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The HIV/AIDS Treatment Information Service (ATIS) has received hundreds of calls regarding protease inhibitors. Many callers are asking the same questions. Here are a few of the questions received and the answers provided by the ATIS staff.
Q1. What can you tell me about the cross resistance
potential with the protease drugs? Is there a greater concern with ritonavir
and indinavir sulfate than with saquinavir?
A. Potential cross resistance to the protease inhibitor (PI) medications is still under investigation. Researchers have confirmed that a potential cross-resistance with indinavir sulfate and ritonavir has been seen in vivo. Researchers found that in some people, HIV first became resistant to the protease inhibitor indinavir and then became resistant to several other protease inhibitors when tested later. Unpublished data from the pharmaceutical company, Hoffmann LaRoche, showed that 12 of 13 individuals treated with saquinavir monotherapy for six months exhibited no cross-resistance to ritonavir. There is evidence that development of resistance to any of the approved PIs could lead to development of cross resistance to the newer experimental PIs (e.g. VX478 &Viracept). A clinical trial combining the protease inhibitors saquinavir and ritonavir is currently being sponsored by Abbott Laboratories to address some of these cross-resistance questions. A cross-resistance between indinavir sulfate and saquinavir is currently under study and the data are still being collected. It is important that patients fully understand the need to take the drug regimen of combination therapy exactly as prescribed by their physician to lessen the possibility of developing viral resistance to these drugs. Missing even occasional doses can lead to the development of resistance.
Q2. Which protease inhibitor is the best? What are the most effective nucleoside analogue/protease inhibitor combinations?
A. The “best” protease inhibitor for an individual is dependent on their personal/ medical circumstances. Considerations of tolerance/toxicity profile (side effects), drug to drug interactions must also come into play. Currently there are only 6-9 months of data on several of these medications, and clinical trials are still underway to evaluate the effectiveness of nucleoside and protease combinations.The combination of AZT/3TC/Crixivan has received press coverage for its ability to increase CD4 counts as well as its ability to significantly decrease viral load. However, this was a clinical trial that studied a small number of individuals (26 participants); information about the effectiveness of triple combination therapy is based on interim data after six months and continues at 12 months of followup. Additional followup is needed for longer periods of time to conclusively answer the questions about the efficacy of this regimen. There is also 6-9 month data on ritonavir in combination with nucleosides that is comparable.
Q3. Is it appropriate to use a protease inhibitor, for example, as a starting therapy with varying levels of viral burden (high/low/unknown) or only after exhausting nucleoside combination therapy?
A. This is a complex question that addresses two separate issues: when to initiate therapy based on viral load, and when to add a protease inhibitor to a treatment regimen.
The question of when to start antiretroviral therapy based on viral load was addressed by a panel of HIV/AIDS experts for the International AIDS Society (IAS). Their recommendations on antiretroviral therapy for HIV disease were published in the Journal of the American Medical Association, July 10, 1996. The panel' s recommendations includes the use of combination therapy as well as setting a standard to monitor viral load in initiating and changing therapy. The recommendations for initiating therapy are as follows:
| Status | Recommendation* |
|---|---|
| Symptomatic HIV disease (includes symptoms such as recurrent mucosal candidiasis, oral hairy leukoplakia, and chronic and unexplained fever, night sweats, and weight loss). | Therapy recommended for all patients. |
| Asymptomatic CD4+ cell count <0.500 x 109/L. | Therapy recommended. Some doctors would defer therapy in a subset of patients with stable CD4+ cell counts between 0.350 and 0.500 X 109/L and plasma HIV RNA levels consistently below 5,000-10,000 copies/mL. |
| Asymptomatic , CD4+ cell count <0.500 x 109/L. | Therapy recommended for patients with 30,000-50,000
HIV RNA copies/mL or rapidly declining CD4+ cell counts. Therapy should be considered for patients with >5,000-10,000 HIV RNA copies/mL. |
When to add a protease inhibitor to a treatment regimen is best decided by the patient and his health care provider and is based upon the medical status of the individual. The IAS guidelines note that initial therapy, including a protease inhibitor, may be most appropriate for those who are symptomatic, or for those who appear to be progressing rapidly, based on declining CD4+ counts or high plasma HIV RNA levels. Evaluating how the individual responds to a chosen therapy is now monitored by measuring viral load. Reductions in HIV RNA viral load generally occur within 4 weeks of starting or changing treatment.
* NOTE: The HIV RNA viral loads are only a very loose guideline as the measurement can vary depending on the specific test employed and the collection and processing procedure used.
Q4. Are there recommendations for using protease inhibitors in children?
A. There are no current recommendations for the use of protease inhibitors in children; clinical trials have just begun studying these compounds in pediatric patients. The protease inhibitors, ritonavir and indinavir sulfate, are undergoing Phase I/II trials at the National Cancer Institute, Bethesda, Maryland.
Q5. It has been reported that adding a protease inhibitor to my treatment regimen will cause the level of virus in my blood to be “undetectable.” Does that mean I am no longer infected?
A. No. Individuals with “undetectable” levels of HIV RNA in the blood are still infected and able to transmit the virus. The two FDA-approved tests to measure viral load, the RT-PCR and the bDNA, are not sensitive enough to pick up less than 200 copies/mL and 500 copies respectively, of HIV RNA in the blood. “Undetectable” levels of HIV RNA means that with these tests, smaller amounts of the virus cannot be measured due to the limitations of the test itself. Newer tests, which are under development, will be able to measure very small amounts of virus in the blood. In addition, virus may be present in lymph nodes, tissues or other organs that cannot be measured in the blood.
Q6. If the protease inhibitors can keep the viral load below the limit of detection, can this medication ever be discontinued?
A. Information about the long term use of protease inhibitors is not yet available. Questions about discontinuing these medications once the level of viral load becomes undetectable still need to be evaluated in clinical studies. Patients should not discontinue protease inhibitors or any medication without discussing it with their physician.
Q7. If my CD4+ cell count increases as the result of taking a combination of drugs, including a protease inhibitor, should I continue the prophylaxis medications I am taking?
A. There are no data currently available to suggest either continuing prophylaxis medications or stopping them when an individual' s CD4+ count increases. That's because it is not known whether the new cells mature and function as normal CD4+ cells would. Some clinicians are stopping prophylaxis, but probably more so for Mycobacterium Avium Complex (MAC) than for Pneumocyctis Carinii Pneumonia (PCP). This may be due to the fact that the drugs for MAC prophylaxis are more expensive and have more side effects and interactions with protease inhibitors than those taken for PCP prophylaxis. At this time, most clinicians recommend continuing the prophylaxis medications their patients are on.
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