Research Initiative Treatment Action (RITA!); Vol 5, No. 4 October 1999
L. Joel Martinez
The treatment history of HIV/AIDS, at least in the mainstream of U.S. medicine, has been a rough process of piling up pills in the hopes of producing better clinical results.
After round-the-clock zidovudine monotherapy had run its course, clinicians and scientists declared "two, better than one," and "three, better than two," when referring to the therapeutic efficacy of antiretrovirals.
Protease inhibitors and viral load tests put the brakes on the escalation. Highly active antiretroviral therapy (HAART), generally consisting of three drugs, seemed to do the trick—for some patients, for the moment, at least. For other patients, for whom three and four drugs have not controlled the rage of viral replication or have contained it only temporarily, the next treatment paradigm has yet to be determined.
There has been an effort to purge the terms "salvage" and "rescue" when describing the subsequent treatment options for those patients who have virologic breakthrough on various drug regimens. The more accurate, though less dramatic, "second" and "third line" therapies have become the preferred descriptions.
In any case, the situation for those needing subsequent therapies is a serious one requiring immediate attention.
The Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents developed by the Panel on Clinical Practices for Treatment of HIV Infection state that optimal therapy should achieve viral load levels that are "undetectable, that is, below 500 copies of HIV RNA per ml of plasma."
Having failed to achieve this goal of an unquantifiable viral load once, twice, maybe even three times, to what lengths should the clinician and patient go to achieve this numerical goal? Scientific evidence now points to viral load levels that are even lower (below 50 and 20 copies) as the only acceptable levels, complicating the matter further. Are other goals then acceptable, especially in the context of second and third line therapies?
If the doctor and patient are to pursue goals other than some level of unquantifiable viral load, the nature of these goals is yet to be clearly defined. Improved clinical outcome is the ultimate goal; without other guidance, many clinicians are still pursuing an optimal or at least improved surrogate marker result.
Triple drug therapy is an odds wager. By combining drugs that have different resistance profiles the odds that any single virus particle will have all the mutations necessary to outmaneuver all the drugs at one particular moment is great. Only the luckiest of viruses would arise armed with all the shields necessary to dodge the many antiretroviral bullets.
Why do patients experience virologic breakthrough with HAART despite these odds? Resistance sufficient to overcome combination drug therapy arises when HIV replication occurs despite the presence of drugs. Mutations may preexist in the patient if, for example, drugs were prescribed sequentially as was done before the advent of HAART therapy or when suboptimal levels of drugs are created either through nonadherence by the patient, deleterious drug interactions or aberrations of absorption or metabolism.
If HIV has acquired several of the mutations before the initiation of HAART, it can more easily develop other mutations necessary to escape the drug regimen altogether.
One strategy that has been proposed is a continuation of the historical trajectory of treatment—namely, more and more drugs. Mega-HAART (more recently called GIGHAART in a clinical study) is a strategy in which patients take anywhere from 6 to 9 antiretroviral drugs.
Several clinicians have reported success with the use of this everything-including-the-kitchen-sink method. In a summary report of the Second International Workshop on Salvage Therapy for HIV (Toronto, May 1999), Steven Deeks, MD, reports on prospective, observational studies conducted by investigator Julio Montaner, MD, of Canada.1,2 In one of these studies patients who had been heavily pretreated received nine antiretroviral drugs, including four nucleoside analogs, two protease inhibitors, two non-nucleoside inhibitors and hydroxyurea (Hydrea). Forty-four of 88 patients had at least one viral load measurement below levels of quantification (the numerical limit of quantification was not given). Of those patients, forty-five percent remained suppressed for a median of 30 weeks. Similar results were reported by Grossman, et al3 in a cohort of 34 patients in which "complex protective regimens" consisting of 6 to 8 drugs, including abacavir (Ziagen), adefovir and efavirenz (Sustiva) were given.
A study with less favorable results was reported by French clinician Christine Katlama, MD, at the Third International Workshop on HIV Drug Resistance & Treatment Strategies held in San Diego this past June.4 In that study patients who had failed multiple HAART regimens and showed evidence of high levels of resistance to multiple drugs in all classes as evidenced by both genotypic and phenotypic tests were placed on therapy consisting of eight or 9 drugs. In contrast to the Montaner study cited above, the Katlama study included only 13 patients. The median viral load for this group of patients was 180,000 copies and the median CD4 T cell count was 80.
Not surprisingly, seven of 13 patients discontinued therapy before week 12 due to a combination of drug intolerance and opportunistic infections. However, despite the fact that ten of 13 patients showed high levels of phenotypic and genotypic resistance to all three classes of drugs (nucleoside analogs, non-nucleoside inhibitors and protease inhibitors) an antiviral effect was seen in most of these patients. By week four, 12 patients had shown a median viral log drop of 1.22 log; by week eight a 1.86 log drop in viral load was seen in 9 patients; and by weeks 12 through 16 the median viral load in six patients had dropped 2.35 log. Two patients who had discontinued therapy due to side effects were rechallenged with the GIGHAART regimen and after 2 months had viral load reductions of 3.87 and 2.46 logs.
The Katlama study is significant in that it illustrates that viral load reduction can be achieved even in the most heavily experienced patients with resistance to multiple classes of drugs. If the goal of therapy is, in fact, viral load reduction then this study demonstrates that it can be accomplished in the most adverse of circumstances. Yet, this study also points out the greatest limitation of this type of approach: the high incidence of side effects and adverse events.
