Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An immunological comparison of three different third companions (abacavir [ABC], efavirenz [EFV], ritonavir-boosted indinavir [IDVr]) on a backbone of either zidovudine plus didanosine (AZT/ddI) or zidovudine plus lamivudine (AZT/3TC) was performed in 76 HIV-infected, advanced-naive patients. Baseline median CD4 count and viremia were 217/microL and 238,301 copies/mL, respectively. Immunologic parameters were measured at baseline and after months of therapy. By the end of the study, 36 patients (mostly in the protease inhibitor [PI]-containing arms) had dropped out of the study; 22/36 cases of drop out were due to tolerability issues. All regimens resulted in increases in CD4 counts, with the most solid changes seen in patients using ABC as a third companion. Median HIV plasma viremia at month 12 was <50 copies/mL, and viremia was undetectable in 26/38 patients (68%). At the end of the study period, HIV antigen- and mitogen-stimulated proliferation overall was better in patients using either of the PI-boosted third companions. In these patients, the strongest down-modulation of activation marker-bearing cells was also observed. Finally, CD8+/28-/CD45RA+ lymphocytes (effector cells) were increased in all groups of patients with the exception of individuals receiving PI-boosted therapies. Results of this pilot study, although very preliminary, suggest that different combinations of antivirals result in a range of effects on immune cell functions. The clinical implications of these results need to be further analyzed in follow-up studies and in larger cohorts of patients.
HIV Clin Trials
PMID:An immunological comparison of third companion in advanced drug-naive HIV-infected patients. 1716 15

HIV-1C has become the dominant HIV-1 subtype in the global AIDS epidemic. Historically, the evolution of drug-resistant mutations was characterized primarily among antiretroviral (ARV)-treated HIV-1B infections. Whereas the non-B viruses are susceptible to the currently used ARVs, some differences between HIV-1 subtypes in response to ARV regimens have been reported. We analyzed the profile of ARV-associated mutations in HIV-1C infection treated with ZDV/ddI-containing regimens in an open-label, randomized 3 x 2 x 2 factorial study comparing ZDV/3TC vs. ZDV/ddI vs. d4T/3TC and EFV vs. NVP regimens in drug-naive adults in Botswana. The overall rate of virologic failure in the ZDV/ddI-containing arms was 14%. We addressed the development of NRTI-associated mutations in 23 virologically failed patients in the ZDV/ddI-containing arms. The 67N 70R 215Y genotype with wild-type amino acids at codon positions 41 and 210 was a dominant pattern of NRTI-associated mutations at the time of virologic failure. The mutation T215Y was the first step in the evolution of the 67N 70R 215Y genotype and was followed by mutations K70R and D67N. Representing a mixture of TAM-1 (41L/210W/215Y) and TAM-2 (67N/70R/215F /219Q) pathways, the 67N 70R 215Y genotype with wild-type amino acids at codon positions 41, 210, and 219 is a unique TAM pathway that is rarely seen in HIV-1B infection. Although limited by relatively small numbers, our data suggest that the 67N 70R 215Y genotype may be the HIV-1C-specific response to the first-line ZDV/ddI-containing regimen at the time of virologic failure. The presence of the 67N 70R 215Y genotype with wild-type amino acids at codon positions 41, 210, and 219 in HIV-1C infection suggests that the evolution of ARV-associated mutations and TAM pathways might be unique in non-B HIV-1 subtypes treated with particular ARV regimens.
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PMID:The reverse transcriptase 67N 70R 215Y genotype is the predominant TAM pathway associated with virologic failure among HIV type 1C-infected adults treated with ZDV/ddI-containing HAART in southern Africa. 1767 69

Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage. The syndrome was reproduced in only 1 male mouse after continuous dietary dosing, and TMC125 was demonstrated to affect coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [APTT], clotting factors II, VII and XI), particularly in males. This was counteracted by vitamin K supplementation, supporting the hypothesis that the effects were mediated via a vitamin K deficiency. It is therefore concluded that the observed cardiac changes were not caused by a direct cardiotoxic effect but occurred after a state of disabled clotting ability with subsequent effects on mouse cardiac muscle. Therefore, clotting times can be used as adequate safety biomarkers in clinical trials. To date, no changes have been observed at therapeutic doses of TMC125, following human monitoring of PT and APTT. One other NNRTI, Efavirenz (Sustiva), has been reported to cause prolongation of coagulation times in rats and monkeys.
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PMID:Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K. 1877 60

