Pharmacokinetics of Nelfinavir and Efavirenz in Antiretroviral-Naive, Human Immunodeficiency Virus-Infected Subjects when Administered Alone or in Combination with Nucleoside Analog Reverse Transcriptase Inhibitors
Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir,
or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time
curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both
drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.
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[Show abstract][Hide abstract]ABSTRACT: For antiretroviral therapy, the 95% adherence “threshold” is based on nucloside-exposed patients who are receiving partially
suppressive, unboosted protease inhibitor regimens. Using unannounced pill counts and electronic medication monitoring, viral
suppression is common with a 54%–100% mean adherence level to nonnucleoside reverse-transcriptase-inhibitor regimens. Although
perfect adherence is an important goal, viral suppression is possible with moderate adherence to potent regimens.
Full-text · Article · Nov 2006 · Clinical Infectious Diseases
[Show abstract][Hide abstract]ABSTRACT: Adherence of 95% or more to unboosted protease regimens is required for optimal virologic suppression in HIV-1-infected patients. Whether the same is true for nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy is unclear.
To assess the relationship between adherence to NNRTI-based therapy and viral load in treatment-naive patients.
Observational cohort study.
Private-sector HIV and AIDS disease management program in South Africa.
2821 adults infected with HIV who began NNRTI-based therapy between January 1998 and March 2003 (2764 patients [98%] were enrolled after December 2000).
Adherence was assessed by monthly pharmacy claims. The primary end point was sustained viral load suppression (<400 copies/mL) in 100% of recorded viral load measurements throughout follow-up. Secondary end points included time to initial viral load suppression and time to subsequent virologic failure (>400 copies/mL).
The median follow-up period was 2.2 years (interquartile range, 1.7 to 2.7 years). The proportion of patients with sustained viral load suppression ranged from 13% (41 of 325 patients) in patients who filled less than 50% of antiretroviral drug prescriptions to 73% (725 of 997 patients) in those who filled 100% of antiretroviral drug prescriptions. Each 10% increase in pharmacy claim adherence greater than 50% was associated with a mean absolute increase of 0.10 in the proportion of patients with sustained virologic suppression (P < 0.001). Predictors for shorter time to virologic failure after initial suppression in multivariable Cox regression included CD4+ T-cell counts of 0.50 x 10(9) cells/L or less (hazard ratio, 1.60 [95% CI, 1.22 to 2.10] vs. CD4+ T-cell counts >0.20 x 10(9) cells/L), baseline viral load greater than 10(5) copies/mL (hazard ratio, 1.39 [CI, 1.14 to 1.70]), nevirapine-based regimen (hazard ratio, 1.43 [CI, 1.16 to 1.75]), and low pharmacy claim adherence (hazard ratio, 1.58 [CI, 1.48 to 1.69], per 10% decrease in adherence to 50%).
Observational study with adherence stratification at study end and lack of standardized timing for outcome measurement.
Virologic outcomes improve in a linear dose-response manner as adherence to NNRTI-based regimens increases beyond 50%.
No preview · Article · Apr 2007 · Annals of internal medicine
[Show abstract][Hide abstract]ABSTRACT: HIV type 1 (HIV-1) protease inhibitors (PI) have been shown to have anticancer activity in non-HIV-associated human cancer cells. The underlying mechanism of this effect is unclear. Here, we show that the PIs nelfinavir and atazanavir cause cell death in various malignant glioma cell lines in vitro. The underlying mechanism of this antitumor effect involves the potent stimulation of the endoplasmic reticulum (ER) stress response (ESR), as indicated by increased expression of two ESR markers, GRP78 and CHOP, and activation of ESR-associated caspase-4. Induction of ESR seems to play a central role in PI-induced cell death because small interfering RNA-mediated knockdown of the protective ER chaperone GRP78 sensitizes cells; whereas knockdown of proapoptotic caspase-4 protects cells from PI-induced cell death. Furthermore, the treatment of cells with PIs leads to aggresome formation and accumulation of polyubiquitinated proteins, implying proteasome inhibition. Thus, our results support a model whereby PIs cause tumor cell death via triggering of the ESR, inhibition of proteasome activity, and subsequent accumulation of misfolded proteins. Inhibition of glioma growth via ESR takes place in the in vivo setting as well, as nelfinavir inhibits the growth of xenografted human malignant glioma, with concomitant induction of the proapoptotic ER stress marker CHOP. Because ER stress has also been reported as the mechanism for insulin resistance and diabetes, our ER stress model of PI function may also explain why these drugs may induce insulin resistance as one of their most common side effects.