An Infant Formula with Partially Hydrolyzed Whey Protein Supports Adequate Growth and Is Safe and Well-Tolerated in Healthy, Term Infants: A Randomized, Double-Blind, Equivalence Trial.

The current study evaluates the safety and tolerance of a partially hydrolyzed whey protein-based infant formula (PHF) versus an in intact cow's milk protein formula (IPF). Breastfed infants were included as a reference group. In a multi-country, multicenter, randomized, double-blinded, controlled clinical trial, infants whose mothers intended to fully formula feed were randomized to PHF (n = 134) or IPF (n = 134) from ≤14 days to 17 weeks of age. The equivalence analysis of weight gain per day within margins of +/-3 g/d (primary outcome), the recorded adverse events, growth and gastro-intestinal tolerance parameters were considered for the safety evaluation. Equivalence of weight gain per day from enrolment until 17 weeks of age was demonstrated in the PHF group compared to the IPF group (difference in means -1.2 g/d; 90% CI (-2.42; 0.02)), with estimated means (SE) of 30.2 (0.5) g/d and 31.4 (0.5) g/d, respectively. No significant differences in growth outcomes, the number, severity or type of (serious) adverse events and tolerance outcomes, were observed between the two formula groups. A partially hydrolyzed whey protein-based infant formula supports adequate infant growth, with a daily weight gain equivalent to a standard intact protein-based formula; it is also safe for use and well-tolerated in healthy term infants.

Insulin sensitivity in multiple pathways is differently affected during zidovudine/lamivudine-containing compared with NRTI-sparing combination antiretroviral therapy.

OBJECTIVE: The extent and manner by which HIV nucleoside reverse transcriptase inhibitors contribute to insulin resistance is unclear. We evaluated the effect of zidovudine/lamivudine (ZDV/3TC) on glucose metabolism. METHODS: combination antiretroviral therapy-naive men were randomized to lopinavir/ritonavir (LPV/r, 400/100 mg twice a day) + ZDV/3TC or LPV/r (533/133 mg twice a day) + nevirapine (NVP). Computerized tomography, dual-energy X-ray absorptiometry scans, and hyperinsulinemic euglycemic clamps using stable isotopes were performed before and after 3, 12, and 24 months of combination antiretroviral therapy. RESULTS: Insulin-stimulated peripheral glucose disposal decreased by 25% after 3 months in patients on zidovudine/lamivudine/lopinavir/ritonavir (ZDV/3TC/LPV/r) (P < 0.001) and this decreased rate persisted thereafter, followed by a transient decrease in insulin-mediated inhibition of lipolysis. In the nevirapine/lopinavir/ritonavir (NVP/LPV/r) group, hepatic insulin sensitivity had improved compared with baseline after 24 months. After the initial 3 months, limb fat decreased in the ZDV/3TC/LPV/r arm up to 24 months [-849 +/- 345 g (P = 0.017)], and visceral adipose tissue increased over 2 years [+36.2 +/- 13.3 cm2 (P = 0.009)]. In the NVP/LPV/r group, a generalized increase in fat mass was observed. CONCLUSIONS: Treatment with ZDV/3TC/LPV/r versus NVP/LPV/r differentially affects glucose and lipid metabolism. The ZDV/3TC/LPV/r regimen induced peripheral insulin resistance, a transient increase in basal lipolysis and a transient decrease in insulin-mediated inhibition of lipolysis, whereas hepatic insulin sensitivity improved with the NVP/LPV/r regimen.

Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production.

