Guide to Phenotypic Testing

ViroLogic’s clinical cutoff information for CRIXIVAN^® (indinavir sulfate) is displayed on the ViroLogic phenotypic report

HIV resistance testing may be a valuable tool to help guide treatment

• In vitro resistance testing may help to maximize the effectiveness of antiretroviral therapy for your patients¹
• The NIH recommends resistance testing to help guide treatment when¹:
  • Patients experience virologic failure during HAART
  • Patients experience suboptimal viral load suppression after starting treatment
• Two types of resistance testing are available^1,2:
  • Genotypic testing detects mutations in your patient’s virus that may be associated with resistance to each antiretroviral agent
  • Phenotypic testing uses various concentrations of antiretroviral agents to measure the susceptibility of your patient’s virus to that antiretroviral agent
• Genotypic testing does not necessarily predict phenotypic resistance

Phenotypic testing helps tailor your patient’s therapy based on his or her resistance profile

• Shows the degree (“fold” increase) of resistance for the patient’s virus to each antiretroviral agent
• Provides information on which agents are most likely to supress the virus (“susceptibility”) and which are least or not likely (“resistance”)
• Helps guide the selection of appropriate agents for your patient’s next treatment regimen

CRIXIVAN^® (indinavir sulfate) in combination with other antiretroviral agents is indicated for the treatment of HIV infection. This indication is based on 2 clinical trials of approximately 1 year’s duration that demonstrated (1) a reduction in the risk of AIDS-defining illness or death and (2) a prolonged suppression of HIV RNA.

CRIXIVAN:

• Does not cure HIV infection
• Does not reduce the transmission of HIV
• Should only be taken in combination with other drugs for HIV

IMPORTANT SAFETY INFORMATION

Contraindications

CRIXIVAN is contraindicated in patients with clinically significant hypersensitivity to any of its components.

Selected Warnings

ALERT: Find out about medicines that should NOT be taken with CRIXIVAN.

Nephrolithiasis/urolithiasis has occurred in clinical studies in adult patients (12.4%; range across individual trials, 4.7% to 34.4%) and in pediatric patients (29%) receiving CRIXIVAN. The cumulative frequency of nephrolithiasis events increases with increasing exposure to CRIXIVAN; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure and pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur (including flank pain with or without hematuria or microscopic hematuria), temporary interruption (eg, 1 to 3 days) or discontinuation of therapy may be considered. Adequate hydration (at least 48 ounces daily for adults) is recommended in all patients treated with CRIXIVAN.

• Resistance is a continuum rather than a threshold phenomenon
• The phenotypic testing cutoff:
  • Shows when the efficacy of each antiretroviral agent against the patient’s virus starts to significantly decrease
  • Corresponds to a number representing the “fold” change in inhibitory concentration for each agent
• Two types of phenotypic testing cutoffs exist³:
  • Biologic cutoff is determined using viral strains in the laboratory
  • Clinical cutoff is determined using isolates from actual HIV patients in clinical trials
• Higher clinical cutoffs imply greater likelihood of overcoming resistance
• Phenotypic drug susceptibility does not ensure clinical virologic response¹:
  • There are few data on the specific level of resistance that is associated with failure
    of different agents
  • Minor viral species may not be detected

In patients treated with CRIXIVAN, acute hemolytic anemia, including death in some patients, and hepatitis, including hepatic failure and death, have been reported.

There have also been reports of hyperglycemia and new onset or exacerbation of preexisting diabetes mellitus in patients receiving protease inhibitors.

Concomitant use of CRIXIVAN with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including CRIXIVAN, are used concurrently with other HMG-CoA reductase inhibitors metabolized by the CYP3A4 pathway (eg, atorvastatin).

Selected Drug Interactions

Help build barriers to resistance
An approach that may prevent resistance⁴:

Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of CRIXIVAN with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse reactions, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil.

There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, has been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Before prescribing CRIXIVAN, please read the Prescribing Information.

References: 1. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Department of Health and Human Services (DHHS), February 4, 2002. 2. Hirsch MS, Brun-Vézinet F, D’Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society—USA Panel. JAMA. 2000;283:2417–2426. 3. Product information from Virologic, Inc. South San Francisco, Calif. 4. Condra JH. Resisting resistance: maximizing the durability of antiretroviral therapy. Ann Intern Med. 1998;128:951–954.