We have shown that CYP2B6 c.516G>T and c.983T>C SNPs are the most important predictors of EFV plasma concentration after taking into account all other SNPs, including genetic variation in the 3'-UTR, and variables affecting EFV metabolism.
The 573 HIV-tuberculosis co-infected patients who initiated antiretroviral therapy had a median CD4 count of 92 cells/mm(3) and HIV-1 RNA of 5.6 log10 copies/mL. Mortality at week 48 was 6.1% (35/573). Fifty-three (9.2%) patients presented a tuberculosis-IRIS within 12 weeks of starting antiretroviral therapy. Being female and having a low CD4 count, high HIV-1 RNA load, low body mass index and smear-positive pulmonary tuberculosis were independently associated with tuberculosis-IRIS. After adjustment for baseline body mass index, CD4 count and hemoglobin, occurrence of tuberculosis-IRIS was independently associated with 48-week mortality (aOR 2.72 95%CI 1.14-6.54). Immunological and HIV-1 virological responses and tuberculosis treatment outcomes were not different between patients with and without tuberculosis-IRIS.
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Antiretroviral therapy received mixed reviews in 1998. The approvals of efavirenz (Sustiva) and abacavir (Ziagen) have increased drug options. The use of genotypic and phenotypic resistance assays has helped clinicians make better treatment decisions. However, long-term side effects of HAART (e.g., high cholesterol, diabetes, and lipodystrophy) have emerged in patients who have responded to HAART regimens. Finally, it is becoming increasingly obvious that HIV must be managed by HIV-experienced clinicians, as studies show that their patients are healthier, live longer, and are less costly to care for than those managed by generalists.
Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products.
Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.
In total 1539 patients were included in the analysis. Most were clinically and immunologically stable (clinical failure: 2.7% (AZT) and 2.8% (TDF); immunological failure: 4.6% (AZT) and 4.8% (TDF)). In EFV-based regimens (n = 1162), TDF was significantly associated with higher rates of virologic suppression than AZT (93.8% vs. 88.1%; weighted odds ratio: 2.15 (95% CI: 1.29-3.58; P = 0.003)). In NVP-based regimens, a similar trend was observed, but not significant (89.4% vs. 86.7%; 1.99 (0.83-4.75, P = 0.121)).
The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers.
The burden of human immunodeficiency virus (HIV) is mainly concentrated to resources-limited countries where the response to available antiretroviral therapy is often limited by the occurrence of toxicity or by the emergence of HIV drug resistance. Efavirenz and nevirapine are the antiretroviral drugs most prescribed in resources-limited countries as part of antiretroviral combination therapy. Their metabolism and conjugation are largely influenced by enzymatic genetic polymorphisms. The genetic variability of their metabolism could be associated to different metabolic phenotypes causing reduced patients' adherence because of toxicity or drug-drug interactions with concomitant therapies. The purpose of this review is to summarize published evidence on pharmacogenetic and pharmacokinetic aspects related to efavirenz and nevirapine, the influence of concomitant anti-tubercular, anti-malarial or contraceptive treatments, and the impact of human genetic variation and drug-drug interaction on the virologic and immunologic response to antiretroviral therapy in resources-limited countries.
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Since the mid-1990s, highly active antiretroviral therapy (HAART) has modified the clinical course of human immunodeficiency virus (HIV) infection, reducing the rate of disease progression, the incidence of opportunistic infections, and mortality. The authors of this paper performed an economic analysis to estimate the cost-effectiveness of the HAART regimens in Italy for managing HIV-infected patients according to national guidelines.
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A cohort consisting of 54 HIV-seropositive MSM were recruited with written informed consent. Samples of plasma and whole blood were collected to characterize prevalent HIV-1 subtypes with overlapped polymerase chain reaction followed by sequencing and phylogenic analysis. The genotypes of anti-HIV drug resistance were analysed.
Three classes of antiretroviral agents are usually available for the treatment of HIV infection: nucleoside reverse transcriptase inhibitors (IN), non-nucleoside reverse transcriptase inhibitors (INN) and protease inhibitors (IP). Two methods by reversed-phase liquid chromatography were developed for the analysis of 19 antiretroviral molecules belonging to these three therapeutic classes and used in medicinal products. Both of these HPLC techniques use a C18 column and UV detection. The first method is for IN family analysis and allows eight molecules to be separated: zalcitabine, lamivudine, amdoxovir, emtricitabine, didanosine, stavudine, zidovudine and abacavir. The second method is for INN and IP family analysis and allows 11 molecules to be separated: fosamprenavir, nevirapine, indinavir, amprenavir, saquinavir, atazanavir, ritonavir, lopinavir, efavirenz, nelfinavir and tipranavir. The combination of these two methods makes possible the quality control of mono-, bi- or tri-therapy pharmaceutical products and the detection of illegal products sold particularly in developing countries.
