Rescue Regimens: The Value of Protease-Inhibitor Boosting
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.
In order to fully understand the concept of rescue regimen therapy, we must first identify what necessitates rescue therapy: resistance. Achieving long-term treatment success depends largely upon planned sequential use of multi-drug combinations called HAART, highly active antiretroviral therapy. At this point in the evolution of anti-HIV/AIDS therapies, there are three classes of antiretroviral drugs approved for the treatment of HIV. The three principal HIV/AIDS antiretroviral drug classes are: nucleoside reverse transcriptase inhibitors (nucleosides), protease inhibitors (PIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs).
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.
The goal of antiretroviral therapy is to completely suppress viral replication and delay -- or even prevent -- drug resistance. Resistance in HIV therapy is defined as the virus' failure to respond following treatment and the subsequent active reproduction of itself. An increasing viral load is often the first sign that HIV drug resistance has developed. Below are three major reasons that HIV is able to develop resistance to a given treatment:
Weak treatment regimens: If the drug combination prescribed is not strong enough to block HIV completely, drug resistance can develop. Higher drug levels may be required from future therapies to effectively suppress the virus.
Inadequate dosage levels: Different people taking the same dose of the same medicine will often absorb or break down those medicines differently, which may result in low drug levels, which in turn may lead to the development of resistance.
Poor treatment adherence: Missing doses, taking them late or not following the food instructions with medications can lead to resistance, as it often results in low drug levels. Just a few missed doses of a drug can cause drug resistance. In such cases, a random mutant virus can become the dominant virus in the person's system, causing the body to develop resistance to that drug.
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.
Once you have experienced a viral load rebounding after HIV treatment, future treatment options may become more limited. The best way to determine which combinations will be effective at this point is through resistance testing. Two methods of testing currently exist: genotype testing and phenotype testing. Genotyping maps out the reverse transcriptase and protease inhibitor genes to determine resistance mutations to specific drugs. By doing this, you are able to assess HIV drug resistance based on genetic indicators, or letters of the code, which have mutated. Phenotyping more directly measures resistance by examining the ability of HIV to grow in the presence of each of the available drugs. Phenotype testing is conducted by growing recombinant HIV virus with the patient's resistance pattern in a test tube in the lab. These tests then measure resistance by adding antiretrovirals to the culture medium to determine which are susceptible to the virus.
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.
Rescue Regimens and PI Boosting
Rescue regimen is a term used for therapy alternatives following a viral load rebound from all three classes of antiretrovirals. What to choose as a rescue regimen can be challenging. As the previous section has outlined, resistance mutations limit these options significantly. The addition of a new class, when available, is a unique opportunity to suppress the virus, but currently only three classes are available. In addition, higher drug levels are a strong consideration in a rescue regimen, as these higher drug levels may help to overcome resistance. Furthermore, boosting agents can help simplify the dosing of protease inhibitors, such as fewer doses of Crixivan when it is combined with Norvir or Rescriptor.
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.
Hypersusceptibility can be another reason for the addition of an NNRTI in a rescue regimen. Hypersusceptibility occurs when the virus has become extremely susceptible, or vulnerable, to a medication. Often, a patient who has experienced resistance to nucleosides and protease inhibitors may respond well, in terms of HIV suppression, to the addition of an NNRTI in rescue therapy. Several studies lead us to believe that it is nucleoside-resistant mutations in the reverse transcriptase gene which may confer hypersusceptibility to NNRTIs. One such study is CCTG 575, which indicated that patients who had at least six months experience on antiretroviral therapy, including at least one nucleoside, showed hypersusceptibility to the introduction of an NNRTI in phenotypic testing. In the specific case of Sustiva, those with Sustiva had significantly lower viral loads by month two when compared with those without the Sustiva-hypersusceptible virus. Furthermore, by month four, there were also markedly higher increases in CD4 cells for hypersusceptible patients.
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.
Where Do We Go from Here?
PI boosters such as Norvir and Rescriptor can play a significant role in rescue therapy since higher drug levels can help in overcoming resistance. Long-term planning can have an immense impact on future therapy options, which can become critical as resistance mutations limit the choice of medications available in rescue therapy. You should speak with your physician about which treatment strategy and rescue regimens will prove most tolerable and effective.
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