Jacques Durant

Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study

Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. Results. Mean change in HIV-1 RNA at day 8 was −1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. Conclusions. DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus. Clinical Trials Registration. www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574).

PharmAdapt: A randomized prospective study to evaluate the benefit of therapeutic monitoring of protease inhibitors: 12 week results

Objective: A randomized study to evaluate the usefulness of protease inhibitor (PI) therapeutic drug monitoring (TDM) in antiretroviral-experienced HIV-infected patients. Methods: In the control arm, treatment was modified according to genotypic resistance testing. In the TDM arm, therapy was modified on the basis of genotypic resistance testing and at week 8 according to PI plasma trough levels measured at week 4. The major endpoint was the change in HIV-RNA levels at week 12. Results: A total of 183 patients, 96 in the control arm and 87 in the TDM arm, were included in the study. Low-dose ritonavir to enhance the associated PI was prescribed to 62.5% of patients in the control arm and 65.5% of patients in the TDM arm. Using our PI concentration targets, 17/81 patients (21%) in the TDM arm were considered to have suboptimal or partly optimal PI plasma levels at week 4. Physician and protocol-driven PI modifications were performed in 18/85 patients (23.5%) in the TDM arm, and in seven of 94 patients (7%) in the control arm (P < 0.01). Week 12 HIV RNA dropped 2 log10 copies/ml in the control arm and 1.7 log10 copies/ml in the TDM arm, respectively. Conclusion: We found no statistically significant difference between the TDM arm and control arm in virological outcome at week 12. The utility of TDM could be dependent on the presence of low-dose ritonavir as a booster and the antiretroviral experience of the studied population. Effective non-toxic target concentrations for resistant viruses have still to be determined.

Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders?

Objective:To assess changes over time in neuropsychological test results (NPr) and risk factors among a regularly followed HIV-infected patient population. Methods:Prospective cohort of HIV-infected patients randomly selected to undergo neuropsychological follow-up. Test score was adjusted for age, sex and education. Patients were divided into five groups: normal tests, neuropsychological deficit (one impaired cognitive domain), asymptomatic neurocognitive disorders (ANIs), mild neurocognitive disorders (MNDs) and HIV-associated dementia (HAD). Demographic and background parameters including CSF drug concentration penetration effectiveness (CPE) score 2010 were recorded. Changes in NPr and associated risk factors were analyzed. Results:Two hundred and fifty-six patients underwent neuropsychological tests and 96 accepted follow-up approximately 2 years later. The groups were comparable. Upon neuropsychological retesting, six patients improved, 31 worsened and 59 were stable. The proportion of patients with HIV-associated neurocognitive disorders (HANDs) rose from 26 to 45%, with ANIs and MNDs still mostly represented. Most patients initially diagnosed with HANDs remained stable, five of 25 showed clinical improvement and three of 25 deteriorated. Of 33 patients with normal tests, four deteriorated, whereas 24 of 38 with initial neuropsychological deficit had poorer NPr, and contributed most of the new HAND cases. Patients with clinical deterioration had a lower CPE score both at inclusion (6.9 vs. 8.1; P = 0.005) and at the end of follow-up (7.2 vs. 7.8; P = 0.08) than those with improved or stable performance. This was confirmed by multivariate analysis. Conclusion:Patients with higher CPE scores upon inclusion and at the end of follow-up were at lower risk of clinical worsening, suggesting that combination antiretroviral therapy with better CSF penetration could protect against cognitive deterioration.

Economic evaluation of drug resistance genotyping for the adaptation of treatment in HIV-infected patients in the VIRADAPT study.

Background: Costs of antiretroviral therapy for HIV‐infected patients have increased at a time when most countries are attempting to contain health care costs. Part of this increase results from HIV drug resistance associated with virologic failure and a subsequent shift to more complex and costly therapies. Genotypic guided treatment is associated with better virologic outcome. However, it is not yet known whether it will be cost effective. Methods: We present here an economic evaluation based on the results from the VIRADAPT study, a prospective, open‐label, randomized trial comparing patients assigned to standard of care (n = 43), versus genotypic guided treatment (n = 64) for 6 months. Total follow‐up for the extended trial was 1 year. Costs were computed from the viewpoint of the health care system. Hospitalization data were retrieved from the VIRADAPT study case report forms, costs were estimated from the cost of the corresponding diagnosis‐related groups derived from the French national cost data base: these were actual costs and not charges. Data on the volume of tests prescribed, drugs, and clinic visits were retrieved from the VIRADAPT study database. The unit costs of tests and clinic visits were determined using the French national Social Security reimbursement price; costing of drugs used were based upon purchase price by either retail pharmacies or hospitals. Genotyping using TruGene HIV‐1 assay was estimated at

Effects of subinhibitory concentrations of vancomycin and teicoplanin on adherence of staphylococci to tissue culture plates.

500 per test from manufacturer’s data (all figures in this paper are expressed in U.S. dollars). Results: Total mean (standard deviation) yearly costs per patients were

Long-Term Treatment with Lopinavir-Ritonavir Induces a Reduction in Peripheral Adipose Depots in Mice

20,412 (±

Unusual Cutaneous Manifestations of Miliary Tuberculosis

10,129) in the standard of care group and

Sensitive Enzyme Immunoassay for Measuring Plasma and Intracellular Nevirapine Levels in Human Immunodeficiency Virus-Infected Patients

18,484 (±

A case of gnathostomiasis in a European traveller returning from Mexico.

9,652) in the genotyping group (p = .35). Drug costs represented 55% of total costs. There was a trend toward a decrease in drug costs in the genotyping arm (p = .07), the greatest reduction being in the decreased use of protease inhibitors in the genotyping arm. The additional expense of genotyping appeared to be offset by the savings obtained in drug costs. Conclusion: In our study, the cost of drug resistance testing is offset by a reduced use of protease inhibitors and their attendant costs. Although not reaching statistical significance, this trend in the reduction of drug costs and drug use presents a great interest for future trials.

Cervical intra-epithelial neoplasia in women infected with human immunodeficiency virus

Bacterial adhesion is the first step in infection of medical devices. Staphylococcus aureus and Staphylococcus epidermidis are the pathogens recovered most often. The effects of subinhibitory concentrations of vancomycin and teicoplanin on the adherence of eight clinical strains of S. aureus and eight strains of S. epidermidis to tissue culture plates in vitro were tested. The mean relative inhibitions of adherence at one-fourth and one-eighth the MIC were statistically different for teicoplanin and vancomycin. Slime production seemed not to be involved in adherence.