Published in the Bulletin of Experimental Treatments for AIDS October 1998 issue, by the San Francisco AIDS Foundation.

October 1998 Table of Contents

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A New Approach to Initial Antiretroviral Therapy: Protease-Sparing Combination Regimens

Leslie Hanna

One of the most publicized topics at the 12th World AIDS Conference in Geneva this past summer was a novel approach to anti-HIV therapy: potent antiretroviral combination regimens that exclude protease inhibitors. Two years ago in Vancouver, BC, at the last international AIDS conference, the concept of the antiretroviral "cocktail" or combination regimen that included a protease inhibitor as a matter of course was more or less universally embraced.

What has happened since then? Why are people today discussing the possibility of not using protease inhibitors, when a mere two years ago, no one could wait to get access to them? After reviewing antiretroviral therapies as a whole, this article will focus on new protease-sparing treatment regimens.

Basics Antiretroviral Treatment Options

The topic of protease-sparing regimens fits into an overall discussion of treatment decision-making and strategies.

To date, 12 antiretroviral drugs have received U.S. Food and Drug Administration (FDA) approval for the treatment of HIV infection; these form the mainstay of the HIV treatment repertoire. They are AZT (Retrovir), ddC (Hivid), ddI (Videx), d4T (Zerit), and 3TC (Epivir), the nucleoside analog reverse transcriptase inhibitors, or NRTIs; saquinavir (Invirase or Fortavase), ritonavir (Norvir), indinavir (Crixivan), and nelfinavir (Viracept), the protease inhibitors; and nevirapine (Viramune), delavirdine (Rescriptor), and efavirenz (Sustiva), recently FDA-approved on September 18, the non-nucleoside reverse transcriptase inhibitors, or NNRTIs. This is the primary pool of drugs from which people with HIV and their physicians choose when devising combination antiretroviral regimens.

There are additional drugs that may be used to treat HIV that are available through expanded access programs but which are not yet FDA-approved for that use. These include amprenavir (Agenerase), abacavir (Ziagen), and adefovir (Preveon), antiretrovirals in development that look promising and that are expected to receive FDA approval in the near future. Still other drugs used to treat HIV that are not approved for that indication include hydroxyurea and immunomodulators, e.g., interleukin 2. Finally, there are a number of other anti-HIV drugs just entering or in the early stages of clinical development, that may soon be added to the so-called armamentarium of anti-HIV medicines.

Cross-resistance is an increasingly important consideration for people evaluating anti-HIV treatment options. Cross-resistance means that once resistance to one drug of a given class has developed, it is conferred upon other drugs of the same class, which cease to be potent treatment options.

Although the newer ("second generation") drugs in any given class tend to be more potent inhibitors of HIV replication than their predecessors, an individual who has taken and failed on earlier members of that class may be less able to benefit from the improved action of newer class members. As people with HIV/AIDS live longer and try various anti-HIV treatment options, cross-resistance is an increasingly significant barrier to the success of new treatments.

Strategic Maneuvers

For several years, a basic and ongoing debate has concerned when to initiate anti-HIV treatment, and how many drugs to use. This debate is particularly relevant for people who seroconverted months or even years earlier, in contrast with recent seroconverters.

The debaters may be divided into two basic camps. One is the "hit early, hit hard" camp promulgated by David Ho, MD, which favors early, aggressive treatment for all people with HIV, even those with little to no immune system damage. Underlying this approach is the philosophy that the most important aspect of HIV treatment is to suppress the virus as completely as possible, as soon as possible. An example of a treatment strategy that accords with this thinking is combination treatment that includes two protease inhibitors (along with other drugs) as soon as possible after learning of HIV seroconversion.

The other camp holds a more conservative "hit hard when necessary" position. Proponents in this camp favor deferring treatment until an HIV positive person’s clinical or immunological markers suggest that the person is at higher risk of more rapid disease progression. An example of such a decline in health might be indicated by a consistent (i.e., seen on more than two tests in a row) decrease in CD4 cell numbers or increase in viral load.

Valid arguments may be made to support both positions (the aggressive early vs deferred treatment strategies), depending on how one interprets the research data, although cumulative data favor beginning somewhat earlier rather than later. This is because continued HIV replication clearly causes ongoing immune system damage, which facilitates the development of advanced HIV disease or AIDS. Although the eradication of HIV has not been achieved with currently, available therapies, reducing or halting HIV replication is clearly beneficial. The question really is, then, how early is early enough?

