Baseline Genotype as a Predictor of Virological Failure to Emtricitabine or Stavudine in Combination with Didanosine and Efavirenz
Gilead Sciences, Inc., 4611 University Drive, Durham, North Carolina 27707, USA. AIDS Research and Human Retroviruses
(Impact Factor: 2.33).
09/2007; 23(8):988-95. DOI: 10.1089/aid.2006.0310
The presence of drug-associated mutations among ART-naive, HIV-1(+) patients may compromise the response to antiviral therapy. We evaluated the effect of preexisting drug-associated resistance mutations to the response in treatment-naive patients to therapy with emtricitabine (FTC) or stavudine (d4T) in combination with didanosine (ddI) and efavirenz (EFV). Study FTC-301A compared emtricitabine once daily (QD) with stavudine twice daily in combination with didanosine and efavirenz in ART-naive patients. Genotypic analysis was performed on baseline plasma HIV-1 RNA for all available samples and at time of virologic failure (VF). Drug resistance mutations present at baseline were evaluated as predictors of VF using logistic regression. VF rates were compared between subgroups using a two-sided exact test. Baseline drug resistance mutations were observed in 90/546 (16.5%) patients: 56/90 (62.2%) with nonnucleoside analogue (NNRTI) mutations and 42/90 (46.6%) with nucleoside analogue mutations. In a stepwise, multiple regression analysis, the presence of the K103N mutation at initiation of therapy was associated with VF in both arms (p = 0.001), however, there was a higher incidence of VF in the stavudine arm compared to the emtricitabine arm regardless of the presence or absence of mutations at baseline (p = 0.001). In this study, the presence of drug-associated resistance mutations in ART-naive patients was significantly correlated with subsequent development of virologic failure underscoring the utility of testing for resistance in addition to the use of potent and well-tolerated first line regimens in treatment-naive patients.
Available from: ru.ac.za
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ABSTRACT: African Potato (Hypoxis hemerocallidea), (AP) is an African traditional medicine (TM) that is commonly used for various nutritional/medicinal purposes and also by people infected with the human immuno deficiency virus HIV and AIDS patients as an immune booster. The use of AP has also been recommended by the former Minister of Health of South Africa for use by HIV positive people. The main phytochemical component of AP is a norlignan glucoside, hypoxoside, and other relatively minor components have also been reported. A recent in vitro study reported the effects of AP extracts, hypoxoside and rooperol (the metabolite of hypoxoside) on human metabolic enzymes such as the cytochrome P450 (CYP450) group of enzymes and also on the transporter protein, p-glycoprotein (P-gp). This research focussed on investigating the clinical significance of those in vitro effects on the pharmacokinetics of efavirenz (EFV) in humans. EFV was chosen as the substrate drug because it is in first-line regimen of treatment of HIV/AIDS in South Africa, and also has been reported to be a substrate for the specific CYP isozymes, 3A4 and 2B6, in common with APs metabolic involvement with 3A4.
A high performance liquid chromatography method with ultra-violet detection (HPLC-UV) for the quantitative determination of EFV in plasma was developed and successfully validated according to international standards with good reproducibility, accuracy, recovery, linear response and requisite sensitivity. The preparation of the plasma samples for analysis was effected by using a simple and rapid precipitation method, and the mobile phase consisted of readily available solvents. EFV in plasma samples was found to be stable under the relevant storage conditions studied. The oral dose of AP, administered as a freshly prepared traditional decoction, was standardised based on the hypoxoside content, and the quality of all the AP decoctions was analysed immediately prior to administration, using a validated HPLC-UV method.
