scholarly journals CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

2009 ◽  
Vol 53 (3) ◽  
pp. 863-868 ◽  
Author(s):  
Geetha Ramachandran ◽  
A. K. Hemanth Kumar ◽  
Sikhamani Rajasekaran ◽  
P. Kumar ◽  
K. Ramesh ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
High Performance ◽  
South India ◽  
Blood Levels ◽  
South Indian Population ◽  
South Indian ◽  
Immunodeficiency Virus ◽  
Trough Concentrations ◽  
Hiv 1

ABSTRACT The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 μg/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.

scholarly journals Safety and Efficacy of Starting Antiretroviral Therapy in the First Week of Life

2020 ◽  
Author(s):  
Kenneth Maswabi ◽  
Gbolahan Ajibola ◽  
Kara Bennett ◽  
Edmund V Capparelli ◽  
Patrick Jean-Philippe ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Viral Suppression ◽  
Safety And Efficacy ◽  
Hiv Rna ◽  
Early Infant ◽  
Immunodeficiency Virus ◽  
Trough Concentrations ◽  
Hiv Exposed ◽  
Hiv 1

Abstract Background Early antiretroviral therapy (ART) is recommended for infants with human immunodeficiency virus (HIV) infection. However, few antiretroviral options are available for neonates. Methods The Early Infant Treatment Study in Botswana tested HIV-exposed infants within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6 mg/kg twice daily, zidovudine (ZDV), and lamivudine (3TC) at age &lt; 7 days. NVP trough concentrations were tested at 1 and 2 weeks. NVP was switched to ritonavir-boosted lopinavir (LPV/r) at week 2, 3, 4, or 5 according to delivery gestational age. Results Forty HIV-infected infants started ART at median age 2 days (range, 1–5 days). NVP trough concentrations were highly variable and below therapeutic target (3000 ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only 1 unscheduled treatment modification was required. Within 4 weeks of transition to LPV/r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV/r palatability. At 12 weeks, 22 (55%) of 40 were &lt;40 copies/mL (93% &lt;400 copies/mL); by 24 weeks, 27 of 38 (71%) were &lt; 40 copies/mL (84% &lt; 400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA or other factors. Conclusions NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV/r, but by 12 and 24 weeks most children achieved and maintained viral suppression. Clinical Trials Registration U01AII4235.

scholarly journals Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

2004 ◽  
Vol 48 (11) ◽  
pp. 4328-4331 ◽  
Author(s):  
Robert DiCenzo ◽  
Derick Peterson ◽  
Kim Cruttenden ◽  
Gene Morse ◽  
Garret Riggs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Valproic Acid ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Blood Samples ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Trough Concentrations ◽  
Hiv 1

ABSTRACT Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C 0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

scholarly journals Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients

2003 ◽  
Vol 47 (1) ◽  
pp. 118-123 ◽  
Author(s):  
Cecile Goujard ◽  
Isabelle Vincent ◽  
Jean-Luc Meynard ◽  
Nathalie Choudet ◽  
Diane Bollens ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Hiv 1

ABSTRACT The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C min,ss) was 1.92 μg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 μg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C max,ss) was 7.12 μg/ml, the area under the concentration-time curve from 0 to 10 h (AUC0-10) was 32.06 μg · h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUCss) was 35.74 μg · h/ml. Decreases in the mean values of C min,ss (29%), C max,ss (42%), AUC0-10 (42%), and AUCss (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C min,ss markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C min,ss above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.

scholarly journals Relationship between Human Immunodeficiency Virus Type 1 Gag Multimerization and Membrane Binding

2000 ◽  
Vol 74 (11) ◽  
pp. 5142-5150 ◽  
Author(s):  
Akira Ono ◽  
Dimiter Demirov ◽  
Eric O. Freed
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Human Immunodeficiency Virus Type ◽  
Membrane Binding ◽  
Full Length ◽  
C Terminus ◽  
Immunodeficiency Virus ◽  
Viruslike Particles ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Gag precursor, Pr55Gag, is necessary and sufficient for the assembly and release of viruslike particles. Binding of Gag to membrane and Gag multimerization are both essential steps in virus assembly, yet the domains responsible for these events have not been fully defined. In addition, the relationship between membrane binding and Gag-Gag interaction remains to be elucidated. To investigate these issues, we analyzed, in vivo, the membrane-binding and assembly properties of a series of C-terminally truncated Gag mutants. Pr55Gag was truncated at the C terminus of matrix (MAstop), between the N- and C-terminal domains of capsid (CA146stop), at the C terminus of capsid (p41stop), at the C terminus of p2 (p43stop), and after the N-terminal 35 amino acids of nucleocapsid (NC35stop). The ability of these truncated Gag molecules to assemble and release viruslike particles and their capacity to copackage into particles when coexpressed with full-length Gag were determined. We demonstrate that the amount of truncated Gag incorporated into particles is incrementally increased by extension from CA146 to NC35, suggesting that multiple sites in this region are involved in Gag multimerization. Using membrane flotation centrifugation, we observe that MA shows significantly reduced membrane binding relative to full-length Gag but that CA146 displays steady-state membrane-binding properties comparable to those of Pr55Gag. The finding that the CA146 mutant, which contains only matrix and the N-terminal domain of capsid, exhibits levels of steady-state membrane binding equivalent to those of full-length Gag indicates that strong Gag-Gag interaction domains are not required for the efficient binding of HIV-1 Gag to membrane.

