Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the Treatment of HIV-1 Infection in Adults

Staszewski, Schlomo; Morales-Ramirez, Javier O; Tashima, Karen T.; Rachlis, Anita; Skiest, Daniel J.; Stanford, James; Stryker, Richard; Johnson, Philip C.; Labriola, Dominic; Farina, Dianne; Manion, Douglas J.; Ruíz, Nancy

doi:10.1056/nejm199912163412501

Cited by 927 publications

(587 citation statements)

References 40 publications

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“…1,7,[9][10][11][12][13][14] Gastrointestinal (GI)-related side effects such as nausea, vomiting, and diarrhea have been among the most commonly reported medication toxicities leading to regimen discontinuation in numerous studies. 1,7,12,13,15,16 Other studies have shown that certain patient characteristics such as race, gender, or socioeconomic status may predict higher rates of regimen discontinuation.…”

Section: Introductionmentioning

confidence: 99%

Short-Term Discontinuation of HAART Regimens More Common in Vulnerable Patient Populations

Robison

Westfall

Mugavero

et al. 2008

AIDS Research and Human Retroviruses

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The durability of HAART regimens is often limited by antiretroviral toxicity and nonadherence, which lead to virologic failure. We sought to determine sociodemographic and psychosocial patient factors predictive of shortterm discontinuation of HAART regimens overall and stratified by the reason for discontinuation. A retrospective cohort study of the UAB 1917 Clinic Cohort evaluated short-term HAART regimen discontinuation (within 12 months of regimen initiation) between 1/1995 and 8/2004 classified as (1) gastrointestinal (GI) toxicity, (2) non-GI toxicity, (3) virologic failure or nonadherence (VF/NA), (4) loss to follow-up, and (5) other. Multivariable multinomial logistic regression models accounting for dependent observations were fit to assess the relationship between patient factors and type-specific regimen discontinuation. Among the 738 study participants, 1026 of 1852 HAART regimens (55%) were discontinued within 12 months of initiation. In multivariable analysis, discontinuation for GI toxicity was more common in patients lacking private health insurance and those with a history of intravenous (IV) drug use, whereas non-GI toxicity was more common in younger patients and females. African-American patients and those with a history of IV drug use were more likely to stop a regimen due to VF/NA. Loss to follow-up was more common in younger patients, individuals who were uninsured, and those with a history of IV drug use. Short-term discontinuation of HAART regimens is more common in vulnerable populations that bear a disproportionate burden of the U.S. HIV/AIDS epidemic. More vigilant monitoring of patient populations at higher risk of toxicity and virologic failure may allow for improved HAART regimen durability. 1347

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Section: Introductionmentioning

confidence: 99%

Short-Term Discontinuation of HAART Regimens More Common in Vulnerable Patient Populations

Robison

Westfall

Mugavero

et al. 2008

AIDS Research and Human Retroviruses

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“…7 Furthermore, persistent viral replication (plasma HIV RNA >500 copies/mL) has been reported under HAART in 10-40% of anti-viral therapy-naive individuals as a result of transmission of drug-resistant HIV-1 variants. 8 The management and effective treatment options for HIV/ AIDS clearly depend upon the development of PIs and other novel anti-HIV therapeutics, which can effectively combat drug-resistant HIV strains, possess better pharmacokinetic properties, have no or less toxicities, and come at reduced costs of synthesis.…”