A subset of considerations relates to the time of HIV seroconversion. That is, the decision-making process about antiretroviral treatment is likely to be different for recent seroconverters, compared with people who have been living with HIV for a long or indeterminate period of time when they begin considering antiretroviral therapy. Still -- regardless of time of seroconversion -- once an individual has definitely decided to begin antiretroviral therapy, the best strategy appears to be to begin with three drugs.

Overall, there are no conclusive data to suggest a definitive best treatment strategy. This lack of a treatment approach that can be globally applied has led to the promotion of the concept of individualization of HIV therapy. On some level, individuals and their physicians must make the treatment choices that fit their best understanding of the data, as well as their overall preferences (i.e., based on self-knowledge and comfort with risks and uncertainties). Certainly, it behooves individuals with HIV to seek information that will allow them to make the best-informed choices possible, and to stay abreast of new treatment developments; implicit in these idealized scenarios is the critical factor of access to health care.

Regarding the number of drugs to use, all experts today agree that combination antiretroviral therapy is better than monotherapy. The question is, what number of drugs is optimal? Three? Four? More? Another question is, which drugs are best used in combination? Recently, some experts have suggested that omitting protease inhibitors altogether from some antiretroviral regimens, particularly initial treatment regimens, may be appropriate for some patients. This new concept aroused widespread interest at the Geneva conference.

Protease Inhibitor Problems

Protease inhibitors remain among the most important HIV disease treatments yet developed. To date, four protease inhibitors have been approved by the FDA for the treatment of HIV disease, and more are in various stages of research and development (R&D) at pharmaceutical companies and universities. Protease inhibitors continue to play a significant role in treating HIV disease. Already, protease inhibitor use has greatly benefited the health and lives of tens of thousands of people.

Yet protease inhibitors are not without problems, many of which have clearly emerged over the past two years. There is a high degree of cross-resistance among the drugs, they must be taken several times daily according to a strict schedule, and they can involve significant side effects.

Because of the pharmacokinetics of protease inhibitors, the drugs must be taken at very strict and regular intervals, both for anti-HIV efficacy as well as to avoid the dire consequence of antiviral resistance. The strict dosing regimens demanded by the drugs have spurred discussions about adherence, and have motivated drug company R&D teams to try to design drugs that may be taken less frequently or less strictly. Not surprisingly, but unfortunately, many people who have missed doses for whatever reason may have begun to set up conditions that promote the development of HIV resistance, or have already developed full-fledged resistance and cross-resistance, such that the drugs are no longer effective.

Some people in need of potent antiretroviral therapy are unable to take protease inhibitors because they cannot tolerate the more notable side effects, e.g., severe nausea or diarrhea.

Another significant side effect possibly associated with protease inhibitor therapy is disrupted fat metabolism. This may involve hyperlipidemia, the development of dangerously elevated blood levels of triglycerides and cholesterol, which carries a secondary risk of cardiac problems including, potentially, heart attack. Already, there has been at least one report of a heart attack in an HIV positive person with protease inhibitor-related hyperlipidemia -- a man only 26 years old.

Another manifestation, lipodystrophy, involves the redistribution of body fat that results in noticeable physical changes in some people. These changes have been given names such as "buffalo hump" and "protease paunch," and are characterized by accumulations of fatty tissue at the back of the neck, in the breasts, or on the abdomen or lower torso. These developments are sometimes accompanied by loss of subcutaneous fat in the face, and wasting of the buttocks and extremities. First noted over the past few years, lipodystrophy is tentatively, although not conclusively, attributed to treatment with protease inhibitors. Another serious side effect associated with protease inhibitor use is diabetes, which some people taking the drugs have developed.

Australian researchers David Cooper, MD, and Andrew Carr, MD, have published data indicating that protease inhibitors are likely to affect human enzymes as well as the HIV protease enzyme. The undesired effect is a disruption of normal lipid (fat) metabolism. Donald Kotler, MD, AIDS researcher and chief of gastrointestinal immunology at St. Luke’s-Roosevelt Hospital in New York City, on the other hand, believes that there may be another explanation. Effects like "buffalo hump," he says, are not unique to people with HIV who take protease inhibitors, or even to people with HIV. Rather, the effects may be due to long-term or chronic viral infection. Kotler emphasizes that fat redistribution is seen in other chronic infections.

Many people have taken protease inhibitors without developing serious side effects and their health status has improved while taking them, but for a markedly finite amount of time before their immunological markers indicate that benefits are waning. That is, CD4 cell counts have begun to fall and viral loads have begun to rise.

For all of their limitations, protease inhibitors will continue to play a vital role in treating HIV. Questions about when to begin using them, as well as how best to use them, are becoming increasingly important.