scholarly journals Mechanisms by Which the G333D Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Facilitates Dual Resistance to Zidovudine and Lamivudine

2007 ◽  
Vol 52 (1) ◽  
pp. 157-163 ◽  
Author(s):  
Shannon Zelina ◽  
Chih-Wei Sheen ◽  
Jessica Radzio ◽  
John W. Mellors ◽  
Nicolas Sluis-Cremer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Steady State Kinetic ◽  
Immunodeficiency Virus ◽  
State Kinetic ◽  
Hiv 1

ABSTRACT Recent studies have identified a role for mutations in the connection and RNase H domains of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) resistance to nucleoside analog RT inhibitors (NRTI). To provide insight into the biochemical mechanism(s) involved, we investigated the effect of the G333D mutation in the connection domain of RT on resistance to zidovudine (AZT) and lamivudine (3TC) in enzymes that contain both M184V and thymidine analog mutations (TAMs; M41L, L210W, and T215Y). Our results from steady-state kinetic, pre-steady-state kinetic, and thermodynamic analyses indicate that G333D facilitates dual resistance to AZT and 3TC in two ways. First, in combination with M184V, G333D increased the ability of HIV-1 RT to effectively discriminate between the normal substrate dCTP and 3TC-triphosphate. Second, G333D enhanced the ability of RT containing TAMs and M184V to bind template/primer terminated by AZT-monophosphate (AZT-MP), thereby restoring ATP-mediated excision of AZT-MP under steady-state assay conditions. This study is the first to elucidate a molecular mechanism whereby a mutation in the connection domain of RT can affect NRTI susceptibility at the enzyme level.

scholarly journals Mechanism of Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase by a Stavudine Analogue, 4′-Ethynyl Stavudine Triphosphate

2008 ◽  
Vol 52 (6) ◽  
pp. 2035-2042 ◽  
Author(s):  
Guangwei Yang ◽  
Jimin Wang ◽  
Yao Cheng ◽  
Ginger E. Dutschman ◽  
Hiromichi Tanaka ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Reverse Transcriptase ◽  
Structural Basis ◽  
Mechanism Of Inhibition ◽  
Steady State Kinetic ◽  
Immunodeficiency Virus ◽  
State Kinetic ◽  
Hiv 1

ABSTRACT 2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine (4′-Ed4T), a recently discovered nucleoside reverse transcriptase (RT) inhibitor, exhibits 5- to 10-fold-higher activity against human immunodeficiency virus type 1 (HIV-1) and less cytotoxicity than does its parental compound d4T (stavudine). Using steady-state kinetic approaches, we have previously shown that (i) 4′-ethynyl-d4T triphosphate (4′-Ed4TTP) inhibits HIV-1 RT more efficiently than d4TTP does and (ii) its inhibition efficiency toward the RT M184V mutant is threefold less than that toward wild-type (wt) RT. In this study we used pre-steady-state kinetic approaches in an attempt to understand its mechanism of inhibition. With wt and the M184V mutant RTs, 4′-Ed4TTP has three- to fivefold-lower Kd (dissociation constant) values than d4TTP, while d4TTP has up to eightfold-higher Kd values than dTTP. Inhibition is more effective in DNA replication with RNA template than with DNA template. In general, the M184V mutant exhibits poorer binding for all three nucleoside triphosphates than does wt RT. The structural basis for the lower binding affinity of d4TTP than of dTTP could be the lack of hydrogen bonds from the missing 3′-hydroxyl group in d4TTP to the backbone amide of Y115 and also to the side chain of Q151. The structural basis for the higher binding affinity of 4′-Ed4TTP than of d4TTP could be the additional binding of the 4′-ethynyl group in a preformed hydrophobic pocket by A114, Y115, M184, F160, and part of D185.

scholarly journals Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients.