Efavirenz is the lead compound of a series of benzoxazinones originally developed by DuPont Merck. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) under development for the potential treatment of viral infections, including HIV. In June 1998, the company submitted an NDA to the US FDA for the use of efavirenz (as Sustiva) for the treatment of HIV infection [289361]. In July 1998, DuPont purchased Merck's interest in DuPont Merck and the company's name changed to DuPont Pharmaceuticals. The two companies decided to continue to share marketing rights to Sustiva (to be marketed by Merck as Stocrin outside the US, Canada, and certain European countries) [291738]. As of October 1997, triple combination studies of efavirenz were ongoing, or planned, with nelfinavir, indinavir or ritonavir, or other retroviral inhibitors, for the treatment of opportunistic and pediatric viral infections [265945]. Efavirenz is also being evaluated as monotherapy and in combination with zidovudine (Retrovir, AZT) and lamivudine (Epivir, 3TC) (qv). Results of a study in eight HIV-infected patients, reported at the 12th World AIDS Conference in July 1998, showed that efavirenz administration, in dual and triple combinations, achieved HIV-RNA levels in plasma and cerebrospinal fluid (CSF) below the level of detection (fewer than 400 copies/ml) [290881,293994]. In March 1998, Merck signed a letter of intent with Trimeris to conduct a trial of efavirenz in combination with Trimeris's HIV fusion inhibitor, T-20, (qv). The trial will enroll up to 48 HIV-infected individuals at three sites in the US. All enrolled patients will be those who have begun to fail their existing triple combination therapy. Prior exposure to NNRTIs and protease inhibitors, other than indinavir, will be among the exclusion criteria for the study. The first 10 days of the study were planned as a dose-optimization period to assess the safety, pharmacokinetics and antiviral activity of multiple ascending doses of T-20. After completion of this period, subjects will be eligible to participate in an extension period of at least six months, during which T-20 will be administered in combination with efavirenz and two protease inhibitors [281696]. A 137-patient phase III study showed that efavirenz, in combination with zidovudine and lamivudine, caused significant reduction in viral levels and increased CD4 cell levels. The results were presented at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection (Hamburg, Germany, October 1997) [265945]. At the Fourth Conference on Retroviruses and Opportunistic Infections, in January 1997, data were presented from a clinical trial of efavirenz in combination with indinavir, which showed that, in 82% of the patients, viral load was reduced to undetectable levels, as measured by the Amplicor assay [231410]. Further retrospective analysis showed that the viral load was a significant predictor of long-term (over 52 weeks) viral suppression [265945]. A double-blind, phase II pilot study of efavirenz showed significant activity in HIV-RNA suppression and CD4 cell recovery when evaluated for two weeks alone, and even better results when used in combination with indinavir (Crixivan, qv); 80% of patients achieved HIV-RNA below level of quantification and CD4 cell count elevation averaging 140 cells/mm3. The study evaluated 16 patients for 12 weeks and is ongoing [219671,227966]. A total of 21 patients received indinavir (800 mg, eight hourly) for two weeks, followed by combination therapy with efavirenz (200 mg, once daily). Another group of nine patients received indinavir alone for 26 weeks, followed by the addition of stavudine (Zerit) and efavirenz. In combination use, indinavir dosing was 1.0 g every eight hours. At 26 weeks, approximately 40% of the patients receiving indinavir alonehad plasma levels below 400 copies/ml of HIV-RNA. After stavudine and efavirenz were added, and following 16 weeks of the triple combination, 83% of the patients had plasma levels below 400 copies/ml [247754].
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PMID:Efavirenz DuPont Pharmaceuticals Co. 1846 25

