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New Study Results Find That Patients Treated With Boosted INVIRASE, A Potent Anti-HIV Treatment, Showed No Significant Resistance to Protease Inhibitors

Posted on: Monday, 25 July 2005, 09:00 CDT

RIO DE JANEIRO, Brazil, July 25 /PRNewswire/ -- Patients starting HIV treatment with Roche's protease inhibitor INVIRASE(R) (saquinavir mesylate) boosted with a small dose of ritonavir show no significant resistance to protease inhibitors, according to a study presented today at the 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment(1).

These data are important to physicians and patients because resistance to treatment is one of the major challenges in trying to control HIV/AIDS. The virus (HIV) can become resistant to an anti-HIV drug, or combinations of drugs, because it reproduces at such a rapid rate that mutations occur, allowing the virus to partly, or fully, resist the effects of treatment.

"These data show that early treatment with INVIRASE resulted in an outstanding level of HIV suppression without the development of significant protease inhibitor resistance," said lead investigator Jintanat Ananworanich, M.D., of the HIV Netherlands Australia Thailand Research Collaboration (HIV- NAT), Bangkok.

Prior to publication of this new study, limited data existed on the potential development of resistance following treatment with ritonavir-boosted INVIRASE. Now, this study shows that no significant resistance against protease inhibitors developed, even in the few patients who experienced treatment failure.

In December 2004, Roche received approval from the U.S. Food and Drug Administration (FDA) of a new 500 mg film-coated tablet formulation of INVIRASE, designed for use in combination with a small dose of ritonavir and other anti-HIV drugs for the treatment of HIV infection. The new formulation of INVIRASE, which was approved under a six-month priority FDA review, reduces pill count for each dose by more than half (from five pills to two, twice-daily) compared to the INVIRASE 200 mg capsules.

About the study

In the study, 258 antiretroviral (ART)-naive Thai patients with a baseline CD4 count of 200-350 cells/mm3 received Invirase/ritonavir 1600/100 mg once-daily plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) for six months. Investigators reported that only 10 of 258 patients (4%) experienced viral failure (two consecutive viral loads >500 copies/mL) after a median of 29.6 weeks of therapy. None of the patients in the study acquired major protease inhibitor resistance mutations. At viral failure, seven patients had minor protease mutations or natural polymorphisms, which, in four cases, were seen at baseline.

The data from the STACCATO study (Swiss-Thai-Australia Treatment Interruption Trial) also showed that early use of a regimen of boosted INVIRASE plus two nucleoside reverse transcriptase inhibitors resulted in ninety-one percent of patients achieving undetectable levels of HIV in the

blood (less than 50 copies/ml) at 24 weeks(2).

The approved dosing regimen for INVIRASE is 1000 mg of INVIRASE boosted with 100 mg of ritonavir twice daily. INVIRASE is currently made in 200-mg capsules as well as a new 500 mg tablet formulation.

About INVIRASE

INVIRASE in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV infection. The twice-daily administration of INVIRASE in combination with ritonavir is supported by safety data from the MaxCMin 1 study and pharmacokinetic data. The efficacy of INVIRASE with ritonavir or FORTOVASE (with or without ritonavir coadministration) has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.

INVIRASE(R) (saquinavir mesylate) capsules and FORTOVASE(R) (saquinavir) soft gelatin capsules are not bioequivalent and cannot be used interchangeably. INVIRASE may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with FORTOVASE. When using saquinavir as the sole protease inhibitor in an antiviral regimen, FORTOVASE is the recommended formulation.

INVIRASE is contraindicated in patients with clinically significant hypersensitivity to saquinavir or to any of the components contained in the capsule. INVIRASE/ritonavir should not be administered concurrently with terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam or ergot derivatives. Inhibition of CYP3A4 by saquinavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation.

INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment. Patients with hepatic impairment have not been studied and caution should be exercised when prescribing saquinavir in this population. Concomitant use of INVIRASE with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including INVIRASE, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin).