New Research, New Approaches

Protease-sparing regimens are of interest for a number of reasons, which stem in large part from the fact that many HIV positive people may be taking antiviral therapy for decades. Chronic antiviral therapy poses several potential problems, which people need to plan around and manage, if necessary. One problem, currently associated with protease inhibitor therapy, is abnormal fat metabolism, described in the previous section; one motive behind the new, protease-sparing strategies is the possibility of evading this side effect.

Yet another reason would be to reserve the potent protease inhibitor class of drugs for use later. Another impetus is to reduce the number of pills taken daily. Research that addresses these concerns has just begun.

Following is a review of the trials presented in Geneva that many experts, including Donald I. Abrams, MD, of the University of California at San Francisco, consider to be the most significant with regard protease inhibitor-sparing regimens. So far, results of three key studies have been presented that directly relate to, and so far support, the idea of protease-sparing regimens.

Most results are considered preliminary and cannot yet address whether or not lipodystrophy will occur as a side effect of protease-sparing regimens.

Abacavir, AZT, and 3TC

Margaret Fischl, MD, presented data on a study of the safety and activity of the new nucleoside analog abacavir, formerly known as 1592U89, manufactured by Glaxo Wellcome. The study was randomized, double-blind, and placebo-controlled. Participants received combination treatment with either abacavir/AZT/3TC or AZT/3TC. The people in this study were all antiretroviral-naïve, i.e., they had never before used these or any other antiretroviral drugs, and they had greater than 100 CD4 cells/mm³. The results were based on virologic responses after 16 weeks of treatment. After 16 weeks, people whose HIV RNA levels were greater than 400 copies/mL were allowed to switch to open-label abacavir plus other approved drugs.

Of 173 participants, 87 received the triple regimen that included abacavir, and 86 received the double regimen. Both arms were fairly equivalent in terms of CD4 count at baseline (473 and 427, respectively) and after 16 weeks (both arms increased by 100 CD4 cells/mm³). The biggest difference was in terms of viral load; those taking the double combination experienced an initial viral load decrease that drifted back to baseline by week 8, whereas those taking the triple, abacavir-containing combination had a 2-log decrease in viral load at week 16.

Furthermore, the proportion of people whose viral load dropped below a target threshold was higher in the triple combination arm. Of people taking the 3-drug combination, 75% dropped below 400 copies/mL (became "undetectable" according to the commonly used viral load assay) and 54% dropped below 50 copies/mL (became "undetectable" according to an ultrasensitive viral load assay), compared to 35% and 15%, respectively, in the 2-drug arm.

Results were analyzed several ways. According to an intent-to-treat analysis, 54% of the participants taking three drugs had fewer than 50 copies/mL, while according to an on-treatment analysis, 67% of those taking three drugs had fewer than 50 copies/mL at 16 weeks (see Conference Coverage for an explanation of intent-to-treat and related statistical issues).

In multiple clinical trials conducted to date, hypersensitivity (sometimes referred to as allergic) reactions have been noted to occur in about 3% of people taking abacavir. Fever and pain precede by two to three days rash and lymph node enlargement, all of which characterize hypersensitivity. The development of fever and pain in any person taking abacavir may indicate the early stages of a hypersensitivity reaction; therefore, any such person should immediately seek medical attention. In this study, researchers reported that the triple regimen (abacavir/AZT/3TC) was well tolerated overall, with only two people developing strong hypersensitivity reactions. Approximately 11% of the participants in the study discontinued abacavir due to adverse events. The current approach is to monitor for signs of hypersensitivity, and to discontinue abacavir if these develop. Rechallenge with abacavir (trying again after stopping the drug) is contraindicated for people who have developed hypersensitivity reactions, which may be life-threatening.

The general conclusion of the study was that the triple combination of abacavir/AZT/3TC is as potent and effective as other triple combinations that include either a protease inhibitor or a NNRTI. It should be noted that all three drugs target the same step in viral replication (the reverse transcriptase enzyme), and therefore may be of limited utility over the long run. Still, this combination may provide effective treatment that allows a person to defer or save for later the potent classes of protease inhibitors and NNRTIs.

At this time, conclusions are considered preliminary. If future study findings bear out current hopes, then abacavir may become a favored first-line HIV treatment. A 48-week Glaxo Wellcome trial that will produce better, more clinically interesting information began earlier this year. In this trial, abacavir/AZT/3TC will be compared with another triple regimen, indinavir/AZT/3TC. Investigators will also measure fat levels and collect data on the occurrence of lipodystrophy.

