Looking back over the last twenty years, we have seen a great evolution in the long-term management of HIV/AIDS. From the initial stages of only one treatment option to the development of three unique classes of medication, we have witnessed a great change in the landscape of this disease. In particular, during the mid 1990s, we began to see our patients living longer with the discovery of protease inhibitors and the outlook of AIDS shifted from a deadly and unmanageable disease to a chronic condition with long-term options.
The current challenge of many physicians in this specialty and people living with HIV is how to choose the right therapy for now while still keeping in mind the need for future options when treatment fails. When you have cycled through the three classes of HIV drugs and treatment fails, the next choice of therapy is what we have dubbed "rescue regimens," which we will explain as we continue.
Nucleosides were the first members of the family of HIV drugs. They inhibit the activity of reverse transcriptase, a portion of HIV needed for the virus to replicate. Nucleosides are often the basis of multi-drug combinations. Protease inhibitors are the latest major addition to the family of HIV/AIDS antiretroviral treatments.
Non-nucleoside reverse transcriptase inhibitors, like their similarly named drug cousins, interfere with HIV's ability to reproduce. NNRTIs are now being used in combination cocktails as antiretroviral therapy to control HIV and slow the development of resistance. NNRTIs should be used only in combinations that are designed to maximally suppress the HIV virus as researchers, clinicians, and patients have learned that the potential for developing high-level resistance to NNRTIs can result from a single change in the HIV virus. Among these, Rescriptor also has the important ability to increase or boost the drug levels of other medications in combination therapy.
Protease -- a protein-cutting enzyme -- is a portion of the HIV virus in part responsible for the ability of the virus to infect healthy cells. Protease inhibitors block the protease enzyme, causing the HIV to reproduce itself in a form that cannot invade healthy cells. To develop resistance to the protease enzymes, HIV must develop many mutations. Therefore, this family of medications may be used when viral loads are very high.
One recent study in Hartford, Connecticut looked at 40 inner-city clinic patients to measure adherence. Researchers found that as the percentage of doses missed increased, the percentage of viral load increased as well. Specifically, when the percentage of dosage taken fell below 80 percent, the treatment success rate failed to be suppressed in one half of patients. For example, if a group of people are taking medicines twice a day (60 doses per month), and they each miss six days of the medicine in one month, half of them would be unable to suppress their viral load. Less than one third of patients taking less than 70 percent of their dosage had undetectable viral loads. Common causes of non-adherence include forgetting to take medication (57 percent), negative side effects (39 percent), feeling well/not feeling a need for therapy (22 percent), and suspecting that therapy is not working (20 percent).
One of the results of resistance, which should be considered in planning your HIV therapy, is cross-resistance. Research has shown that some drugs share similar mutation patterns which confer cross-resistance to other drugs within their class. Because of cross-resistance, you can get resistant to medications which you have actually never taken. Despite the large number of approved HIV medications, the number of sequential treatment options that will be effective for an individual patient is sharply limited by cross-resistance. Although each class of drug combats HIV in a different way, cross-resistance should be considered an important factor in selecting each treatment regimen. Knowing which options will exist for future regimens is critical in the long-term management of HIV.
Both of these tests have many pluses and minuses. Phenotyping, for instance, offers a direct measurement of HIV drug susceptibility and results, which can be easier to understand than genotyping results. However, these particular tests are expensive, slow, insensitive for minor virus populations and extremely difficult to conduct; in fact, phenotype tests are so difficult to conduct that they are considered an art form. Genotype tests, while quicker to perform and less expensive than phenotype tests, have their own limitations. Primarily, given the fact that more than 100 resistance mutations have been described, genotypic data does not always offer straightforward interpretations and may require the physician to have a lot of knowledge on how to interpret the findings. Despite their limitations, both of these tests can be extremely helpful in evaluating which drugs the virus has become resistant to and considering what future drugs might be effective and if higher drug levels will be beneficial. They also allow us to judge if a new drug class should be introduced.
To further explain boosting agents' utility in rescue regimens, it is helpful to first understand the way in which all protease inhibitors and NNRTIs are metabolized, or broken down and removed from the blood. Most PIs and NNRTIs are metabolized by the same system, or pathway, in the liver: cytochrome P-450. Some HIV medications slow down the liver enzymes like a plug might stop the water from going through the drain in a bathtub. This function allows the drugs using those enzymes to be broken down more slowly, boosting the level of these drugs within the body and allowing them to remain in the body longer.
Two antiretroviral drugs -- Norvir and Rescriptor -- possess this unique ability of inhibiting cytochrome P-450 and, in turn, boosting the levels of other drugs. Norvir has the greatest degree of success as a boosting agent among the PIs; it is an effective agent at boosting the levels of Invirase, Fortovase, Crixivan, Agenerase and Viracept. Kaletra contains a small dose of Norvir right in the capsule and is also considered a boosted combination. Among the NNRTIs, Rescriptor is the most successful boosting agent with select PIs; it is a valuable boosting agent when used in conjunction with Crixivan, Viracept, Agenerase, Invirase or Fortovase. Rescriptor is the only NNRTI effective in this role, as both Sustiva and Viramune do not boost the levels of PIs.
In addition, when using PI boosters such as Norvir and Rescriptor, certain facts must be considered. First, Norvir is a PI and Rescriptor is an NNRTI. Norvir has been associated with the following side effects: nausea, diarrhea, liver toxicity, high cholesterol and high triglycerides. Rescriptor, while only more recently observed for use in PI-boosting, appears to have a better side effect profile; it is free of significant gastrointestinal side effects, liver toxicity or cholesterol elevation but has been associated with an occasional rash.
One recent study, ACTG 359, evaluated Rescriptor's effect on the drug levels of several protease inhibitor combinations, including Viracept (NFV), Fortovase (SQV), and Norvir (RTV). The following combinations were studied both with and without Rescriptor: NFV + SQV; NFV + SQV + ADV; RTV + SQV; RTV + SQV + ADV. In this study, Rescriptor is shown to have significantly increased the drug levels of each combination. The percentage of patients with a viral load less than or equal to 500 who maintained a virologic response at 16 weeks was more than 10 percent higher across the board than those patients not receiving Rescriptor in their combination. At 48 weeks, the trend continued, showing that in the specific case of patients on the combination of NFV + SQV + ADV, the percentage of patients maintaining a viral load of 500 or less more than doubled with the addition of Rescriptor.
Both Norvir and Rescriptor can greatly enhance drug levels in a rescue regimen, with the effect of Norvir being somewhat more pronounced. Knowing when to select which one of these boosting agents can be the real challenge.
This study suggests that NRTI-resistance mutations may sensitize viral isolates to NNRTIs, making NNRTIs a sound choice for rescue therapy. It also supports the use of phenotypic resistance testing in nucleoside-experienced patients, as it may uncover hypersusceptibility for future therapy choices.
Sorana Segal-Maurer, M.D. is with the Division of Infectious Diseases, New York Hospital Queens in Flushing, New York. Malte Schütz, M.D. is with Triad Health Practice, Advocate Illinois Masonic Medical Center, Chicago, Illinois