These kitchen-sink approaches require motivated patients with adequate resources. The success or undoing of these strategies may lie in the patient's ability to adhere to complex schedules and willingness to sacrifice some quality of life. The irony, as Deeks points out in his report, may lie in that the patients often fail initial therapies due to nonadherence and end up needing more difficult and complex second and third line therapies. The added complexity and side effects are distinct disadvantages of these regimens.
The other question that remains with these mega-HAART approaches is their durability. The best result would be one in which patients were maximally suppressed and remained suppressed indefinitely. In reality these approaches work for a limited time in many cases. The question then becomes whether some degree of suppression, however brief, will result in clinical benefit for the patient. That issue is yet to be resolved.
There is an abundance of treatment success stories of persons who begin treatment with combination therapy, achieve maximal viral suppression and quickly begin to see clinical benefits from the drugs. Generally these stories involve patients who have never previously taken antiretrovirals. These so-called naïve patients have the benefit from having wild-type virus that is still sensitive to antiretroviral drugs.
For clinicians these naïve patients represent the ideal setting in which to begin combination therapies. It is in these patients that HAART regimens will have the greatest chance of success. One group of German researchers has gone to some lengths to try to recreate this naïve environment in patients who no longer possess these drug sensitive strains of HIV. The theory behind the experiments is the expectation that if drug therapies are stopped for some time in highly drug-experienced patients, HIV will revert from a highly resistant viral strain to a strain that resembles a drug-sensitive wild-type. The assumption is that if HIV evolves to become resistant to drugs, once the drug pressure is removed the evolution will be reversed.5
To assess the utility of this theory, Veronica Miller, MD, and colleagues at the JW Goethe Institute identified a group of 39 patients who had discontinued therapy after failing a protease-inhibitor based regimen. These patients had phenotypic resistance data before and after discontinuation of their therapy. At the time that the therapy was stopped the patients had phenotypic resistance to a median of eight drugs.
Patients stopped drugs for at least two months prior to starting their multi-drug regimen. After the drug holiday genotypic testing revealed that 26 of the 39 patients had reverted to wild-type virus. The remaining 13 patients still had predominantly drug resistant virus.
Of the 26 patients whose virus reverted to wild-type, 18 achieved viral load levels below 500 copies at 24 weeks after restarting therapy. In the patients whose virus did not revert to wild-type only two were able to reach viral load levels below 500 copies at 24 weeks.
The clinical implications of this type of drug holiday are unclear for several reasons. First, patients taking a drug holiday in Miller's cohort experienced a median 0.71 log increase in viral load and a median decline in 89 CD4 T cells.6 This in itself puts patients at increased risk of clinical progression, especially if they are in a precarious situation to begin with.
Additionally, the study was short, lasting only twenty-four weeks. Given that persons infected with HIV have a swarm of virus that consists of many genetic variants, it is likely that patients whose HIV reverted to wild-type, still harbored multi-drug resistant viruses that will reemerge with time. The question left unanswered is whether the patients would have had the same response if had they gone directly to the new drug regimens without the intervening drug holiday.
For now, the virtues or drawbacks of drug holidays in the face of second or third line therapies requirements are not fully known. Without clinical and research substantiation, drug holidays are currently recommended only for patients who need a break from drug toxicities.
Finally, Spanish researchers presented a different approach to the use of therapies. Their therapeutic strategy included two regimens consisting of three to four drugs. Patients were asked to alternate between the two regimens on a monthly basis. The theoretical basis for this strategy is for the drugs to stay one step ahead of the developing mutations. As the resistance mutations start to form, new drugs to which the virus is still sensitive are introduced. Only 11 of 17 patients completed the 24-week study and of these only 6 had unquantifiable viral loads. Only 4 patients had a greater than one log reduction in viral load. The goal of this strategy was to avoid the excessive pill burden and toxicity of mega-HAART regimens. It should be noted, however, that 6 of the 17 patients withdrew because of adverse events.7
Pharmaceutical companies keep investigating drugs with similar mechanisms of action and only slightly different resistance profiles. Their aim still is to have a product out in the market as soon as possible. To facilitate their efforts they continue to focus their efforts on drugs that show efficacy in naive populations. What is needed is a concerted effort to find drugs that will work in novel ways, in ways that will be useful to the many patients who have few drug options left. It is evident that manipulation of the existing drugs may produce marginally better results, but not results that are effective and durable. Developing novel approaches, especially approaches that are work for heavily experienced patients remains one of the industry's greatest challenge.
1 Summary Report: Second International Workshop on Salvage Therapy for HIV Infection (Toronto, Canada, May 19-21, 1999), Medscape HIV/AIDS 5(3), 1999.
3 Grossman, et al., Second International Workshop on Salvage Therapy for HIV Infection, Abstract 023, 1999.
4 Katlama, et al., Antiviral Therapy 1999; (Supplement 1); 77 (Abstract 113).
5 A theory oddly reminiscent of the feelings expressed by Madonna in the song "Like a Virgin."
6 Patients whose virus reverted to wild-type had greater increases in viral load (+0.98 log) and greater losses in CD4 T cells (-122 cells) than those whose virus did not revert.
7 Soriano, et al., Second International Workshop on Salvage Therapy for HIV Infection, Abstract 014, 1999.
Surrogate Marker: a laboratory test, such as viral load, used to predict the future clinical condition of a patient.
Wild-type virus: the virus as it occurs in nature, as distinguished from mutant forms that evolve from drug pressure.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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