OBJECTIVE: The purpose of this study was to investigate the mechanism by which the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) increases high-density lipoprotein cholesterol (HDLc) in treatment-experienced human immunodeficiency virus-1 (HIV-1)-infected patients. METHODS AND RESULTS: Twelve HIV-1 infected patients, with stably suppressed HIV-1 viral load using AZT/3TC/abacavir for > or =6 months, added NVP to their current antiretroviral regimen. Patients received a primed bolus infusion of the stable isotope L-[1-(13)C]-valine for 12 hours before, as well as 6 and 24 weeks after, the addition of NVP to study apolipoprotein A-I (apoA-I) kinetics. Absolute production rate (APR) and fractional catabolic rate (FCR) of apoA-I were calculated using SAAM-II modeling. Major HDLc-modulating enzymes were assessed. Plasma apoA-I and HDLc levels increased significantly after 24 weeks of treatment by, respectively, 13+/-4% (P=0.01) and 16+/-6% (P=0.015). Concomitantly, apoA-I production rate at 24 weeks increased by 17+/-7% (P=0.04). ApoA-I catabolism did not change. A modest increase of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity was observed. CONCLUSIONS: NVP increases apoA-I production, which contributes to the HDLc increase after introduction of NVP-containing regimens. In view of the potent antiatherogenic effects of apoA-I, the observed increase may contribute to the favorable cardiovascular profile of NVP.

First line zidovudine/lamivudine/lopinavir/ritonavir leads to greater bone loss compared to nevirapine/lopinavir/ritonavir.

OBJECTIVE: We studied changes in bone mineral density (BMD) and bone turnover after initiation of combination antiretroviral therapy (cART) and the contribution of zidovudine/lamivudine (ZDV/3TC) in particular. DESIGN: Randomized clinical trial comparing lopinavir/ritonavir(LPV/r) + ZDV/3TC with LPV/r + nevirapine (NVP) in 50 cART-naive men. METHODS: Dual energy X-ray absorptiometry (DXA) and quantitative computed tomography scans (QCT) were performed at baseline and 3, 12, and 24 months after cART initiation. Serum 25-hydroxy-vitamin D3, parathyroid hormone (PTH), osteocalcin, and urine deoxypyridinoline (DPD)/creatinine ratio were measured. RESULTS: BMD decreased rapidly in both femoral neck and lumbar spine after cART initiation. BMD loss during 24 months measured by DXA, but not by QCT, was greater in the ZDV/3TC/LPV/r group compared to the NVP/LPV/r group [femoral neck: -6.3% +/- 1.0% (P < 0.0001) compared to -2.3% +/- 0.9% (P = 0.01), between-group P = 0.0006); lumbar spine: -5.1% +/- 0.8% (P < 0.0001) compared to -2.6% +/- 0.7% (P = 0.0006), between-group P = 0.07]. Osteocalcin [+1.60 +/- 0.32 (P < 0.0001) and +1.81 +/- 0.29 (P < 0.0001) nmol/l] and the urine DPD/creatinine ratio [+1.35 +/- 0.44 (P = 0.0029) and +1.19 +/- 0.38 nmol/mmol (P = 0.0024)] increased in both groups over 24 months, with no significant difference between groups. PTH increased to a greater degree in the NVP/LPV/r group [+2.0 +/- 0.31 pmol/l (P < 0.0001)] compared to [+0.81 +/- 0.33 pmol/l (P = 0.021) in the ZDV/3TC/LPV/r group]. CONCLUSION: BMD in both femoral neck and lumbar spine decreased rapidly after initiation of cART, in parallel to an increase in bone turnover. The greater bone loss in the ZDV/3TC/LPV/r group compared to the NVP/LPV/r group suggests that ZDV/3TC contributes to this process. The PTH increase does not explain this greater bone loss.

Zidovudine/lamivudine for HIV-1 infection contributes to limb fat loss.

BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00122226.

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 +/- 0.016 mm (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 = .43]) 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 cART. Trial registration. ClinicalTrials.gov identifier: NCT00122226 .

Zidovudine/lamivudine contributes to insulin resistance within 3 months of starting combination antiretroviral therapy.

