Speaker: Charles Hicks, MD, Associate Professor of Medicine, Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina

Tipranavir (TPV) (Boehringer Ingelheim), a novel non-peptidic protease inhibitor (PI), now in late phase 3 clinical development, plus low-dose ritonavir(r) (Norvir drug, Abbott) was found to be significantly superior to currently available comparator protease inhibitors (CPIs) boosted by ritonavir (CPI/r). After 24 weeks of treatment, the virus was suppressed in patients with advanced HIV disease who had been exposed to more than three antiretroviral agents.

The researchers arrived at this conclusion from an interim analysis of the RESIST-1 (Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir) study. This study, a randomized, controlled, open-label, phase 3 clinical trial conducted in the U.S., Canada, and Australia, was designed to evaluate the safety and efficacy of tipranavir boosted with low-dose generic ritonavir versus a low-dose ritonavir-boosted CPI in treatment-experienced patients with documented PI resistance.

A total of 620 patients were randomly assigned to TPV/r 500 mg/200 mg or CPIs combined with ritonavir at its standard boosting dose. The CPIs included lopinavir (Kaletra®, Abbott), saquinavir (Fortovase®, Roche), amprenavir (Agen-erase®, GlaxoSmithKline), and generic indinavir (Crixivan drug, Merck). All of the patients combined their PIs with an optimized-background (OB) regimen of antiretroviral agents. These drugs were selected on the basis of the patients’ treatment history and baseline results of genotypic resistance testing.

At the 24th week, treatment response, defined as a 1 log₁₀ or greater decrease in viral load from the baseline, was achieved in 41.5% of the patients in the TPV/r treatment group and in 22.3% of patients in the CPI/r arm. Furthermore, a greater proportion of patients taking TPV/r achieved a viral load below the levels of quantification (defined as less than 400 copies/ml and less than 50 copies/ml) compared with those who received CPI/r. A total of 34.7% of TPV/r-treated patients and 16.5% of the CPI/r patients achieved viral loads of less than 400 copies/ml; 25.1% of the TPV/r patients achieved less than 50 copies/ml, compared with 10% of patients receiving CPI/r-based therapy.

Patients taking TPV/r experienced greater increases in their CD4+ cell counts (+36 cells/mm³) than did those taking a CPI/r (+6 cells/mm³).

Four-NRTI Second-Line Regimen for Early Virological Failure

Speaker: Allan E. Rodriguez, MD, Associate Professor of Medicine, Division of Infectious Diseases, University of Miami School of Medicine, Miami, Florida

A single-class quadruple therapy of nucleoside reverse transcriptase inhibitors (NRTIs), consisting of a fixed-dose combination of abacavir, lamivudine, and canadian zidovudine (Trizivir®, GlaxoSmithKline) plus tenofovir disoproxil fumarate (TDF) (Viread®, Gilead) may become the treatment of choice for HIV-infected patients who are experiencing early virological failure with highly active antiretroviral therapy (HAART), composed of two NRTIs plus a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen.

Fifty-one patients with HIV infection who were experiencing early virological failure on a regimen of drug zidovudine (Retrovir generic, GlaxoSmithKline) or stavudine (d4T) (Zerit generic, Bristol-Myers Squibb) plus lamivudine (3TC) (Epivir tablet, GlaxoSmithKline), combined with either a PI or an NNRTI, were switched to open label Trizivir® twice daily plus tenofovir once daily in a planned 24-week interim analysis. The study’s objectives were virolog-ical efficacy of Trizivir® plus tenofovir. The primary endpoint was an HIV-1 RNA level of less than 400 copies/ml, and the secondary endpoints included safety and tolerability.

At 24 weeks, the virological response to twice-daily Trizivir® and once-daily tenofovir was high; 93% of patients had HIV-1 RNA levels of less than 400 copies/ml, and 80°% had HIV-1 RNA levels of less than 50 copies/ml. CD4 cell counts were relatively high at baseline, with a median 436 cells/mm³, and they remained stable throughout the study periods. The median change from baseline for CD4 cell counts at the 24th week was 10 cells/mm³. No patients experienced confirmed virological failure through the 24th week.

Lopinavir/Ritonavir plus Efavirenz Offers NRTI-Sparing Regimen in HIV Infection

Speaker: Francois Raffi, MD, Professor, Infectious Diseases Department, University Hospital, Nantes, France

Final results of a 48-week pilot study indicated the soundness of the following concept: a nucleoside reverse transcriptase (NRTI)-sparing regimen of lopinavir/ritonavir (LPV/r) (Kale-tra®, Abbott) and efavirenz drug (EFV) (Sustiva generic, DuPont), a protease inhibitor (PI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI). Both of these drugs are potent preferred agents in their respective classes. This regimen provides a safe, well-tolerated, and effective treatment approach and avoids the cross-resistance seen between drugs in the same class and mitochondrial toxicity problems associated with NRTIs.

Eighty-six patients with HIV infection were enrolled into the BIKS (Bitherapy of Kaletra and Sustiva) study, a pilot, multi-center, open-label trial. Of the 86 patients, 65 were antiretro-viral (ARV)-naive and 21 were ARV-experienced but NNRTI-naive. The study was designed to evaluate the safety and immunological and virological activity of dual-therapy LPV/r 533/133 mg twice daily and EFV 600 mg once daily in patients with HIV infection.

It should be noted that dose adaptation is required for patients taking this two-agent combination. The LPV/r dose should be increased by one third because of an induction of lopinavir metabolism by EFV, which reduces the lopinavir area-under-the-curve (AUC) concentration by 40%.

The baseline mean HIV RNA level was 4.8 log_w copies/ml, and the mean CD4 cell count was 307/mm³. buy antibiotics in canada

The duration of the study was 48 weeks, with a 24-week extension and follow-up at day 0 (zero) and at weeks 4, 8, 16, 24, 36, and 48.

At 48 weeks, 65 patients were evaluable, with 21 patients having discontinued the study. In this latter group, only one patient in the ARV-naive group had experienced virological failure, at week 24. The remaining discontinuations were a result of patients being lost to follow-up and emerging ADEs. A high proportion of patients who remained in the study to its conclusion achieved virological success.

At 24 weeks, a mean HIV RNA level below 400 copies/ml was reported in 93% of the active-treatment population (67 of 72 patients) and in 78% of the intent-to-treat population (67 of 86 patients).

At 48 weeks, a mean HIV RNA level of less than 50 copies/ml was observed in 91% of the active-treatment population (59 of 65 patients) and in 69% of the ITT population (59 of 86 patients). Overall, virological failure was documented in four patients, three of whom had been noncompliant with their medications.
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Among patients with a detectable plasma viral load at the 24th or 28th week, genotypic testing showed an absence of PI resistance mutations and two cases of emergence of k13N resistance.