Among patients with human immunodeficiency virus (HIV) infections psychiatric disease poses a particular challenge for caregivers. Neuropsychiatric side effects of efavirenz have been described in up to 40% of patients showing dizziness, insomnia, unusual dreams, mood instability, personality alterations and thought disorders. In immigrants from Africa and South America these side effects may be related to elevated plasma concentrations of efavirenz due to polymorphisms of cytochrome P450 isozymes (especially G516T). Alleles for these polymorphisms are more frequent in African and South American patients. We report a case of a 52-year-old patient from Guinea who was referred to the department of neurology under the diagnosis of HIV-associated neurocognitive disorder (HAND). Since the start of combined antiretroviral therapy (cART) including efavirenz the patient had suffered severe personality alterations, acoustic and visual hallucinations and delusions which led to discrimination and reduced quality of life. Diagnostic procedures including magnetic resonance imaging (MRT) and spinal fluid analysis resulted in normal values and did not explain the disease. After switching to nevirapin instead of efavirenz the psychotic symptoms disappeared within 5 days.
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Using biological cut-offs to define resistance, assigned NRTI and randomized drug regimens, continuous and dichotomous phenotypic susceptibility scores (PSS) were calculated for each virus. Efavirenz hypersusceptibility as a dichotomous value was defined as less than 0.4-fold resistance. Associations between virological failure and continuous and dichotomous PSS were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models.
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Hypersusceptibility to nevirapine and efavirenz was detected using each of the methods described above. R values correlating the other methods with single-cycle assay values were between 0.66 and 0.96. In addition to the high correlations, the different methods gave similar numeric results.
In participants who continued EFV-based regimens, neuropsychological performance improvement from baseline was maintained over 3 years. EFV-based treatment was generally well tolerated, but small increases from baseline in EFV-associated symptoms, bad dreams, and anxiety were detected.
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To quantify exposure to LPV and EFV in children receiving therapy in a routine clinical setting in order to identify risk factors associated with inadequate drug exposure.
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Three recent studies have examined switching people with lipodystrophy from a protease inhibitor to an NNRTI-type drug. Two studies switched patients to Viramune (Nevirapine) and found fat levels in the blood had dropped and the appearance of wasting had improved. In a third study that switched patients from Crixivan to Sustiva, general improvements in tissue loss and belly size were observed, but cholesterol and triglyceride levels became higher than normal. This may make Viramune the drug of choice for people with lipodystrophy and high cholesterol levels. Contact information is provided.
The introduction of highly active antiretroviral therapy (HAART) as standard of care has changed the natural history of HIV infection into a manageable chronic disease requiring long-term antiretroviral (ARV) treatment. However, response to HAART is often limited by the occurrence of toxicity or by the emergence of drug resistance. Antiretroviral treatment is characterized by differing rates of adverse events and responses. Genetic variations between human beings account for a relevant proportion of this variability. A relevant number of associations between human genetic variants and predisposition to adverse events have been described and for some antiretroviral drugs a clear and casual genotype-phenotype correlation has already been established. The strong association between abacavir hypersensitivity reaction and HLA-B*5701 has been demonstrated in both observational and blinded randomized clinical trials in racially diverse populations and represents the best example of the clinical utility of pharmacogenetic screening in HIV medicine. Genotyping for HLA-B*5701 before prescribing an abacavir containing regimen has been introduced into routine clinical practice as the standard of care for all patients. Other well-established associations include CYP2B6 alleles and efavirenz central nervous system side effects, UGT1A1 alleles and atazanavir-associated hyperbilirubinemia and HLA class II allele HLA-DRB*0101 and nevirapine-associated hypersensitivity. Despite genetic associations having been described for peripheral neuropathy, lipodystrophy, hyperlipidaemia, pancreatitis and renal proximal tubulopathy, numerous barriers exist to the successful introduction of widespread genetic testing to the clinic. Future prospects point in the direction of individualization of antiretroviral therapy through insights from host genetics. The present paper is aimed to provide a comprehensive review of the published literature and to summarize the state of research in this area. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.
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50 plasma samples, previously characterized by population sequencing and that had shown ≥1 resistance associated mutation (RAM), were retrospectively tested by the UDS assay, including 18 B and 32 non-B subtypes; viral loads between 114-1,806,407 cp/ml; drug-naive (n=27) and drug-experienced (n=23) individuals.
