PI Perspective #26

December 1998     View PDF     En español

Strategies: Protease-Sparing Regimens

Since the Geneva International AIDS Conference, the notion of using therapy combinations which delay the use of protease inhibitors has been a hotly debated topic. The rationale for protease-sparing regimens is to use a three-drug combination that reduces viral load below the limit of detection while saving protease inhibitors for later use.

The theoretical advantage of a protease-sparing regimen is not only that it saves the most potent therapy for later use, but that it also delays the risk of side effects associated with long-term use of protease inhibitors. Those who promote the protease-sparing regimens believe that this makes for a better long-term strategy and may extend the length of time that drugs are effective.

Not everyone agrees with the rationale behind protease-sparing regimens. Some researchers still believe that the best shot a person has against HIV infection is the first shot. They argue that even initial therapy should begin with our strongest anti-HIV drugs. This, they believe, will result in the longest duration of effective therapy while also introducing the most potent drugs at a time when the patient is in the best health and best able to fend off side effects. At the moment, there simply is no hard data to say which of these strategies will help a person live longer. They are simply matters of opinion.

In recent months, the promotion of protease-sparing regimens, particularly with the use of efavirenz (Sustiva), has reached a fever pitch. Many doctors are routinely using the efavirenz regimen as a first choice for people just starting therapy, and some cases, taking people off of protease inhibitor combinations in favor of an efavirenz combination.

The data which serves as the primary justification for using the efavirenz / protease-sparing regimen is a single trial in people who have never previously taken anti-HIV therapy which compared the efavirenz combination to a typical indinavir (Crixivan) combination. That study, reported in PI Perspective #25, seemed to show the efavirenz combination to be equal, if not superior, to the indinavir combination. Even though the simplicity of use offered by efavirenz is a real benefit, there is good reason for caution in making wholesale judgments about the value of this approach. They can be easily summarized:

• The principle efavirenz vs. protease inhibitor study has officially reported results from only 24 weeks of follow-up. Unreviewed data extends this to 36 weeks. In comparison, protease inhibitor studies now show durable treatment response over two years of follow-up, even in people who have previously used anti-HIV therapy.
• Because efavirenz was easier to use than indinavir (once daily dosing vs. 3 times daily without food), it is not clear whether the study outcome is a result of efavirenz being a more potent drug or a result of better adherence. If better adherence explains the outcome, then these study results are not applicable to patients who are able to adhere effectively to an indinavir regimen.
• The principle efavirenz vs. protease inhibitor study was “open label” rather than “blinded.” This means that patients and physicians alike knew which drug the patients were getting (referred to as “open label”). Many people joined this trial primarily to gain access to efavirenz. When they got indinavir instead of efavirenz, some dropped out yet were counted ultimately as “failures” on indinavir. This may have produced bias in the results of the study. In any case, open label studies are never considered to be as reliable as double-blinded studies (studies where neither the participants nor the personnel of the research site know what therapy is being received in an attempt to eliminate bias).
• Efavirenz (like nevirapine and delavirdine) presents a “low genetic barrier” to drug resistance. This means that the appearance of a single genetic mutation can completely cripple the drug’s effectiveness. In contrast, protease inhibitors like indinavir typically require 2 or 3 or more mutations before complete failure. Consequently, many researchers wonder whether efavirenz combinations will remain effective as long as a typical protease inhibitor combination. It may work very well initially, but the real question is how well will it hold up over time?
• The group that received indinavir in this study performed more poorly than people in almost any other indinavir study. In other studies of similar patient populations given the same indinavir combination, a significantly greater percentage of people reached and sustained viral suppression below the limit of detection. Why the indinavir group performed weakly in this study is unclear, but it is evident that the experience with indinavir was not typical.

Promoters of the efavirenz combination also strongly imply that efavirenz is a better choice for such protease-sparing regimens than other drugs in this class, notably nevirapine and delavirdine. Salesmanship aside, there is simply no evidence to support this view. No studies have directly compared efavirenz to other drugs in its class. Both nevirapine and delavirdine came to market with the reputation of being somewhat weaker than protease inhibitors, but this perception was derived primarily from studies which used them in inadequate, two-drug combinations.