mentioning

confidence: 99%

Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV

Ghosh¹,

Dawson²,

Mitsuya³

2007

Bioorganic & Medicinal Chemistry

197

183

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Our structure-based design strategies which specifically target the HIV-1 protease backbone, resulted in a number of exceedingly potent nonpeptidyl inhibitors. One of these inhibitors, darunavir (TMC114), contains a privileged, structure-based designed high-affinity P2 ligand, 3(R),3a(S),6a (R)-bis-tetrahydrofuranylurethane (bis-THF). Darunavir has recently been approved for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to previously existing HAART regimens. Keywords protease inhibitors; darunavir; design and synthesisThe AIDS (acquired immunodeficiency syndrome) epidemic has become one of the most pressing medical concerns of our time. 1 The World Health Organization (WHO), as of 2006, estimated that over 40 million people are infected with HIV (human immunodeficiency virus), the causative agent of AIDS. 2 During replication in the HIV life-cycle, gag and gag-pol gene products are produced as precursor polyproteins which are subsequently processed by a virally encoded protease to provide structural proteins (p17, p24, p9 and p7) and essential viral enzymes, including protease (PR), reverse transcriptase (RT) and integrase (IN). 3 All three retroviral enzymes have been identified as potential drug targets. Specifically, the critical function of HIV protease has made it an important target for the treatment of HIV/AIDS. The approval of the first protease inhibitor (PI), saquinavir and its introduction into highly active antiretroviral therapy (HAART), with reverse transcriptase inhibitors, led to significantly enhanced HIV management and improved the quality of life of HIV/AIDS patients. 4Since the advent of the first PI, saquinavir, a number of PIs have been introduced in the regimens of highly active antiretroviral therapy or HAART. Thus improved HAART regimens have shown reduced viral load, increased CD4+ T-cell counts 5 and drastically lowered AIDSrelated deaths in the US and industrialized nations. 6 While HAART proved to be a large step forward, there are still serious drawbacks with the first generation anti-protease therapeutics. * Corresponding author. Tel.: 765-494-5323; fax: 765-496-1612; e-mail: akghosh@purdue.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. These include: (1) severe side effects and drug toxicities, (2) higher therapeutic doses due to "peptide-like" character, (3) costly synthesis which leads to high treatment cost, and perhaps the most alarming, (4) the rapid emergence of drug resistance. Indeed, the emergence of multidrug-resistant HIV strains has greatly compromised current...

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“…2,3,5,[10][11][12] More recently, based on studies showing greater effectiveness and tolerability, HIV-infected patients are increasingly prescribed antiretroviral regimens, which include HIV-1-specific non-nucleoside analog reverse transcriptase inhibitors (NNRTIs), such as nevirapine (NVP) and efavirenz (EFV), instead of PIs. [13][14][15][16][17] In addition, the emergence of HIV-1 drug resistance among antiretroviral-experienced patients has led to the more frequent use of HAART, which includes both PIs and NNRTIs. 17 However, nevirapine use has been associated with significant hepatic injury, severe cutaneous hypersensitivity reactions (with or without hepatitis) and, rarely, death.…”

mentioning

confidence: 99%

“…Accordingly, the United States Food and Drug Administration has issued warnings regarding the risk of NVP-related hepatotoxicity. 5,15,[18][19][20][21][22][23][24][25][26][27][28] Conversely, although reported, little published information is available regarding the risk of hepatotoxicity among patients receiving efavirenz. [29][30][31] Furthermore, most data regarding NNRTI-associated hepatotoxicity are derived from anecdotal reports, which may focus attention on exceptional cases or high-risk populations, or from clinical trials, which are frequently restricted to persons at low risk for adverse events.…”

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confidence: 99%

Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: Role of hepatitis C and B infections

et al. 2002

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Hepatologists are frequently asked to evaluate human immunodeficiency virus (HIV)-infected patients with abnormal liver enzymes and to assess the causal role of medications, such as antiretroviral drugs. Recently, the use of HIV-1 specific non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine (NVP) and efavirenz (EFV), has been associated with severe hepatic injury. We prospectively studied the incidence of severe hepatotoxicity (grade 3 or 4 change in alanine or aspartate transaminase levels) among 568 patients receiving NNRTI-containing antiretroviral therapy, including 312 and 256 patients prescribed EFV and NVP, respectively. Hepatitis C virus (HCV) and hepatitis B virus (HBV) were detected in 43% and 7.7% of patients, respectively. Severe hepatotoxicity was observed in 15.6% of patients prescribed NVP and 8.0% of those prescribed EFV, but only 32% of NVP and 50% of EFV-associated episodes were detected during the first 12-weeks of therapy. The risk was significantly greater among persons with chronic viral hepatitis (69% of cases) and those prescribed concurrent protease inhibitors (PIs) (82% of cases). Nonetheless, 84% of patients with chronic HCV or HBV did not experience severe hepatotoxicity. Severe hepatotoxicity occurs throughout the course of NNRTI therapy and is more common among patients prescribed nevirapine, those coinfected with HCV or HBV, and those coadministered protease inhibitors. (HEPATOLOGY 2002;35:182-189.)

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Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the Treatment of HIV-1 Infection in Adults

Abstract: As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.

Cited by 927 publications

References 40 publications

Short-Term Discontinuation of HAART Regimens More Common in Vulnerable Patient Populations

Short-Term Discontinuation of HAART Regimens More Common in Vulnerable Patient Populations

Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV

Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: Role of hepatitis C and B infections

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