A single dose, two-phase sequential study was conducted over a period of 31 days in 10 healthy volunteers. The clinical study was approved by the Rhodes University Ethical Standards Committee, and all the participants agreed to the conditions of the study by giving their informed consent. On day 1 of the study, human subjects were administered a 600 mg EFV tablet and blood samples were collected before dosing and at various intervals over a period of 48 hr post dosing. From day 16, a traditionally prepared AP decoction was administered daily at a standardized dose of 15 mg/kg/day per subject until day 30. On day 29, volunteers were administered a single 600 mg dose of EFV as was done on day 1. Plasma samples were harvested immediately after blood sample collection and frozen at -80 ºC until assayed. Geometric mean ratios of relevant pharmacokinetic parameters, Cmax (maximum plasma concentration achieved following dosing) and AUC0-48 (area under the curve of a plot of drug plasma concentrations versus time representing the extent of absorption) of EFV before and after co-administration of 14 successive daily doses of AP were compared and evaluated to determine whether an interaction had occurred. All subjects completed the study and the geometric mean ratios of Cmax and AUC0-48 were 97.30 and 102.82 with corresponding 90% confidence intervals (CIs) of 78.81-120.14% and 89.04-118.80%, respectively. Whereas the acceptance criteria for the ratios of the AUCs fell within the preset 90% CIs indicating no interaction, the Cmax ratios fell outside the limits. Although the protocol was developed in accordance with the United States of America Food & Drug Administration’s Guidance for Drug Interactions, a priori stating that both criteria need to fall within the acceptance limits to indicate no interaction, an argument is presented to waive the Cmax requirement for the declaration of an interaction. As a result, the pharmacokinetic data generated during this study indicated that the effect of AP on the pharmacokinetics of EFV is not clinically significant. Hence, co-administration of AP is unlikely to affect the clinical use of EFV.
In summary the objectives of this project were:
1. To develop and validate a suitable HPLC-UV method for the quantitative determination of EFV in plasma.
2. To perform a mini-validation of the determination of hypoxoside for use as a marker in the quality control and standardisation of AP decoctions.
3. To conduct a clinical interaction study in order to determine whether AP affects the pharmacokinetics of EFV following concurrent administration.
4. To apply the validated HPLC-UV method to determine plasma concentrations of EFV in plasma of human subjects.
5. To use appropriate statistical methods and treatments such as a non-compartmental pharmacokinetic analysis to determine the occurrence of an interaction.
Available from: Susan P Holmes
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ABSTRACT: T215 revertant mutations such as T215C/D/E/S that evolve from the nucleoside reverse transcriptase (RT) inhibitor mutations
T215Y/F have been found in about 3% of human immunodeficiency virus type 1 (HIV-1) isolates from newly diagnosed HIV-1-infected
persons. We used a newly developed sequencing method—ultradeep pyrosequencing (UDPS; 454 Life Sciences)—to determine the frequency
with which T215Y/F or other RT inhibitor resistance mutations could be detected as minority variants in samples from untreated
persons that contain T215 revertants (“revertant” samples) compared with samples from untreated persons that lack such revertants
(“control” samples). Among the 22 revertant and 29 control samples, UDPS detected a mean of 3.8 and 4.8 additional RT amino
acid mutations, respectively. In 6 of 22 (27%) revertant samples and in 4 of 29 control samples (14%; P = 0.4), UDPS detected one or more RT inhibitor resistance mutations. T215Y or T215F was not detected in any of the revertant
or control samples; however, 4 of 22 revertant samples had one or more T215 revertants that were detected by UDPS but not
by direct PCR sequencing. The failure to detect viruses with T215Y/F in the 22 revertant samples in this study may result
from the overwhelming replacement of transmitted T215Y variants by the more fit T215 revertants or from the primary transmission
of a T215 revertant in a subset of persons with T215 revertants.
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ABSTRACT: Combination antiretroviral therapy (ART) has proven to be effective in treating human immunodeficiency virus (HIV) infection. Chronic administration of antiretrovirals presents significant challenges, including the risk of selecting treatment-resistant viral strains that can determine treatment failure and can be transmitted. In many countries, a large proportion of the HIV-infected population goes through the correctional system at least once. Scarce data are available on circulation of resistant HIV strains in correctional facilities. We evaluated the prevalence of antiretroviral resistance among both naïve and treatment-experienced HIV-infected inmates of a correctional institution in Genoa, Italy.
The prevalence of antiretroviral resistance among the HIV-infected inmates observed at our institution who underwent genotypic testing from January 2004 to June 2007 was retrospectively reviewed.
45 genotypes from 43 inmates were available. Most of the naïve patients (14/16; 87.5%) showed a wild-type (WT) genotype, as well as most of the ART-experienced patients who had discontinued ART (10/13; 76.9%). A high proportion of WT genotype (6/16; 37.5%) was also observed among the subjects apparently failing HAART.
The prevalence of mutated strains in treatment-naïve individuals of the studied cohort is comparable to what is reported in nonimprisoned naïve subjects of our region. The high prevalence of WT genotypes in ART-failing patients makes it likely that they were not taking their treatments, probably to gain legal benefits from their worsening health conditions. Thus, resistance testing can also be considered as an additional tool for assessing adherence to ART for forensic/medicolegal evaluation. However, further and larger studies are necessary to validate it.
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