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Blood samples were obtained from 130 HIV-infected patients receiving efavirenz in combination with other antiretroviral agents for more than 3 months. Efavirenz plasma concentrations were measured by high-performance liquid chromatography. An evaluation of CNS side-effects was performed and the viral load, CD4 cell count and other clinical and laboratory data were assessed. In 85 patients, these measures were repeated at 3 month intervals.
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In sub-Saharan Africa, most HIV-infected patients receive antiretroviral therapy (ART) without virological monitoring. Longitudinal data on secondary resistance are rare.
Tuberculosis (TB) remains an important problem in patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). Concomitant administration therapy of both TB and HIV is fraught with difficulties. Despite the fact that the use of highly active antiretroviral therapy (HAART) led to significant improve quality of life and decrease morbidity including mortality-associated to HIV/AIDS, adverse drug effects lead to interruptions in both HIV and TB therapy. In addition, an important problem when HAART is initiated in patients with TB is the possibility of developing immune reconstitution inflammatory syndrome (IRIS). A six-month regimen consisting of isoniazid, rifampicin, pyrazinamide, and ethambutal for two months followed by isoniazid and rifampicin for four months is a standard regimen for the treatment of known or presumed drug-susceptible TB disease. The following strategy may minimize the risk of IRIS. Patients with CD4 cell counts < 100 cells/mm3, efavirenz-based HAART regimen is recommended and should be initiated as soon as the patients can tolerate TB treatment. Patients with CD4 cell counts 100-350 cells/mm3, HAART should be started at two months after TB treatment initiation. HAART should be deferred with closed follow-up of CD4 cell counts if patients have CD4 cell counts > 350 cells/mm3.
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We prospectively studied 35 HIV-infected participants (18 on d4T+3TC+EFV (stavudine+lamivudine+efavirenz), eight on AZT+3TC+EFV (zidovudine+lamivudine+efavirenz), and nine who were antiretroviral therapy-naïve) and 20 HIV-negative controls. Antioxidant profile (total antioxidant status, glutathione reductase, glutathione peroxidase, uric acid, ceruloplasmin, zinc, and albumin), CD4 cell count, plasma viral load, dietary intake, and history of smoking and alcohol use were determined at baseline and at twelve months.
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Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously.
Since their discovery, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become one of the cornerstones of highly active anti-retroviral therapy (HAART). Currently, three NNRTI agents, efavirenz, nevirapine and delavirdine are commercially available. Efavirenz and nevirapine, used in combination with nucleoside reverse transcriptase inhibitors (NRTIs), provide durable regimens with efficacy comparable to protease inhibitor (PI) containing therapies. When virological failure occurs following treatment with an NNRTI, the resistance mutations can confer reduced sensitivity to the entire agent class. Therefore, the strategy for the development of next generation NNRTIs has been to focus on compounds which have improved potencies against the clinically relevant viral mutants. Agents with improved virological profiles and which maintain the ease of administration and favorable safety profiles of the current agents should find use in anti-retroviral naïve patients as well as in components of salvage regimens in the anti-retroviral experienced patient. This review summarizes the recent developments with compounds in clinical trials as of January 2002 as well as to summarize information on new agents appearing in the primary and patent literature between January 2001 and December 2002.
Data from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, P = 0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, P = 0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification.
A case-cohort study was used to determine the effect of baseline nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance, as assessed by viral genotyping, on the response to efavirenz-containing regimens in AIDS Clinical Trials Group A5095. The sample included a random cohort of efavirenz-treated subjects plus unselected subjects who experienced virologic failure. Of 220 subjects in the random cohort, 57 (26%) had virologic failure. The prevalence of baseline NNRTI resistance was 5%. The risk of virologic failure for subjects with baseline NNRTI resistance was higher than that for subjects without such resistance (hazard ratio 2.27 [95% confidence interval], 1.15-4.49; P = .018). These results support resistance testing before starting antiretroviral therapy.
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Little is known about how different antiretrovirals effect inflammation and monocyte activation in human immunodeficiency virus (HIV) infection.