RNA copies/week/ml three times daily arm; -1.4 [1.1] HIV RNA copies/week/ml twice daily arm; P = 0.3). Both arms were associated with substantial toxicity expressed as serious adverse events and study drug interruptions. The twice daily arm experienced greater dyslipidaemia. Mean (SD) changes in time-weighted CD4+ T-cell count from baseline were similar [88 (84) cells/week/microl three times daily arm; 70 [109] cells/week/microl twice daily arm; P = 0.3). CONCLUSIONS: RTV-boosted IDV 800/100 mg twice daily demonstrated comparable efficacy to unboosted IDV 800 mg three times daily dosing. Both regimens were associated with substantial toxicity. Use of lower doses of RTV-boosted IDV may result in better tolerability without loss of efficacy and warrant further researc

Simplifying protease inhibitor therapy with once-daily dosing of saquinavir soft-gelatin capsules/ritonavir (1600/100 mg): HIVNAT 001.3 study

Objective: To determine the feasibility of switching therapy for HIV-1-infected patients with plasma viral loads of 0.05 mg/L. Median values for the area under the plasma concentration-versus-time curve from 0 to 24 hours (AUC(0-24h)), maximal concentration (C-max). and C-24h for SQV were 48.1 6.98 mg/L. and 0.17 mg/L respectively, Body weight was inversely correlated with SQV AUC(24h) and C-24h (p <.01). Conclusions: Clinical and pharmacokinetic data support once-daily SQV-SGC/RTV ( 1600/100 mg) with two NRTIs as a convenient and safe therapeutic regimen to maintain viral suppression and immune function in HIV-1-incected patients with plasma viral loads of <50 copies/m

Dose-escalating study of the safety and pharmacokinetics of nelfinavir in HIV-exposed neonates

The pharmacokinetics of nelfinavir (NFV) in neonates younger than 4 weeks of age was assessed. Three cohorts of HIV-exposed neonates were enrolled in cohorts to receive 15, 30, and 45 mg of NFV/kg twice daily in combination with stavudine and didanosine for 4 weeks after birth. Trough NFV concentrations (C(min)) were measured at 1 and 7 days of age. Intensive pharmacokinetic evaluations were performed at 14 and 28 days of age. The median NFV C(min) values in the 15 mg/kg (6 patients), 30 mg/kg (5), and 45 mg/kg (11) cohorts at 1, 7, 14, and 28 days of age were 0.19, 1.21, 0.51, and 0.33; 1.02, 3.18, 0.73, and 0.55; and 0.67, 3.21, 0.70, and 0.73 mg/L, respectively. The median area under the plasma concentration-versus-time curve values over 12 hours in the three cohorts at 14 and 28 days of age were 14.4 and 8.7, 19.4 and 15.8, and 23.4 and 18.5 (h. mg)/L, respectively. No serious adverse events were observed. In conclusion, the systemic exposure of NFV decreased after 7 days of age, possibly because of hepatic enzyme maturation, autoinduction of NFV metabolism, and/or changes in NFV absorption. The highly variable systemic exposure observed in the study indicates that therapeutic drug monitoring seems warranted to ensure adequate NFV dosing in this populatio

Ketoconazole is inferior to ritonavir as an alternative booster for saquinavir in a once daily regimen in Thai HIV-1 infected patients.

Contains fulltext : 52575.pdf (publisher's version ) (Closed access)OBJECTIVE: To improve the pharmacokinetics of protease inhibitors, boosting with low-dose ritonavir is performed. However, toxicity, storage conditions and high costs of antiretroviral treatment may necessitate interruption of ritonavir. Ketoconazole was investigated as a potential booster of once-daily (o.d.) saquinavir. METHODS: In a single-group, two-period design, 25 virologically and immunologically stable patients on saquinavir/ritonavir 2000/100 mg o.d. were switched to saquinavir/ketoconazole 2000/400 mg o.d. for 2 weeks. Two steady-state pharmacokinetic curves were recorded at both periods. RESULTS: Fourteen females and 11 male patients were included. Median age was 34 years [interquartile range (IQR), 32-42 years], body weight 54 kg (IQR, 47-59 kg) and body mass index 21 kg/m (19-23 kg/m). The mean saquinavir area under the curve (AUC) during boosting with ritonavir was 57.93 +/- 27.96 mg/h/l, maximum observed concentration (Cmax) was 7.50 +/- 3.45 mg/l and concentration at 24 h (Cmin) was 0.35 +/- 0.30 mg/l. When ketoconazole was used, the saquinavir AUC, Cmax, and Cmin were 12.00 +/- 6.97 mg/h/l, 2.43 +/- 1.35 mg/l and 0.03 +/- 0.04 mg/l, respectively. CONCLUSION: Boosting with ketoconazole resulted in 80% lower exposure to saquinavir. Although saquinavir AUC might still be adequate for treatment, concentrations at 24 h reached levels below the recommended trough concentrations of 0.1 mg/l, which may result in selection of resistant HIV-1 viral strains. Therefore, boosting of saquinavir by ketoconazole is not recommended

Pharmacokinetics of Stavudine and Didanosine Coadministered with Nelfinavir in Human Immunodeficiency Virus-Exposed Neonates

We evaluated the pharmacokinetics of stavudine (d4T) and didanosine (ddI) in neonates. Eight neonates born to human immunodeficiency virus-infected mothers were enrolled to receive 1 mg of d4T per kg of body weight twice daily and 100 mg of ddI per m(2) once daily in combination with nelfinavir for 4 weeks after birth. Pharmacokinetic evaluations were performed at 14 and 28 days of age. For d4T, on days 14 and 28, the median areas under the concentration-time curves from 0 to 12 h (AUC(0–12)s) were 1,866 and 1,603, ng · h/ml, respectively, and the median peak concentrations (C(max)s) were 463 and 507 ng/ml, respectively. For ddI, on days 14 and 28, the median AUC(0–10)s were 1,573 and 1,562 h · ng/ml, respectively, and the median C(max)s were 627 and 687 ng/ml, respectively. Systemic levels of exposure to d4T were comparable to those seen in children, suggesting that the pediatric dose of 1 mg/kg twice daily is appropriate for neonates at 2 to 4 weeks of age. Levels of exposure to ddI were modestly higher than those seen in children. Whether this observation warrants a reduction of the ddI dose in neonates is unclear