Efavirenz-Based Approaches

Several presentations concerned efavirenz, the drug considered by many to be "the star of Geneva," says Abrams. Formerly known as DMP-266, efavirenz is a NNRTI manufactured by DuPont Pharma.

The most significant study presented in Geneva involved combinations of efavirenz, AZT, and indinavir. Sponsored by DuPont Pharma, results of the "006 trial" were presented publicly for the first time by Schlomo Staszewski, MD. The results were based on data collected to 24 weeks. The ongoing study will collect and ultimately produce results from data gathered over longer periods of time; 36-week data were presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September [editor’s note: not available at press time].

Participants were asymptomatic or mildly symptomatic at entry and naïve to protease inhibitors, NNRTIs, and 3TC; prior experience with any nucleoside analog other than 3TC was permitted. There were 450 people at entry, with a mean CD4 count of 345 cells/mm³ and a mean viral load of 4.8 logs. There were about 150 people in each of three arms: indinavir/AZT/3TC, efavirenz/AZT/3TC, and efavirenz/indinavir.

At the end of 24 weeks, all participants had experienced a 2-log reduction in viral load and a CD4 cell count increase of about 130 CD4 cells/mm³. The real difference in results between the regimens was in the number of participants whose viral load fell below 50 copies/mL, or whose viral load became undetectable; this is where the efavirenz-containing triple regimen was seen to have a slight statistically significant advantage over the indinavir-containing triple regimen.

RESULTS OF THE 006 TRIAL

Overall conclusions were that the protease-sparing triple combination treatment regimen of efavirenz/AZT/3TC produced antiviral results that were better than those of the triple combination that included a protease inhibitor. Thus, the efavirenz regimen may become a significant, powerful initial treatment option.

The study had some features that limit the interpretation of results. One of the limitations is the study's length -- results were only available to 24 weeks. Others are that compliance with indinavir was not measured and the indinavir arms had a large drop-out rate; it is thought that data collected from the arms that included indinavir may not reflect the actual potency of that treatment.

As requested by the FDA, the investigators did an intent-to-treat analysis of the study results. In an intent-to-treat analysis, people who drop out for any reason, sometimes called noncompleters, are regarded as treatment "failures." Since treatment failures are part of a catch-all category, they include people who could not tolerate side effects as well as people who decided they wanted to try another treatment regimen.

In this study, most of the people who dropped out had viral loads greater than 50 copies/mL, so it is plausible that these people dropped out because they decided that their treatment regimen was not working, at least as well as they wanted it to. They may have had side effects that caused them to discontinue. Some HIV treatment advocates have suggested that one reason the indinavir arms did not produce such good results is because of compliance problems; if adherence to indinavir had been 100%, then the numbers would likely have been much more favorable for the indinavir-containing regimens and not nearly as favorable for efavirenz. Side effects may be worse for indinavir; also, the number of pills required is higher. Thus, an intent-to-treat analysis is believed to produce results that most accurately reflect what happens in the real world.

Efavirenz just received FDA approval, on September 18. For information about efavirenz payment assistance, call 800-334-4486. Other information, including the text of the package insert, may be found on the Internet at www.sustiva.com. One of efavirenz’s most attractive features is that it is taken just once daily, with or without food. The efavirenz/AZT/3TC regimen features the very attractive benefit of reduced numbers of pills to be taken, i.e., this regimen requires taking only four pills daily. Again, one of the reasons this triple combination produced such positive results in the study may be that participants had an easier time adhering to the simpler regimen, and therefore took all their pills.

A final note: since efavirenz decreases indinavir blood levels, indinavir doses must be increased when taking efavirenz.

Hydroxyurea-Based Approaches

Hydroxyurea, a drug developed originally for cancer, is rapidly becoming an important treatment option for HIV (see Drug Watch). Another key study, presented in Geneva by Sergio Lupo, MD, looked at hydroxyurea as a first-line treatment. This international study is the largest controlled hydroxyurea-based study conducted to date.

Hydroxyurea works well when used with ddI because of a favorable interaction between the two drugs. Although ddI is the drug most commonly used in combination with hydroxyurea, other drugs that are being studied for use in place of ddI include adefovir, abacavir, and 3TC. (For instance, results of another study reported as effective the combination of hydroxyurea, d4T, and 3TC.) In Lupo’s study, 183 participants received some combination of the drugs d4T, AZT, hydroxyurea, and ddI. Participants had an average viral load of 40,000 copies/mL at baseline, which is considered a relatively moderate to low viral load at entry. They were randomized to one of four treatment arms: 1) ddI/AZT, 2) ddI/d4T, 3) ddI/hydroxyurea, or 4) ddI/d4T/hydroxyurea. Three-quarters completed 24 weeks of treatment, at which time viral load information was obtained for 118 participants.