1997 ◽  
Vol 41 (9) ◽  
pp. 1892-1897 ◽  
Author(s):  
M T Borin ◽  
S R Cox ◽  
B D Herman ◽  
B J Carel ◽  
R D Anderson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Fungal Infections ◽  
Reversed Phase ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Blood Samples ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Delavirdine Mesylate

Fluconazole, an inhibitor of certain human cytochrome P-450 isozymes, is used for the prevention and treatment of a broad range of fungal infections that predominantly affect immunocompromised individuals. This study evaluated the influence of fluconazole on the steady-state pharmacokinetics of delavirdine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, in 13 HIV-1-infected patients with CD4 counts ranging from 186 to 480/mm3. Both the control group (n = 5) and the fluconazole group (n = 8) received 300 mg of delavirdine mesylate every 8 h for 30 days; subjects in the fluconazole group took a 400-mg, once-daily dose of fluconazole on study days 16 to 30. Harvested plasma from serial blood samples collected on days 15, 16, and 30 were assayed for concentrations of delavirdine and its N-desalkyl metabolite by a reversed-phase high-pressure liquid chromatography (HPLC) method. Blood samples obtained on days 16 and 30 were also assayed for fluconazole by HPLC. Delavirdine mesylate alone and in combination with fluconazole was well tolerated. There were no significant differences (P > 0.16) in delavirdine pharmacokinetic parameters between treatment groups on day 15 or day 30. After coadministration of fluconazole and delavirdine mesylate for 2 weeks (day 30), no significant differences (P > 0.058) were observed in any delavirdine pharmacokinetic parameters relative to those after receiving delavirdine mesylate alone (day 15) after in the fluconazole group. Fluconazole pharmacokinetic parameters were similar to those previously reported for healthy volunteers and HIV-positive patients. On the basis of these findings, fluconazole and delavirdine mesylate may be taken concurrently without adjustment of the dose of either drug.

scholarly journals Multiple-Dose Pharmacokinetics and Pharmacodynamics of Abacavir Alone and in Combination with Zidovudine in Human Immunodeficiency Virus-Infected Adults

2000 ◽  
Vol 44 (8) ◽  
pp. 2061-2067 ◽  
Author(s):  
James A. McDowell ◽  
Yu Lou ◽  
William S. Symonds ◽  
Daniel S. Stein
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Multiple Dose ◽  
Total Daily Dose ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Time Curve ◽  
Immunodeficiency Virus ◽  
Multiple Dose Pharmacokinetics ◽  
Hiv 1

ABSTRACT Abacavir (1592U89) is a nucleoside reverse transcriptase inhibitor with potent activity against human immunodeficiency virus type 1 (HIV-1) when used alone or in combination with other antiretroviral agents. The present study was conducted to determine the multiple-dose pharmacokinetics and pharmacodynamics of abacavir in HIV-1-infected subjects following oral administration of daily doses that ranged from 600 to 1,800 mg, with and without zidovudine. Seventy-nine subjects received abacavir monotherapy for 4 weeks (200, 400, or 600 mg every 8 hours [TID] and 300 mg every 12 h [BID]) and thereafter received either zidovudine (200 mg TID or 300 mg BID) or matching placebo with abacavir for 8 additional weeks. Pharmacokinetic parameters were calculated for abacavir after administration of the first dose and at week 4 and for abacavir, zidovudine, and its glucuronide metabolite at week 12. The concentrations of abacavir in cerebrospinal fluid were determined in a subset of subjects. Steady-state plasma abacavir concentrations were achieved by week 4 of monotherapy and persisted to week 12. At steady state, abacavir pharmacokinetic parameters (area under the plasma concentration-time curve for a dosing interval [AUCtau] and peak concentration [C max]) were generally proportional to dose over the range of a 600- to 1,200-mg total daily dose. Coadministration of zidovudine with abacavir produced a small and inconsistent effect on abacavir pharmacokinetic parameters across the different doses. At the clinical abacavir dose (300 mg BID) zidovudine coadministration had no effect on the abacavir AUCtau, which is most closely associated with efficacy. Zidovudine pharmacokinetics appeared to be unaffected by abacavir. Statistically significant but weak relationships were found for the change in the log10 HIV-1 RNA load from the baseline to week 4 versus total daily AUCtau and C tau(P < 0.05). The incidence of nausea was significantly associated with total daily AUCtau andC max. In conclusion, abacavir has predictable pharmacokinetic characteristics following the administration of multiple doses.

scholarly journals Laboratory characteristics of HIV-1 clade C-infected long-term non-progressors at a tertiary human immunodeficiency virus care centre in South India

2008 ◽  
Vol 57 (7) ◽  
pp. 913-915
Author(s):  
Uma Shanmugasundaram ◽  
Kailapuri G. Murugavel ◽  
Esaki Muthu Shankar ◽  
Pachamuthu Balakrishnan ◽  
Suniti Solomon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
South India ◽  
Human Immunodeficiency Virus Care ◽  
Care Centre ◽  
Immunodeficiency Virus ◽  
Clade C ◽  
Hiv 1
Sign in / Sign up

Export Citation Format

Share Document