Subsequent three-drug combinations using either drug as the anchor for a regimen have shown results similar to the efavirenz study in regards to the percentage of people who achieve viral load below the level of detection. Since efavirenz has been priced nearly 60% to 70% above nevirapine and delavirdine respectively, the comparative value of these three drugs is important. Until directly comparative studies are run, there is no valid basis for suggesting that any one of them is superior to any other. In other words, people contemplating the use of a protease-sparing regimen should not automatically assume that such a regimen must be based on the use of efavirenz.

Whether efavirenz, delavirdine or nevirapine is used as an anchor for a protease-sparing regimen, it is important to use any of these drugs in combination with at least two nucleoside analogue drugs (e.g. AZT [zidovudine, Retrovir], ddI [Videx], d4T [Zerit], etc.) which are new to the individual. A brief comparison between the three non-nucleoside reverse transcriptase inhibitors is provided in the article on “Protease Sparing Regimens.”

While the three drugs are probably roughly equivalent, no head-to-head comparative studies have yet been conducted. Some issues to consider when making a decision about the three drugs might include their dosing schedules, side effect profiles and drug interactions.

Efavirenz is probably the easiest drug to use, requiring only once daily dosing. Of the three drugs, it probably has the most side effects, however. Like the protease inhibitors, efavirenz has been shown to elevate triglycerides and cholesterol levels, in some people. People considering a protease-inhibitor-sparing regimen because of fears the long-term effects of elevated cholesterol and triglyceride levels should be aware that this is also a potential side effect of this drug. Moreover, efavirenz use is associated with neurologic side effects, including bizarre dreams, feelings of disorientation and feelings of being “hungover.”

Delavirdine is commonly being used as an adjunctive therapy to a protease inhibitor containing regimen, to modulate the blood levels of other drugs to allow for decreasing dosing. In general practice today, delavirdine is rarely the cornerstone of a triple-drug regimen. This was because early studies were not conducted using delavirdine in a three-drug regimen (only in two-drug regimens) and its effective was under question. More recent study results, where delavirdine was used in a three-drug combination, showed that it was potent when used in an optimal strategy regimen with two other drugs. While it requires three times daily dosing, it is probably causes the least side effects of the three drugs. While both delavirdine and nevirapine has rash as the most common side effect, the incidence of rash is much lower among people using delavirdine.

Nevirapine requires only twice daily dosing, making it easier to take than delavirdine and because it doesn’t have the additional neurologic and metabolic (e.g. increasing cholesterol/triglycerides) side effects of efavirenz it is increasingly being used as the “middle ground” option for people choosing a protease-inhibitor-sparing regimen, particularly for people who are co-infected with HIV and hepatitis or who have other signs or symptoms of impaired liver function.

While not a concern in protease sparing regimens, an additional point to consider arises when efavirenz is used in combination with a protease inhibitor. When used in combination, the drug substantially diminishes the level of some protease inhibitors. Indinavir levels are reduced by 31% and saquinavir (Fortovase) levels are reduced by 62%. As a result, when efavirenz is combined with either of these protease inhibitors, the dose of the protease inhibitor needs to be adjusted. Nevirapine (Viramune) will also, to a lesser degree, reduce indinavir and saquinavir levels, while delavirdine (Rescriptor) has the opposite effect, increasing the blood levels of some protease inhibitors. This property of delavirdine may allow for either reduced doses of protease inhibitors or increased potency.

Commentary
None of these concerns rule out the use of efavirenz or protease-sparing regimens in general. The unresolved question of long-term durability applies equally to all drugs in the non-nucleoside class and lead some researchers to believe that the best use of this class of drugs will be in combination with protease inhibitors, rather than as an alternative. It is critical to remember that if a patient develops resistance to any of the three current non-nucleoside drugs in a protease-sparing regimen, this class of drugs will not be useful later in the course of HIV disease.

The bottom line is that no one has adequate information to make proven recommendations about the use of these protease-sparing regimens, or about the comparative value of efavirenz, nevirapine and delavirdine. For some people, the simpler dosing regimens offered by all the non-nucleosides may be a compelling, overriding factor in choosing a combination. For others, concerns about the long-term outcome may outweigh factors of convenience. Given a few more years and a few directly comparative trials, people may not have to choose in this manner, but for now, it is all that the data will allow.

Standard Dosing Schedule

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