BACKGROUND: Patients with antiretroviral therapy (ART)-associated lipodystrophy frequently have disturbances in glucose metabolism associated with insulin resistance. It is not known whether changes in body composition are necessary for the development of these disturbances in ART-naive patients starting treatment with different combination ART regimens. METHODS: Glucose metabolism and body composition were assessed before and after 3 months of ART in a prospective randomized clinical trial of HIV-1-positive ART-naive men taking lopinavir/ritonavir within either a nucleoside reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine/lamivudine; n = 11) or a NRTI-sparing regimen (nevirapine; n = 9). Glucose disposal, glucose production and lipolysis were measured after an overnight fast and during a hyperinsulinaemic-euglycaemic clamp using stable isotopes. Body composition was assessed by computed tomography and dual-energy X-ray absorptiometry. RESULTS: In the NRTI-containing group, body composition did not change significantly in 3 months; insulin-mediated glucose disposal decreased significantly (25%; P < 0.001); and fasting glycerol turnover increased (22%; P < 0.005). Hyperinsulinaemia suppressed glycerol turnover equally before and after treatment. The disturbances in glucose metabolism were not accompanied by changes in adiponectin or other glucoregulatory hormones. In contrast, glucose metabolism did not change in the NRTI-sparing arm. Glucose disposal significantly differed over time between the arms (P < 0.01). CONCLUSIONS: Treatment for 3 months with a NRTI-containing, but not a NRTI-sparing, regimen resulted in a 25% decrease in insulin-mediated glucose disposal and a 22% increase in fasting lipolysis. In the absence of discernable changes in body composition, NRTI may directly affect glucose metabolism, the mechanism by which remains to be elucidated.

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 combined.

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

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.

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 research.

Interindividual variability of once-daily ritonavir boosted saquinavir pharmacokinetics in Thai and UK patients.

OBJECTIVES: Differential exposure to saquinavir/ritonavir may lead to therapy failure. The objective was to identify factors that influence variability of saquinavir/ritonavir plasma concentrations. METHODS: Saquinavir/ritonavir data, dosed as 1600/100 mg once daily, from three separate pharmacokinetic studies, in 45 patients from Thailand and the UK, were pooled. Pharmacokinetic parameters were based on non-compartmental analysis. Univariate analysis was performed with saquinavir as the dependent variable, and ritonavir area under the curve (AUC), gender, body weight, body mass index (BMI) and study site as independent variables. Variables with a P value <0.10 were included in a multivariate linear regression analysis. RESULTS: Higher saquinavir AUCs, maximum concentrations (Cmax) and minimum concentrations (Cmin) were seen in Thai patients than in UK patients. Univariate analysis showed associations between body weight, gender, study site and ritonavir AUC and saquinavir AUC (P < 0.05), whereas BMI (P = 0.13) did not. In the multivariate analysis, ritonavir AUC (P = 0.0001) and study site (P = 0.0021) were significantly related to saquinavir AUC (R2 = 0.50). CONCLUSIONS: The ritonavir AUC and study site appeared to be related to exposure of saquinavir. Study site should be viewed as the total of country- and study-specific differences--such as differences in lifestyle, environment, genetic background and dietary composition--between the analysed studies.

A prospective, randomized trial of structured treatment interruption for patients with chronic HIV type 1 infection.