Persistent low-level viraemia (LLV) during the treatment of antiretroviral therapy (ART) is associated with emergent drug resistance mutation (DRM); however, insight into its driver is limited. The objectives were to study HIV-1 pol sequence evolution in subjects with persistent LLV and evaluate factors associated with sequence changes.
Cytochrome P450 CYP2B6 is a highly polymorphic enzyme that metabolizes numerous drugs, pesticides, and environmental toxins. Sequence analysis of a Rwandese population identified eight functionally uncharacterized nonsynonymous variants c.329G>T (p.G110V), c.341T>C (p.I114T), c.444G>T (p.E148D), c.548T>G (p.V183G), c.637T>C (p.F213L), c.758G>A (p.R253H), c.835G>C (p.A279P), and c.1459C>A (p.R487S), and five novel alleles termed CYP2B6*33 to CYP2B6*37 were assigned. Recombinant expression in COS-1 cells and functional characterization using the antidepressant bupropion and the antiretroviral efavirenz (EFV) as substrates demonstrated complete or almost complete loss-of-function for variants p.G110V, p.I114T, p.V183G, and p.F213L, whereas p.E148D, p.R253H, p.A279P, and p.R487S variants were functional. The data were used to assess the predictive power of eight online available functional prediction programs for amino-acid changes. Although none of the programs correctly predicted the functionality of all variants, substrate docking simulation analyses indicated similar conformational changes by all four deleterious mutations within the enzyme's active site, thus explaining lack of enzymatic function for both substrates. Because low-activity alleles of CYP2B6 are associated with impaired EFV metabolism and adverse drug response, these results are of potential utility for personalized treatment strategies in HIV/AIDS therapy.
Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings.
Nigeria has high rates of mother-to-child HIV transmission. We sought to determine whether new WHO recommendations for long-course antiretroviral therapy (ART) prophylaxis are cost-effective for prevention of mother-to-child transmission (PMTCT) of HIV compared to short-course strategies in Nigeria.
To analyse whether the change of antiretroviral therapy to efavirenz/emtricitabine/tenofovir in a single daily dose (EETu) increases adherence and maintains effectiveness, and establish the cost increase caused by the change.
Buprenorphine metabolism was recently expanded by in vitro identification of a number of hydroxylated metabolites. The identification of two, M1 and M3, in urine suggests that they may be quantitatively significant metabolites. To further understand the in vivo regulation of this mode of metabolism, we evaluated 24-hr urine from subjects (10 per treatment group) on buprenorphine alone or with the antiretroviral agents: efavirenz, delavirdine, nelfinavir, ritonavir, and lopinavir/ritonavir. Quantitative analysis for buprenorphine and traditional metabolites and semi-quantitative analysis of M1 and M3 in urine were performed by liquid chromatography-electrospray ionization-tandem mass spectrometry. The renal clearance of buprenorphine and traditional metabolites were similar for all treatments except for lopinavir/ritonavir, suggesting that urine amounts of M1 and M3 would adequately reflect systemic changes (except lopinavir/ritonavir). Efavirenz decreased M1 and increased M3 consistent with its ability to induce cytochrome P450 (CYP) 3A. Delavirdine increased M1 and decreased M3 consistent with its ability to inhibit CYP3A. Both nelfinavir and ritonavir decreased both M1 and M3, consistent with their ability to inhibit CYP3A and 2C8. These results provide further information on the in vivo response of novel secondary metabolites of buprenorphine to metabolic inhibitors and inducers.
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A total of 197 patients (76% women, median CD4 count 395/mm(3)) started therapy with TDF/FTC, 126 with EFV and 71 with ZDV. During the first six months of ART, 94 patients had digestive AEs (nausea/vomiting) of any grade (EFV 36/126, 29%; ZDV 58/71, 82%, p<0.0001), including 20 sAEs (EFV 3/126, 5%; ZDV 17/71, 24%, p<0.0001). In-patients on TDF/FTC+ZDV with digestive AEs, the median time to the first symptom was two days (IQR: 1-4). Plasma ZDV (Cmax) distributions and pill ZDV dosages were normal. Patients with digestive AEs had higher haemoglobin levels and tended to have higher body mass indices and more frequent past histories of cotrimoxazole (CTX) prophylaxis.
