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Biomolecules Dec 2022Efavirenz (Sustiva) is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus (HIV) type 1 infection or to... (Review)
Review
Efavirenz (Sustiva) is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus (HIV) type 1 infection or to prevent the spread of HIV. In 1998, the FDA authorized efavirenz for the treatment of HIV-1 infection. Patients formerly required three 200 mg efavirenz capsules daily, which was rapidly updated to a 600 mg tablet that only required one tablet per day. However, when given 600 mg once daily, plasma efavirenz concentrations were linked not only to poor HIV suppression but also to toxicity. Clinical data suggested that the standard dose of efavirenz could be reduced without compromising its effectiveness, resulting in a reduction in side effects and making the drug more affordable. Therefore, ENCORE1 was performed to compare the efficiency and safeness of a reduced dose of efavirenz (400 mg) with the standard dose (600 mg) plus two NRTI in antiretroviral-naïve HIV-infected individuals. Nowadays, due to the emergence of integrase strand transfer inhibitors (INSTIs), some consider that it is time to stop using efavirenz as a first-line treatment on a global scale, in the parts of the world where that is possible. Efavirenz has been a primary first-line antiviral drug for more than 15 years. However, at this moment, the best use for efavirenz could be for pre-exposure prophylaxis (PrEP) and repurposing in medicine.
Topics: Humans; Anti-HIV Agents; Reverse Transcriptase Inhibitors; Benzoxazines; HIV Infections
PubMed: 36671473
DOI: 10.3390/biom13010088 -
Clinical Cardiology Dec 2021
Topics: Alkynes; Benzoxazines; Cyclopropanes; HIV Infections; Humans
PubMed: 34694012
DOI: 10.1002/clc.23745 -
Clinical Infectious Diseases : An... Dec 2021Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART).
METHODS
We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm.
RESULTS
There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype.
CONCLUSIONS
CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.
Topics: Female; Humans; Male; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; Oxazines; Piperazines; Pyridones; Weight Gain
PubMed: 32960272
DOI: 10.1093/cid/ciaa1073 -
Clinical Pharmacology and Therapeutics Apr 2021The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women.... (Randomized Controlled Trial)
Randomized Controlled Trial
The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.
Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Arylamine N-Acetyltransferase; Benzoxazines; Body Weight; Cyclopropanes; Cytochrome P-450 CYP2B6; Double-Blind Method; Drug Interactions; Equivalence Trials as Topic; Female; Genotype; HIV Infections; Humans; Isoniazid; Metabolic Clearance Rate; Middle Aged; Pregnancy; Prospective Studies; Reverse Transcriptase Inhibitors; Tuberculosis; Young Adult
PubMed: 32909316
DOI: 10.1002/cpt.2044 -
Asian Pacific Journal of Allergy and... Jun 2022Many drugs used for the treatment of HIV disease can cause drug hypersensitivity reactions. Since 2002, World Health Organization (WHO) has recommended the use of...
BACKGROUND
Many drugs used for the treatment of HIV disease can cause drug hypersensitivity reactions. Since 2002, World Health Organization (WHO) has recommended the use of nevirapine and efavirenz as part of first line antiretroviral therapies for several years. Both of the drugs had equivalent clinical efficacy but differences in toxicity profile.
OBJECTIVE
We aimed to determine the incidence and predictors of nevirapine and efavirenz-associated rash among Indonesian HIV-infected patients.
METHODS
A retrospective cohort study was conducted among Indonesian patients who were using nevirapine or efavirenz between January 2004 to December 2013. All eligible predictors were analyzed using bivariate and multivariate analysis.