BACKGROUND: Structured treatment interruption was evaluated in 74 patients who had been pretreated with antiretrovirals, consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) for 1 year followed by 3 years of highly active antiretroviral therapy containing a protease inhibitor. METHODS: Patients with a CD4 cell count of > or =350 cells/microL and a plasma viral load of <50 copies/mL were randomized to 3 therapy arms: (1) continuous therapy, (2) CD4 cell count-guided theory, and (3) week-on/week-off (WOWO) therapy. The efficacy and safety of structured treatment interruption and antiretroviral use were evaluated in human immunodeficiency type 1 (HIV-1)-infected patients. The study end points were percentage of patients who developed AIDS or who died and a CD4 cell count of > or =350 cells/microL. Intergroup differences were analyzed using analysis of variance and Kruskal-Wallis tests. RESULTS: Baseline characteristics at the start of the structured treatment interruption were similar. At week 48, no patient had died, and 1 patient in the WOWO group had an AIDS-defining condition. The proportions of patients with a CD4 cell count of > or =350 cells/microL were 100%, 87%, and 96% in treatment arms 1, 2, and 3, respectively. The percentages of weeks of antiretroviral use were 100%, 41.1%, and 69.8% in arms 1, 2, and 3, respectively. The adverse events were not significantly different among arms (P=.27). Thirty-one percent of patients in the WOWO group experienced virological failure. CONCLUSION: WOWO therapy maintained a CD4 cell count of > or =350 cells/microL in almost all patients but was associated with high virological failures rates (possibly resulting from previous dual-NRTI therapy), indicating that this strategy is less useful. Receipt of CD4 cell count-guided therapy resulted in comparable clinical outcomes to continuous therapy and may save antiretroviral-associated costs, but this needs to be confirmed by a larger trial.

Significant differences between plasma HIV-1 RNA assays in HIV-1 subtype E infected patients treated with antiretroviral therapy.

UNLABELLED: A total of 72 HIV-1 infected Thai patients treated with didanosine (ddI) or stavudine (d4T) plus ddI at the time of interim analysis were analyzed. Sixty patients (83%) carried subtype E documented by HIV-1 V3 serotyping. HIV-1 RNA levels were measured using three commercial viral load assays. At baseline (n = 57), Quantiplex 2.0 and NucliSens 2.0 showed mean log10 HIV-1 RNA of 0.7 log10 or 5 fold lower than Amplicor 1.5 (mean 4.29 versus 5.0 log10, respectively, p < 0.001). At week 20 of treatment (n = 29), HIV-1 RNA levels were detected in 55.2%, 31%, and 33.5% of subjects tested by Amplicor 1.5, Quantiplex 2.0, and NucliSens 2.0, respectively. IN CONCLUSION: plasma HIV-1 RNA analyses showed comparable values with Quantiplex 2.0 and NucliSens 2.0 assays. In contrast, Amplicor 1.5 resulted in approximately 5 folds higher HIV-1 RNA levels and a 25% higher rate of detection of plasma HIV-1 RNA as compared to the other two assays. As the current goal of therapy is to suppress plasma viral load below the detection limit of the assays, the significant differences between the assays may influence antiretroviral efficacy evaluation and management.

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 <50 HIV-1 RNA copies/mL who are receiving twice-daily saquinavir soft-gelatin capsules (SQV-SGC) plus dual nucleoside reverse transcriptase inhibitors (NRTIs) to a regimen containing once-daily SQV-SGC/ritonavir (RTV). DESIGN: Therapy for patients with plasma viral loads of <50 copies/mL after 2 years of treatment with twice-daily SQV-SGC (1400 mg) plus zidovudine/lamivudine or didanosine/stavudine was switched to once-daily SQV-SGC/RTV (1600/100 mg) with continuing NRTI treatment. METHODS: Safety and efficacy (determined by plasma viral load and CD4 cell count) were evaluated (week 24). For 12 patients, steady-state plasma pharmacokinetics of SQV was determined (week 4). RESULTS: Once-daily SQV-SGC/RTV was well tolerated. No patient changed regimens. After 24 weeks, 64 (93%) of 69 patients had plasma viral loads of <50 copies/mL (the remaining 5 patients had plasma viral loads of <300 copies/mL). The median CD4 cell count increased from 534/mL at the start of once-daily SQV-SGCs/RTV to 695/mL after 24 weeks (p <.001). Compared with the preceding 24 weeks of treatment with twice-daily SQV-SGC, the CD4 cell count improved significantly during once-daily SQV-SGC/RTV therapy (p <.001). All patients maintained SQV trough concentrations (C(24h)) 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 (h.mg)/L, 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-infected patients with plasma viral loads of <50 copies/mL.

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 population.