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To clarify the role of novel mutations selected by treatment with efavirenz or nevirapine, and investigate the influence of HIV-1 subtype on nonnucleoside reverse transcriptase inhibitor (nNRTI) resistance pathways.
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The combination of Efavirenz and Indinavir was generally well tolerated and efficient at reducing HIV-1 RNA. Furthermore, the treatment improved the immunological function.
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An adaptation of the HPLC method previously described for the simultaneous assay of amprenavir, ritonavir, indinavir, saquinavir, nelfinavir and efavirenz after solid-phase extraction is proposed here for the separate analysis of the newer PI lopinavir (LPV) and the NNRTI nevirapine (NVP). After viral inactivation by heat (60 degrees C for 60 min), plasma (600 microl), with clozapine added as internal standard, is diluted 1+1 with phosphate buffer pH 7 and subjected to a solid-phase extraction on a C(18) cartridge. Matrix components are eliminated with 2 x 500 microl of a solution of 0.1% H(3)PO(4) neutralised with NaOH to pH 7. LPV and NVP are eluted with 3 x 500 microl MeOH. The resulting eluate is evaporated under nitrogen at room temperature and is reconstituted in 100 microl MeOH 50%. A 40-microl volume is injected onto a Nucleosil 100, 5 microm C(18) AB column. LPV and NVP are analysed separately using a gradient elution program with solvents constituted of MeCN and phosphate buffer adjusted to pH 5.07 and containing 0.02% sodium heptanesulfonate. LPV and NVP are detected by UV at 201 and 282 nm, respectively. The calibration curves are linear up to 10 microg/ml. The mean absolute recovery of LPV and NVP is 91% and 88%, respectively. The method is precise with mean inter-day C.V.s within 2.1-6.6% and 0.9-1.7% for LPV and NVP, and accurate (range of inter-day deviations -1.1 to +2.4%, and -1.9 to +0.8%, for LPV and NVP, respectively). The method has been validated and is currently applied to the monitoring of LPV and NVP in HIV patients, and has been notably applied in a study aimed at assessing the extent of transplacental passage of nevirapine and PIs, notably lopinavir, at the time of delivery in pregnant HIV-infected women.
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Substantial work on the peripheral and central nervous system complications of HIV was presented at the 16th Conference on Retroviruses and Opportunistic Infections. Six studies of more than 4500 volunteers identified that distal sensory polyneuropathy remains common, ranging from 19% to 66%, with variation based on disease stage, type of antiretroviral therapy, age, and height. Eight studies of more than 2500 volunteers identified that neurocognitive disorders are also common, ranging from 25% to 69%, with variation based on stage of disease, antiretroviral use, diabetes mellitus, and coinfection with hepatitis viruses. Therapy-focused studies identified that resistance testing of cerebrospinal fluid (CSF)-derived HIV may improve management of people with HIV-associated neurologic complications, that poorly penetrating antiretroviral therapy is associated with persistent low-level HIV RNA in CSF, and that efavirenz concentrations in CSF are low but in the therapeutic range in most individuals. Neuroimaging reports identified that people living with HIV had abnormal findings on magnetic resonance imaging (gray matter atrophy, abnormal white matter), magnetic resonance spectroscopy (lower neuronal metabolites), and blood-oxygen-level dependent functional magnetic resonance imaging (lower cerebral blood flow). Other important findings on the basic neuroscience of HIV and diagnosis and management of neurologic opportunistic infections are discussed.
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Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy.
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To determine whether differences in short-term virologic failure among commonly used antiretroviral therapy (ART) regimens translate to differences in clinical events in antiretroviral-naïve patients initiating ART.
A cross-sectional, questionnaire-based cohort of HIV patients who received two nucleoside reverse transcriptase inhibitors combined with either EFV (n = 75) or one or more PIs (n = 77) for at least 4 weeks and were tolerating therapy. The extent of neuropsychiatric disturbances was evaluated based on self-reported symptoms using the psychological evaluation test SCL-90-R. Treatment duration was broken down into quartiles of 30-198 days, >198-365 days, >365-637 days, and >637 days.
This work demonstrates that the encapsulation of EFV, which is poorly water soluble, into polymeric micelles of different poly(ethylene oxide)-poly(propylene oxide) block copolymers significantly improves the oral bioavailability of the drug, and reduces the interindividual variability.