RESULTS
2,071 patients received nevirapine and 1,212 received efavirenz as first line therapies. The cumulative incidence of nevirapine-associated rash was 14% (95%CI: 12.5-15.5%) and evafirenz-associated rash was 4.5% (95%CI: 3.4-5.8%). Severe reactions occurred 1% patients receiving NVP and 0.1% patients receiving EFV, but no patients died due to these conditions. Predictors independently related with nevirapine-associated rash were female gender (adjusted RR = 1.622; 95%CI: 1.196-2.199; p = 0.002), baseline absolute CD4 count above 200 cells/mm3 (adjusted RR = 1.387; 95%CI: 1.041-1.847; p = 0.025), and hepatitis C co-infection (adjusted RR = 1.507; 95%CI: 1.138-1.995; p = 0.004). Baseline ALT level > 1.25 times upper normal limit (adjusted RR = 1.508; 95%CI: 0.998-2.278; p = 0.051) had a tendency to be a good predictor. None of the risk factors investigated was associated with developing efavirenz-associated rash.
CONCLUSION
Female, baseline absolute CD4 count above 200 cells/mm3, hepatitis C co-infection and baseline ALT levels more than 1.25 times upper normal limit were predictors for nevirapine-associated rash in HIV patients.
Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Exanthema; Female; HIV Infections; Hepatitis C; Humans; Incidence; Indonesia; Male; Nevirapine; Retrospective Studies
PubMed: 32061245
DOI: 10.12932/AP-080719-0596 -
Drug Metabolism and Disposition: the... Oct 2019Efavirenz (more specifically the enantiomer) is a cornerstone antiretroviral therapy for treatment of HIV infection. The major primary metabolite is -8-hydroxyefavirenz,... (Review)
Review
Efavirenz (more specifically the enantiomer) is a cornerstone antiretroviral therapy for treatment of HIV infection. The major primary metabolite is -8-hydroxyefavirenz, which does not have antiretroviral activity but is neurotoxic. Cytochrome P450 2B6 (CYP2B6) is the major enzyme catalyzing -8-hydroxyefavirenz formation. genetics and drug interactions are major determinants of clinical efavirenz disposition and dose adjustment. In addition, as a prototypic CYP2B6 substrate, efavirenz and analogs can inform on the structure, activity, catalytic mechanisms, and stereoselectivity of CYP2B6. Metabolism of efavirenz by CYP2B6 remains unexplored. This investigation assessed efavirenz metabolism by clinically relevant CYP2B6 genetic variants. This investigation also evaluated efavirenz hydroxylation by wild-type CYP2B6.1 and variants. -Efavirenz 8-hydroxylation by wild-type CYP2B6.1 and variants exhibited positive cooperativity and apparent cooperative substrate inhibition. On the basis of Cl values, relative activities for -efavirenz 8-hydroxylation were in the order CYP2B6.4 > CYP2B6.1 ≈ CYP2B6.5 ≈ CYP2B6.17 > CYP2B6.6 ≈ CYP2B6.7 ≈ CYP2B6.9 ≈ CYP2B6.19 ≈ CYP2B6.26; CYP2B6.16 and CYP2B6.18 showed minimal activity. Rates of -efavirenz metabolism were approximately 1/10 those of -efavirenz for wild-type CYP2B6.1 and variants. On the basis of Cl values, there was 14-fold enantioselectivity ( > -efavirenz) for wild-type CYP2B6.1, and 5- to 22-fold differences for other variants. These results show that both CYP2B6 516G > T ( and ) and 983T > C ( and ) polymorphisms cause canonical diminishment or loss-of-function variants for -efavirenz 8-hydroxylation, provide a mechanistic basis for known clinical pharmacogenetic differences in efavirenz disposition, and may predict additional clinically important variant alleles. Efavirenz is the most stereoselective CYP2B6 drug substrate yet identified and may be a useful probe for the CYP2B6 active site and catalytic mechanisms. SIGNIFICANCE STATEMENT: Clinical disposition of the antiretroviral -efavirenz is affected by CYP2B6 polymorphisms. Expressed CYP2B6 with 516G>T (CYP2B6*6 and CYP2B6*9), and 983T>C (CYP2B6*16 and CYP2B6*18) polymorphisms had a diminishment or loss of function for efavirenz 8-hydroxylation. This provides a mechanistic basis for efavirenz clinical pharmacogenetics and may predict additional clinically important variant alleles. Efavirenz metabolism showed both cooperativity and cooperative substrate inhibition. With greater than 10-fold enantioselectivity (- vs. - metabolism), efavirenz is the most stereoselective CYP2B6 drug substrate yet identified. These findings may provide mechanistic insights.
