Forty-nine protease inhibitor (PI)-experienced but amprenavir (APV)-The introduction of protease inhibitors (PIs) to antiretroviral therapy led to a profound and sustained suppression of viral loads, slower rates of disease progression, and prolonged survival in the majority of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected patients (12). The success of antiretroviral therapy, however, may be impaired by the emergence of drug-resistant viral strains. Due to the high degree of structural similarity of PIs, resistant viruses may exhibit various degrees of cross-resistance even to a PI to which the patient has not yet been exposed. This makes the management of second-or third-line therapies complex in most cases.Recently, the new PI amprenavir (APV) (VX478, 141W94) has been approved for antiretroviral treatment in several countries. The cytochrome P450 3A4 (CYP 3A4) isoenzyme is primarily responsible for the production of APV oxidative metabolites in humans for which the K i s are similar to those for indinavir and nelfinavir. Drugs that affect or that are affected by CYP3A4 have a potential interaction with APV. At present, there is a treatment paradigm shift in which PIs such as ritonavir (RTV) are used as pharmacokinetic enhancers in PI therapy. For drugs with reasonable bioavailabilities but short halflives, such as APV, the effects of RTV are predominantly on the half-life, the minimal concentration in plasma (C min ) at steady state (C min,ss ), and the area under the curve (AUC). This interaction increases the level of exposure to APV by inhibiting its metabolism, and the resulting decreases in the number of daily doses and the total daily pill count have the potential to improve adherence (8, 16). Coadministration of APV and RTV (r/APV; 450 and 100 mg, respectively) twice daily (b.i.d.) resulted in an approximately 3-to 4-fold increase in the steady-state AUC (AUC 1-12 h,ss ) for APV in plasma, a 10-to 14-fold increase in the APV C min,ss , and a 1-to 1.7-fold increase in the steady-state maximal concentration of APV in plasma compared to those achieved with APV administered alone at 450 mg. The pharmacokinetic parameters for RTV in plasma did not significantly change when RTV was coadministered with APV (4,5,14).The relationship between antiviral efficacy in vivo and the drug concentration in drug-naïve patients has been determined by estimation of the in vivo APV C min needed to provide 90% of the maximum antiviral effect for APV over 4 weeks in a pharmacodynamic sigmoid maximum-effect model, which was found to be 228 ng/ml, which is below the median C min achieved with the standard dose of APV without the addition of RTV (14). The increase in the APV C min obtained by the addition of RTV should have the potential to overcome PI resistance, which is crucial in salvage therapy.In addition to the development of the I50V mutation, three alternative pathways leading to the development of APV resistance have been identified: the V32I mutation plus the I47V mutation, the I54L/M mutation, or, less co...

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log 10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.

Objectives To evaluate the benefits of therapeutic drug monitoring (TDM) in association with genotypic resistance testing and expert advice to optimize therapy in multiexperienced patients infected with HIV‐1. Methods Patients with a viral load>1000 HIV‐1 RNA copies/mL and an unchanged antiretroviral therapy regimen over the last 3 months were randomized into two groups: a genotypic group (G) and a geno‐pharmacological group (GP). Treatment was selected by an expert committee according to genotypic resistance testing (the G and GP groups) and TDM (the GP group) at week 4. Treatment could be modified at each visit according to toxicity, poor virological response and TDM. Results of TDM were withheld from the G group until week 12. The primary endpoint of the study was the percentage of patients with viral load<200 copies/mL at week 12. Results A total of 134 patients were randomized in the study, with 67 in each group, and included in the intent‐to‐treat (ITT) analysis. At baseline, median values were as follows: viral load (log10 copies/mL): G=4.1, GP=4.0; CD4 cell count (cells/μL): G=292, GP=294; and number of prior drugs: G=7, GP=8. The median number of resistance mutations was five in the G group [nucleoside reverse transcriptase inhibitors (NRTIs)=three; non‐nucleoside reverse transcriptase inhibitors (NNRTIs)=one; protease inhibitors (PI)=one] and seven in the GP group (NRTI=four; NNRTI=two; PI=one). At week 8, treatment was adjusted according to the TDM in 13 of the 67 patients in the GP group (19%). By ITT missing equal failure analysis at week 12, and after only one intervention according to plasma concentration results, a viral load<200 copies/mL was achieved in 30 of the 67 patients (45%) in the G group and in 29 of the 67 patients (43%) in the GP group (not significant). In the multivariate analysis, only prior exposure to at least two PIs at baseline gave a poor response to subsequent antiretroviral therapy. At week 24, a viral load<200 copies/mL was achieved in 35 of the 67 patients (52%) in the G group and in 40 of the 67 patients (60%) in the GP group. Conclusions A statistically significant benefit of using TDM was not found in this short‐term study where patients appeared to be adherent. However, combining genotypic resistance testing with the use of an expert committee to monitor subsequent therapy individually in patients with multiple resistance mutations was associated with high antiviral efficacy.

In HIV-infected patients with multiple failures and no therapeutic options at baseline, significant reversion of resistance mutations after prolonged treatment interruption failed to restore antiviral efficacy of a salvage regimen and was clinically deleterious.