After 24 weeks of treatment, 50-60% of the participants experienced viral load decreases below 400 copies/mL, the limit of detection. The greatest viral load decrease, about 2 logs, was seen in the ddI/d4T/hydroxyurea arm.

The non-hydroxyurea-containing regimens produced better CD4 cell increases. People taking AZT/ddI experienced increases of about 100 cells/mm³; those taking ddI/d4T, about 90 cells/mm³; those taking ddI/hydroxyurea, about 17 cells/mm³; and those taking ddI/d4T/hydroxyurea, about 30 cells/mm³. The reason for this is that hydroxyurea suppresses bone marrow, and thus can cause lymphopenia (low levels of white blood cells, of which CD4 cells are a subset). The additive bone marrow toxicity caused by hydroxyurea and AZT is why the drugs should be used cautiously in combination. Also, pregnant women are advised to refrain from using hydroxyurea, which has deleterious effects on fetuses. The slightly lower relative increase in CD4 cell counts does not discourage researchers, who are interested in hydroxyurea-containing combinations for their powerful ability to decrease HIV viral load.

Lupo stated that the results from those using hydroxyurea/ddI/d4T were "comparable to results from trials of protease inhibitor-containing regimens." The study investigators concluded that the protease-sparing combination of hydroxyurea/ddI/d4T produced significant viral load reductions compared to ddI/hydroxyurea, and that hydroxyurea works best when combined with both ddI and d4T. This approach spares two important classes of treatment options, the protease inhibitors and the NNRTIs, allowing them to be reserved for subsequent treatment.

Other Relevant Study Results from Geneva

Robert Curry, MD, and others presented results of a laboratory study that tried to gauge how well people who initially took a protease-sparing antiretroviral regimen would be suited to subsequent take a protease inhibitor-containing regimen. To do so, investigators obtained 24 plasma specimens from patients who had been treated with initial nevirapine/nucleoside analog combination regimens and who had developed resistance to nevirapine. They then tested the specimens with the VIRCO test for phenotypic resistance to examine how responsive to protease inhibitors the HIV strains from those people were.

All 24 sample strains of HIV, all with high-level nevirapine resistance, were fully susceptible to the four approved protease inhibitors (indinavir, nelfinavir, saquinavir, and ritonavir). In a clinical follow-up, the viral load and CD4 cell counts of 40 adults and 19 children with similar nevirapine resistance and protease inhibitor susceptibility patterns responded optimally; the mean viral load decrease was 1.5 logs and the mean CD4 cell increase was 144 cells/mm³. These results support the idea of initial antiretroviral treatment with combinations of NNRTIs and nucleoside analogs, an approach that allows the person to reserve protease inhibitors for later.

In Conclusion

The protease-sparing regimens discussed in this article represent some of the newest regimens on the block. In some of the studies, 3-drug protease-sparing regimens appeared as potent as protease inhibitor-containing regimens. There are other combination regimens that exclude protease inhibitors and appear to be potent anti-HIV regimens, such as delavirdine/AZT/3TC and nevirapine/d4T/ddI; research will continue into these regimens and others.

While it is clear that initial anti-HIV therapy that excludes a protease inhibitor is promising, it is not yet clear how durable the beneficial responses seen in these short studies will be. It also is not yet clear if this approach will avoid side effects such as lipodystrophy. Upcoming studies will provide more data and understanding of these HIV treatment issues.

Curry, R. and others. Retained effectiveness of protease inhibitor (PI) therapy (Rx) following "protease sparing" nevirapine/nucleoside (NVP/nuc) combination therapy. 12th World AIDS Conference. Geneva, Switzerland, June 28-July 3, 1998. Abstract 12231.

Federici, M. and others. Hydroxyurea in combination regimens for the treatment of antiretroviral-naive, HIV-infected adults. 12th World AIDS Conference. Geneva, Switzerland, June 28-July 3, 1998. Abstract 287/12235.

Fischl, M. and others. Safety and activity of abacavir (1592, ABC) with 3TC/ZDV in antiretroviral naïve subjects. 12th World AIDS Conference. Geneva, Switzerland, June 28-July 3, 1998. Abstract 127/12230.

Staszewski, S. and others. A phase II, multicenter, randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus EFV plus zidovudine (ZDV) + lamivudine (3TC) versus IDV + ZDV + 3TC at 24 weeks [DMP-266-006]. 12th World AIDS Conference. Geneva, Switzerland, June 28-July 3, 1998. Abstract 22336.

Page last updated 6 October 1998

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