Michael Stek

Experience of healthcare workers taking postexposure prophylaxis after occupational HIV exposures: findings of the HIV Postexposure Prophylaxis Registry.

OBJECTIVE To collect information about the safety of taking antiretroviral drugs for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP). DESIGN A voluntary, confidential registry. SETTING Hospital occupational health clinics, emergency departments, private physician offices, and health departments in the United States. RESULTS 492 healthcare workers (HCWs) who had occupational exposures to HIV, were prescribed HIV PEP, and agreed to be enrolled in the registry by their healthcare providers were prospectively enrolled in the registry. Three hundred eight (63%) of 492 of the PEP regimens prescribed for these HCWs consisted of at least three antiretroviral agents. Of the 449 HCWs for whom 6-week follow-up was available, 195 (43%) completed the PEP regimen as initially prescribed. Forty-four percent (n=197) of HCWs discontinued all PEP drugs and did not complete a PEP regimen. Thirteen percent (n=57) discontinued > or =1 drug or modified drug dosage or added a drug but did complete a course of PEP Among the 254 HCWs who modified or discontinued the PEP regimen, the two most common reasons for doing so were because of adverse effects attributed to PEP (54%) and because the source-patient turned out to be HIV-negative (38%). Overall, 340 (76%) HCWs with 6-week follow-up reported some symptoms while on PEP: nausea (57%), fatigue or malaise (38%), headache (18%), vomiting (16%), diarrhea (14%), and myalgias or arthralgias (6%). The median time from start of PEP to onset of each of the five most frequently reported symptoms was 3 to 4 days. Only 37 (8%) HCWs with 6-week follow-up were reported to have laboratory abnormalities; review of the reported abnormalities revealed that most were unremarkable. Serious adverse events were reported to the registry for 6 HCWs; all but one event resolved by the 6-month follow-up visit. Fewer side effects were reported by HCWs taking two-drug PEP regimens than by HCWs taking three-drug PEP regimens. CONCLUSIONS Side effects from HIV PEP were very common but were rarely severe or serious. The nature and frequency of HIV PEP toxicity were consistent with information already available on the use of these antiretroviral agents. Clinicians prescribing HIV PEP need to counsel HCWs about PEP side effects and should know how to manage PEP toxicity when it arises.

The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers.

This study evaluated the effect of multiple‐dose efavirenz on the steady‐state pharmacokinetics of the combination of indinavir (800 mg) and low‐dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations.

Continued indinavir versus switching to indinavir/ritonavir in HIV-infected patients with suppressed viral load.

Objective: To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI). Design: Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts ⩾ 100 × 106/l and plasma HIV RNA < 500 copies/ml for ⩾ 3 months. Methods: Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h). Primary endpoint was the proportion of patients remaining < 500 copies/ml at 48 weeks. Results: A total of 323 patients (IDV/RTV, 162; IDV, 161) were evaluable. At 48 weeks, the proportions of patients with plasma HIV RNA < 500 copies/ml were 93%, 88% and 58% in the IDV/RTV arm versus 92% (P = 1), 86% (P = 0.87) and 74% (P = 0.003) in the IDV arm using on-treatment (OT) and intent-to-treat (ITT) [switches included (ITT, S = I) and switches = failure (ITT, S = F)] analyses respectively. Mean increase in CD4 cell count was 88 × 106/cells/l (IDV/RTV arm) and 60 × 106 cells/l (IDV arm) (P = 0.08). More patients discontinued study medication due to adverse events in the IDV/RTV arm than in the IDV arm (P < 0.001). Conclusions: Equivalence of continuing IDV q8h versus switching to IDV/RTV (liquid) q12h in suppressed stable patients was demonstrated by OT and ITT S = I analyses. However, the IDV q8h arm performed better when discontinuations were classified as failures. IDV/RTV q12h can be convenient and equally effective for patients able to tolerate it.

Mitochondrial DNA and RNA Increase in Peripheral Blood Mononuclear Cells from HIV-1–Infected Patients Randomized to Receive Stavudine-Containing or Stavudine-Sparing Combination Therapy

BACKGROUND Mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells (PBMCs) has been suggested as a potential marker of mitochondrial toxicity associated with nucleoside analogue reverse-transcriptase inhibitor-containing therapy. METHODS We quantified mtDNA and mitochondrial RNA (mtRNA) in PBMCs over the course of 48 weeks in 78 patients infected with human immunodeficiency virus type 1 (HIV-1) who were randomly assigned to receive ritonavir-boosted indinavir and efavirenz with or without stavudine. Furthermore, we analyzed the association of mtDNA and mtRNA with clinical signs and symptoms and/or abnormalities in laboratory markers attributed to mitochondrial toxicity. RESULTS No statistically significant difference was found in mtDNA and mtRNA content over time between the 2 treatment arms. When arms were combined, both median mtDNA and mtRNA content showed statistically significant increases over the course of 48 weeks, from 206 to 278 copies/cell (P < .001) and from 154 to 288 copies/cell (P = .003), respectively. No statistically significant difference in mtDNA and mtRNA content was found between patients with and those without adverse events attributed to mitochondrial toxicity. CONCLUSIONS The observed increases in mtDNA and mtRNA content during the first year of treatment may represent a restorative trend resulting from suppression of HIV-1 infection, independent of the treatment used. Future studies should focus on well-defined mitochondrial toxicities and changes in these markers within the corresponding affected tissues simultaneously with those in PBMCs. Furthermore, with respect to studies of peripheral blood, mtDNA and mtRNA content in individual cell subtypes rather than in PBMCs may be better markers of toxicity and deserve further investigation.

Pharmacokinetics of indinavir/ritonavir (800/100 mg) in combination with efavirenz (600 mg) in HIV-1-infected subjects.

Background: Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady‐state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV‐infected Thai subjects who used this nucleoside‐sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study. Methods: At week 4 of the study, 12‐hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV‐infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed. Results: All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L • h) (95% confidence interval [CI], 39.8‐52.5), 0.32 mg/L (95% CI, 0.24‐0.44), and 11.1 mg/L (95% CI, 9.4‐13.0), respectively. A >10‐fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5‐3.7) and 2.1 mg/L (95% CI, 1.6‐2.6), respectively. Conclusions: Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment‐naive patients.

Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009

Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity.

Pharmacokinetics of indinavir/ritonavir (800/100 mg twice a day) combined with efavirenz in HIV-infected patients.

A pharmacokinetics study was performed in HIV-infected patients who used indinavir/ritonavir (800/100 mg twice a day) plus efavirenz in the European and South American Study of Indinavir, Efavirenz and Ritonavir. Indinavir plasma concentrations were similar to values previously obtained in healthy volunteers who used the same combination. Efavirenz concentrations were higher than reported before. The pharmacokinetic data suggest that indinavir/ritonavir plus efavirenz (without dose modifications) should be effective in treatment-naive patients, and this was supported by the treatment response of the participants.