Oral lesions (OL) have an important prognostic value for HIV/AIDS patients. However, the behavior of OL in HIV/AIDS patients undergoing highly active antiretroviral therapy including efavirenz (HAART/EFV) has not been documented. Our objective was to establish the prevalence of OL in HIV/AIDS patients undergoing HAART/EFV and to compare it with the prevalence of OL in patients undergoing antiretroviral therapy including a protease inhibitor (HAART/PI). Seventy-three HIV/AIDS patients undergoing antiretroviral treatment for at least for 6 months at "La Raza" Medical Center's Internal Medicine Unit (IMSS, Mexico City) were included. To detect OL, a detailed examination of oral soft tissues was performed in each patient. Patient records recorded gender, seropositivity time, route of contagion, antiretroviral therapy type and duration, CD4 lymphocyte count/ml, and viral load. Two groups were formed: 38 patients receiving HAART/EFV [two nucleoside analogue reverse transcriptase inhibitors (NARTI) plus efavirenz] and 35 patients receiving HAART/PI (two NARTIs plus one PI). OL prevalence was established in each study group. The Chi-square test was applied (p < 0.05(IC95%)). OL prevalence in the HAART/EFV group (32%) was lower (p < 0.007) than in the HAART/PI group (63%). Candidosis was the most prevalent OL in both groups. Herpes labialis, HIV-associated necrotizing periodontitis, xerostomia, hairy leukoplakia, and nonspecific oral sores were identified. The highest prevalence for all OL was found in the HAART/PI group. These findings suggest that HIV/AIDS patients undergoing HAART/EFV show a lower prevalence of oral lesions than patients undergoing HAART/PI.
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PMID:Short communication: oral lesions in HIV/AIDS patients undergoing HAART including efavirenz. 1850 28

A retrospective study was conducted during 32 months; from 1 May 2003 to 30 December 2005 in haematology department. The objective of the study was to assess the effectiveness of the anti retroviral therapy 157 patients receiving antiretroviral treatment for at least a twelve month-period and presenting AIDS symptoms based on revised CDC criteria were included. The average number of initial T4 lymphocytes is 133/mm3 (extremes 1 and 385) and the initial plasmatic average viral load, quantified in 96 patients is 214,000 copies (extreme 30,000 et 999,000) The initial antiretroviral combinations were as follows: ZDV or D4T + LMV + NVP (59.2%); ZDV or D4T + LMV + EFV (28.7%), ZDV or D4T + LMV + IDNV (8.9%); ZDV or D4T + DDI + NVP (3.2%). The results of the study are: observance rate during the first 12 months (84%), antiretroviral therapy taken irregularly (10.8%), early submission of therapy (5.2%), weight gain after 24 months: +18 kgs, clinical response globally positive. The immune response is characterised by an average increase of 353/mm3 of CD4 after 24 months. Among 96 patients tested, the plasmatic viral load was undetectable in 71% of cases after a 12 month-follow up. Mild adverse drug effects have been noticed, represented by cutaneous and nervous toxicity anaemia and digestive disorders due to indinavir These therapeutic results confirm the importance of the antiretroviral therapy in the improvement of the quality of life of HIV/AIDS patients but a concern remains on the possible drug resistance still not documented.
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PMID:[Evaluation of antiretroviral therapy in HIV-infected adults in the Department of Haematology, University Hospital of Brazzavllle, Congo]. 1854 3

The synthesis and the anti-HIV-1 activity of novel benzo[d]isothiazole hydrazones are reported. Target compounds tested in MT-4 cells cultures for their anti-HIV properties against wild type HIV-1 and HIV strains carrying clinically relevant mutations (EFV(R), Y181C and K103/Y181C) showed good activity against wild type HIV-1 and against the EFV(R) mutant. In terms of SAR the relevant result was that, in the class of benzisothiazole hydrazones, the benzo[d]isothiazol-3(2H)-one moiety (compounds 1 and 4) is an essential structural requirement for the antiretroviral activity.
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PMID:Anti-HIV evaluation of benzo[d]isothiazole hydrazones. 1861 59