Concomitant use of INVIRASE and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Garlic capsules should not be used while taking saquinavir as the sole protease inhibitor, due to the risk of decreased saquinavir plasma concentrations. For a complete list of drugs that should not be taken with saquinavir, please see TABLE 5 in the summary of complete product information.

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease-inhibitor therapy. No initial dose adjustment is necessary for patients with renal impairment. However, patients with severe renal impairment have not been studied, and caution should be exercised when prescribing saquinavir in this population. There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. A causal relationship between protease-inhibitor therapy and these events has not been established, and the long-term consequences are currently unknown.

Varying degrees of cross-resistance among protease inhibitors have been observed. In clinical trials with saquinavir (1000 mg) in combination with ritonavir (100 mg) and other antiretrovirals, the grade 2, 3 and 4 adverse events occurring in greater than or equal to 2% of 148 patients (considered at least possibly related to study drug or of unknown relationship): abdominal

pain (6.1%), back pain (2%), bronchitis (2.7%), constipation (2%), diarrhea (8.1%), diabetes mellitus/hyperglycemia (2.7%), dry lips/skin (2%), eczema (2%), fatigue (6.1%), fever (3.4%), influenza (2.7%), lipodystrophy (5.4%), nausea (10.8%), pneumonia (5.4%), pruritus (3.4%), rash (3.4%), sinusitis (2.7%) and vomiting (7.4%).

INVIRASE is not a cure for HIV infection or AIDS. INVIRASE does not prevent the transmission of HIV.

About Roche -- More Than a Century in the U.S. and the World

Founded in 1896 and headquartered in Basel, Switzerland, Roche is one of the world's leading innovation-driven healthcare groups. Its core businesses are pharmaceuticals and diagnostics. Roche is one of the world's leaders in diagnostics, the leading supplier of pharmaceuticals for cancer, as well as a leader in virology and transplantation. As a supplier of products and services for the prevention, diagnosis and treatment of disease, the Group contributes on many fronts to improve people's health and quality of life. Roche employs roughly 65,000 people in 150 countries, including approximately 15,000 in the United States.

Roche's U.S. operations celebrate their American Centennial in 2005. In another milestone this year, Roche was named in January to Fortune magazine's list of Best Companies to Work for in America. One of an increasingly rare breed of major healthcare companies that still bear their original name, Roche today has more than a dozen U.S. sites located in California, Colorado, Indiana, New Jersey and South Carolina, as well as in Puerto Rico. Roche has alliances and research and development agreements with numerous partners, including majority ownership interests in Genentech and Chugai. Roche's Pharmaceuticals Division offers a portfolio of leading medicines in therapeutic areas including cancer, HIV/AIDS, hepatitis C, transplantation, dermatology and influenza. Roche's Diagnostics Division supplies a wide array of innovative testing products and services to researchers, physicians, patients, hospitals and laboratories world-wide. For further information, please visit our worldwide and U.S. websites (Global: http://www.roche.com/ and U.S.: http://www.roche.us/).

Ritonavir is manufactured by Abbott Laboratories. 1. "Resistance Mutations in ARV-naive Patients Treated with Ritonavir- boosted Saquinavir." Ananworanich, Ruxrungtham, Sirivichayakul, Ubolyam, Jupimai, Schutz, Snowden, Cooper, Hirschel, the Staccato Study Team. Presented at International AIDS Society annual meeting, 2005. 2. ''A Prospective Cohort Study of Efficacy and Safety of 2 NRTI Plus Once-daily Ritonavir Boosted-Saquinavir Hard Gel Capsule (SQV-HGC/r) at 24 weeks.'' Ananworanich J, Ruxrungtham K, Siangphoe U et al. Presented at XV International AIDS Conference, 2004.

Roche

CONTACT: Maureen Byrne of Roche, +1-973-562-2203, Mobile:+1-973-978-3045, maureen.byrne@roche.com; or Noelle Boyd of Manning Selvage &Lee, +1-212-468-4313, noelle.boyd@mslpr.com

Web site: http://www.roche.com/http://www.roche.us/

Source: PRNewswire

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