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Histamine and the nasal vasculature: the influence of H1 and H2-histamine receptor antagonism.

2017-05-01

Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese.

HIV-1 viral load (VL) monitoring is recommended but seldom performed in resource-constrained countries. An evaluation of patients receiving first-line antiretroviral therapy in a multicountry PEPFAR program (RV288) was performed to determine the rates and predictors of virologic suppression. Resistance data from treatment failures are available from Uganda and Nigeria. Each country enrolled 325 subjects into this cross-sectional study. Subjects on first-line therapy were randomly selected for HIV RNA testing (viral load). Regimens included efavirenz or nevirapine with zidovudine/lamivudine or tenofovir/lamivudine. VL was determined from plasma using the Roche COBAS TaqMan HIV-1 Test, High Pure System v1.0 (47 copies/ml). Genotypic resistance testing was performed on samples with VL>1,000 copies/ml. From Uganda, 85% of subjects were undetectable while 7% (23/325) had VL>1,000 copies/ml. The HIV-1 subtype distribution was as follows: A=47.6%, C=14.3%, and D=38.1%. No resistance mutations were found in 14% of subjects. All subjects with resistance had the M184V mutation. Of subjects failing a zidovudine regimen less than 1 year, 88% (7/8) had no thymidine analogue mutations (TAMs), compared to 50% (4/8) failing greater than 1 year. Four subjects (25%) had more than two mutations from the TAM-1 pathway (41L, 210W, 215Y). In Nigeria, 82% were undetectable while 14% (45/325) had VL>1,000 copies/ml. HIV-1 subtype distribution was as follows: 62.8%=CRF02_AG, 34%=pure G, and 2.8%=A. Of the 35 genotyped subjects, 14% (5/35) had no resistance mutations. Of the remainder, 10% (3/30) had no nucleoside analogue mutations while 33% (10/30) had only M184V along with nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. Forty percent (10/25) of subjects on zidovudine failed without TAMs. Another 25% (5/25) of subjects failing on zidovudine had more than two TAM-1 mutations. Individuals failing first-line antiretroviral therapy (ART) may retain sensitivity to one or more nucleoside analogues from the regimen. Knowledge of drug resistance patterns allow for selection of drugs that can be recycled in future regimens. Accumulation of resistance mutations may compromise future treatment options.

To report a case of hypersensitivity manifesting in a rash, fever, and life-threatening hepatitis in a patient initiated on efavirenz therapy.

There were no significant differences in the changes in endothelial function over 1 month between the efavirenz and rilpivirine groups, although efavirenz had worse lipid changes compared with rilpivirine. Longer-term studies are required for confirmation.

Patients with plasma viral RNA >50,000 copies/mL, despite a protease-inhibitor regimen, received abacavir, amprenavir, and efavirenz to assess efavirenz-amprenavir drug interactions and to evaluate safety and antiviral response. Patients first received amprenavir with abacavir and other nucleoside analogs. Amprenavir levels were measured before and after adding efavirenz. Patients then received a second protease inhibitor. There was evidence of genotypic and phenotypic resistance at study entry. No patient had study drugs discontinued because of toxicity. Efavirenz decreased the steady-state area under the curve, maximum plasma concentration, and minimum plasma concentration of amprenavir by 24%, 33%, and 43%, respectively. Three of 10 patients had >1.5 log10 viral response to abacavir and amprenavir. All 8 patients who added efavirenz had >0.5 log10 decline in viral load, and this response lasted >24 weeks for 3 of the patients. A combination regimen that included abacavir, amprenavir, and efavirenz was well tolerated and had sustained activity in some patients. Concomitant efavirenz therapy decreases amprenavir concentrations.

These results demonstrate that ETR and RPV are likely to select for E138K as a major resistance mutation if no or very few other resistance mutations are present and that Y181C may be antagonistic to E138K.

Some of the latest developments in HIV treatment are described and contact information is given for people seeking further information on the topic. Clinical studies and preliminary results for interleukin-2 (IL-2), 1592U89 (abacavir), DMP-266 (efavirenz or Sustiva), and 141W94 (VX-94, Vertex) are described. Pharmaceutical companies are expected to continue developing new HIV drugs, including those in new drug classes, that will be more convenient, palatable, and less prone to resistance.

The ITT population comprised 630 patients (EFV400 = 321; EFV600 = 309); 32% were female; 37%, 33% and 30% were African, Asian and Caucasian, respectively. A total of 585 (EFV400 = 299; EFV600 = 286) completed 96 weeks on randomized therapy. At 96 weeks, proportions with VL <200 copies/mL were EFV400 (90.0%) and EFV600 (90.6%) (difference -0.6; 95% CI -5.2 to 4.0; p=0.72) demonstrating continued non-inferiority. Non-inferior efficacy was also observed for VL thresholds of <50 and <400 copies/mL irrespective of baseline VL (<100,000 versus ≥100,000 copies/mL). There was no between-arm difference in time to loss of virological response (>200 copies/mL) (p=0.47) or mean change from baseline VL (p=0.74). Mean change from baseline in CD4 T-cell counts at week 96 remained significantly higher for EFV400 than EFV600 (difference 25 cells/µL; 95% CI 2-48; p=0.03). There was no difference in the frequency or severity of AEs (EFV400 = 89.4%, EFV600 = 89.3%; difference 0.09; 95% CI -4.73 to 4.90; p=0.97). The proportions ever reporting an AE definitely or probably EFV-related were EFV400 (37.7%) and EFV600 (47.9%) (difference -10.2%; 95% CI -17.9 to -2.51; p=0.01). SAEs did not differ in frequency (EFV400 = 7.5%, EFV600 = 10.4%; difference -2.9%; 95% CI -7.3 to 1.6; p=0.20).