Topics: Alkynes; Animals; Benzoxazines; Cell Line; Cyclopropanes; Cytochrome P-450 CYP2B6; HIV Infections; Humans; Insecta; Polymorphism, Single Nucleotide; Recombinant Proteins; Reverse Transcriptase Inhibitors; Stereoisomerism
PubMed: 31324697
DOI: 10.1124/dmd.119.086348 -
European Review For Medical and... Oct 2020Antiretroviral drugs are the mainstay of treatment for human immunodeficiency virus (HIV) infection. Lifelong highly active antiretroviral therapy (HAART) is indicated... (Review)
Review
OBJECTIVE
Antiretroviral drugs are the mainstay of treatment for human immunodeficiency virus (HIV) infection. Lifelong highly active antiretroviral therapy (HAART) is indicated to prevent disease progression to acquired immunodeficiency syndrome (AIDS). Efavirenz was a first-line component of HAART across the world for many years. The purpose of this article is to review the psychotropic properties of efavirenz, which are the most important adverse events associated with the drug and commonly result in treatment discontinuation.
MATERIALS AND METHODS
A PubMed search was conducted using efavirenz as a search term, which returned 4655 results. Titles and abstracts of articles were screened for relevance, and all relevant articles published in English were included in the narrative review.
RESULTS
Acute exposure to efavirenz may cause profound perceptual disturbances (delusions and hallucinations) whereas chronic exposure may be associated with abnormal dreams and other sleep disturbances, anxiety, depressed mood and suicidality. It may also be abused as a hallucinogen, especially in individuals with a history of poly-substance abuse. Recent research indicates that efavirenz directly affects monoaminergic neurotransmission and may partially substitute for psychedelic drugs, such as lysergic acid diethylamide (LSD). Efavirenz acts as a serotonin 5-HT2A receptor antagonist, a serotonin-dopamine reuptake inhibitor, an inhibitor of monoamine oxidase (MAO) and a vesicular monoamine transporter 2 (VMAT2) inhibitor, which are mechanisms common with many psychotropic drugs. Efavirenz interacts with many of the same molecular targets as the empathogen methylendioxymethamphetamine (MDMA), but the effects of the 2 drugs may differ.
CONCLUSIONS
The exact mechanism of action of efavirenz as a psychotropic drug remains unclear and future studies should focus on evaluating whether prolonged exposure could lead to irreversible side effects.
Topics: Alkynes; Benzoxazines; Cyclopropanes; Humans; Psychotic Disorders; Psychotropic Drugs
PubMed: 33155233
DOI: 10.26355/eurrev_202010_23433 -
The Journal of Antimicrobial... Mar 2019There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz.
BACKGROUND
There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz.
OBJECTIVES
We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance.
METHODS
We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold.
RESULTS
We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (β = 0.38, P = 2.7 × 10-03), plasma 7-hydroxy-efavirenz (β = 0.59, P = 3.7 × 10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (β = -0.31, P = 1.8 × 10-04) and CSF efavirenz (β = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (β = -0.55, P = 3.5 × 10-05), ABCB1 rs115780656 (β = -0.65, P = 4.1 × 10-05) and CYP2A6 -48A→C (β = -0.59, P = 0.01). CYP2A6 -48A→C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (β = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance.
CONCLUSIONS
We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.
Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Blood-Brain Barrier; Central Nervous System; Cognition; Cyclopropanes; Female; HIV Infections; Humans; Male; Middle Aged; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; Viral Load; Young Adult
PubMed: 30535366
DOI: 10.1093/jac/dky481 -
Malawi Medical Journal : the Journal of... Mar 2018Little is published about mental disorders in Malawi, specifically in relation to Human Immunodeficiency Virus (HIV) and it's treatment. Efavirenz is a medication... (Review)
Review
INTRODUCTION
Little is published about mental disorders in Malawi, specifically in relation to Human Immunodeficiency Virus (HIV) and it's treatment. Efavirenz is a medication commonly used as part of triple therapy for HIV treatment. Indeed, in 2013, Malawi introduced 5A with Efavirenz as part of it's 1st line treatment for HIV. There exists some literature documenting known psychiatric side effects of Efavirenz, which include anxiety, mood changes, nightmares, psychosis and suicidal ideation. Little is known about what features are most common in the presentation and what factors in the patient and drug which may make this reaction more likely.
AIM
The aim of this commentary is to review the association between HIV and psychiatric disorder, and consider the neuropsychiatric side-effects of Efavirenz.
METHOD
An evaluative literature review was completed by means of multiple electronic database search as well as an additional manual search to obtain published works identified through the electronic search. Search terms used were: Efavirenz, Acquired Immunodeficiency Syndrome, Africa, Antiretroviral Therapy, Developing Countries, Malawi, Mental Disorders, Public Health, and Psychiatry.
CONCLUSION
This is an important area of study, as potentially large numbers of individuals with HIV are being placed on Efavirenz as first line treatment, yet 60% may experience some form of neuropsychiatric side effects.
Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Female; HIV Infections; Humans; Male; Mental Disorders
PubMed: 29868159
DOI: 10.4314/mmj.v30i1.9 -
The Journal of Antimicrobial... Nov 2009Efavirenz, a non-nucleoside reverse transcriptase inhibitor, has been an important component of the treatment of HIV infection for 10 years and has contributed... (Review)
Review
Efavirenz, a non-nucleoside reverse transcriptase inhibitor, has been an important component of the treatment of HIV infection for 10 years and has contributed significantly to the evolution of highly active antiretroviral therapy (HAART). The efficacy of efavirenz has been established in numerous randomized trials and observational studies in HAART-naive patients, including those with advanced infection. In the ACTG A5142 study, efavirenz showed greater virological efficacy than the boosted protease inhibitor (PI), lopinavir. Efavirenz is more effective as a third agent than unboosted PIs or the nucleoside analogue abacavir. Some, but not all, studies have suggested that efavirenz (added to two nucleoside reverse transcriptase inhibitors) is more effective than nevirapine. Virological and immunological responses achieved with efavirenz-based HAART have been maintained for 7 years. Dosing convenience predicts adherence, and studies have demonstrated that patients can be switched from PI-based therapy to simplified, once-daily efavirenz-based regimens without losing virological control. The one-pill, once-daily formulation of efavirenz plus tenofovir and emtricitabine offers a particular advantage in this regard. Efavirenz also retains a role after failure of a first PI-based regimen. Efavirenz is generally well tolerated: rash and neuropsychiatric disturbances are the most notable adverse events. Neuropsychiatric disturbances generally develop early in treatment and they tend to resolve with continued administration, but they are persistent and troubling in a minority of patients. Efavirenz has less effect on plasma lipid profiles than some boosted PIs. Lipodystrophy can occur under treatment with efavirenz but it may be reduced if the concurrent use of thymidine analogues is avoided. Efavirenz resistance mutations (especially K103N) can be selected during long-term treatment, underscoring the importance of good adherence. Recent data have confirmed that efavirenz is a cost-effective option for first-line HAART. In light of these features, efavirenz retains a key role in HIV treatment strategies and is the first-line agent recommended in some guidelines.
Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; HIV Infections; Humans; Lipodystrophy; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 19767318
DOI: 10.1093/jac/dkp334