Improvements in HIV-RNA assays have made accurate detection of as few as 2 copies/ml possible. This study objective was the evaluation of ultrasensitive HIV-RNA quantitation (beneath current threshold: 50 copies/ml) in patients receiving different antiretroviral regimens. A cross-sectional, ultrasensitive measurement of HIV-RNA levels (detection limit: 2.5 HIV-RNA copies/ml) was performed in 154 HIV-1-infected patients receiving ARV therapy, all classed as full responders according to the 50 copies/ml cut-off. Patients were undergoing treatment with two nucleoside/nucleotide reverse transcriptase inhibitors (N/NtRTIs) plus nevirapine (NVP, n = 48), efavirenz (EFV, n = 57) or lopinavir/ritonavir (LPV/r, n = 49). Undetectable HIV-RNA (<2.5 copies/ml) occurred in 29/48 (60.4%), 24/57 (42.1%) and 14/49 (28.6%) NVP, EFV and LPV/r recipients, respectively. Mean virological-suppression (<50 copies/ml) duration was 28.6 months (median = 22, SD = 17.8), and only in LPV/r recipients length of suppression was associated with significantly lower HIV-RNA levels (P = 0.015). Mean nadir CD4+ cell count of 270 cells/mm(3) (median = 240, SD = 194.5) was significantly lower in the LPV/r arm (P < 0.001). Nadir CD4+ level correlated with virological suppression but had opposite trends between NVP (positive) and LPV/r (negative; two tailed P = 0.01). Logistic regression analysis showed NVP was the only independent factor associated with virologic suppression. NVP has demonstrated a distinct virological advantage at sub-clinical viral loads, possibly due to its greater penetration in extra-vascular compartments, warranting further investigation in the context of persistent low-level viraemia in long-term HAART.
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PMID:Ultrasensitive assessment of residual HIV viraemia in HAART-treated patients with persistently undetectable plasma HIV-RNA: a cross-sectional evaluation. 1915 4

New potent indolylarylsulfone (IAS) HIV-1 NNRTIs were obtained by coupling natural and unnatural amino acids to the 2-carboxamide and introducing different electron-withdrawing substituents at position 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/subnanomolar concentration and were weakly cytostatic. Against the mutant L100I, K103N, and Y181C RT HIV-1 strains in CEM cells, sulfones 3, 4, 19, 27, and 31 were comparable to EFV. The new IASs were inhibitors to Coxsackie B4 virus at low micromolar (2-9 microM) concentrations. Superimposition of PLANTS docked conformations of IASs 19 and 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. The binding mode of 19 was not affected by the L100I mutation and was consistent with the interactions reported for the WT strain.
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PMID:Indolylarylsulfones bearing natural and unnatural amino acids. Discovery of potent inhibitors of HIV-1 non-nucleoside wild type and resistant mutant strains reverse transcriptase and coxsackie B4 virus. 1928 Dec 25

Abstract Between November 2006 and June 2007, HIV-1 reverse transcriptase (RT) and protease (PR) genes of 67 ARV-naive Cambodian patients were amplified and sequenced. At inclusion, the median age and duration of HIV infection were 28 and 1.1 years, respectively. The median CD4 and HIV-1 RNA were 611 cells/ml [IQR: 525-759] and 4.0 log(10) copies/ml [IQR: 3.4-4.6]. Among 67 HIV-1 strains, 95.5% were CRF 01_AE viruses (n = 64) whereas three clustered with subtype B. RT analysis indicated that only 1 patient out of 67, presenting K103N and M184V mutations, was resistant to NVP/EFV and 3TC/FTC. No primary resistance to protease inhibitors was detected in 59 amplified protease genes. The 1.49% (IC 95%: 0.04-8.04%) prevalence of transmitted drug-resistant strains in drug-naive patients was low in our study. Surveys of drug-resistant transmitted viruses should be regularly performed regarding the increasing access to HAART in Cambodia.
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PMID:Low prevalence of drug resistance transmitted virus in HIV Type 1-infected ARV-naive patients in Cambodia. 1938 23


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