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Case Management

Peter S., an Extensively Treated Patient With a Rising Viral Load

What Should You Do When Triple-Drug Therapy Begins to Fail?

April 1997

Peter S. is a 47-year-old former book publisher, now on permanent disability, who discovered that he was infected with HIV in 1985, shortly after the first HIV antibody test was approved for commercial use. Peter and his lover of seven years were tested at the same time. Each tested positive. Peter's partner died of AIDS in 1989.

Both men participated in ACTG 019, the first large-scale clinical trial of zidovudine as antiretroviral monotherapy. Peter responded better to treatment, experiencing fewer side effects and less rapid disease progression than his lover. When Peter's CD4 count began to drop, he switched first to ddI and then to the combination of ddC and ZDV. Two years ago, when Peter developed symptomatic disease and his CD4 count fell to below 10 cells/mm3, he switched to the then-new combination of ZDV and 3TC, and as soon as the protease inhibitors became available he added ritonavir to this regimen.

Unable to tolerate the side effects of ritonavir in combination with two nucleoside analogs, Peter switched therapies once again -- this time to the triple-drug combination of d4T, 3TC, and indinavir. On this regimen he gained weight and reported an overall improvement in both health and outlook. His CD4 count rose within two months to 110 cells/mm3, and his viral load dropped to less than 10,000 particles/mL -- that is, below the level of detection of first-generation HIV RNA assays.

When Peter was seen earlier this year, he still felt well and his CD4 count remained above 100 cells/mm3. However, his viral load -- which only three months before had measured 2,000 particles/mL by the newer, more sensitive, second-generation RNA assays -- had risen to 14,000 particles/mL.

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Peter is clearly failing this triple-drug regimen. With CD4 counts above 100 cells/mm3 he did not previously qualify for open-label nelfinavir, a new protease inhibitor awaiting F.D.A. approval. Now he does, and this expands his therapeutic options.

THE CLINICAL QUESTIONS

  • Would you change Peter's protease inhibitor once again, this time to nelfinavir?
  • Would you make other changes in his drug regimen, and would one of those changes involve adding the non-nucleoside RT inhibitor nevirapine?
  • If Peter asked you what effect these changes might have on the development of resistance, how would you respond?

THE EXPERTS' RECOMMENDATIONS:

Dr. David Hardy, Associate Clinical Professor of Medicine, UCLA School of Medicine; Scientific Director, Pacific Oaks Research; and member of the editorial advisory board of HIV Newsline:

Would you change Peter's protease inhibitor once again, this time to nelfinavir?

Peter's previous treatment reflects the "growing pains" of antiretroviral therapy -- which has evolved, over the past decade, from monotherapy with the only agent then available, zidovudine, to sequential monotherapy, to combination therapy with two nucleoside analogs, to the more complex and more potent three- and four-drug combinations being used today. This evolution has kept long-term patients like Peter alive, but at a cost: many have developed resistance to one or more of the older drugs.

That's the bad news. The good news is that even heavily pretreated patients like Peter probably have not exhausted all of the potentially effective combinations of antiretroviral agents. Peter has a number of therapeutic options, but I would not immediately switch him to nelfinavir. Our clinical experience with this drug -- in patients who have developed resistance to other protease inhibitors -- is still extremely limited, and the available in vitro resistance data suggest that approximately 40% of the HIV isolates taken from patients who have been extensively treated with one or more of the three currently-approved protease inhibitors will exhibit decreased sensitivity to nelfinavir -- especially if these isolates have mutations at codon 82 or codon 84, two common resistance-conferring mutations for indinavir.

(On the other hand, nelfinavir remains an excellent therapeutic option for patients who have not been previously treated with a protease inhibitor, as we reported in the last issue of HIV Newsline. See "Newest protease inhibitor, nelfinavir, is first available in pediatric formulation," Vol. 3, No. 1, pages 18-19.)

Would you make other changes in his drug regimen, and would one of those changes involve adding the non-nucleoside RT inhibitor nevirapine?

My recommendation for Peter would be to switch to a four-drug regimen that includes three antiretroviral agents that he has never taken before:

  • Saquinavir (600 mg b.i.d.)
  • Ritonavir (400 mg b.i.d., progressively escalated as 100 mg b.i.d for 3 days, then 200 mg b.i.d for 3 days, then 300 mg b.i.d. for 3 days, and then 400 mg b.i.d. to improve tolerance)
  • Nevirapine (200 mg q.d. for 14 days, then 200 mg b.i.d)
  • d4T (40 mg b.i.d.)

This recommendation is in line with the current thinking that when a change is made in a patients' antiretroviral regimen, that change should be comprehensive -- for maximum efficacy against strains of HIV that have developed resistance to the drugs used previously. The particular advantage of this therapeutic combination is that all of the agents are dosed twice daily, all of them should or can be taken with food, and all of them can be taken together. All of these factors enhance compliance in patients like Peter, who are almost certainly taking other medications for prophylaxis against, or treatment of, AIDS-related OIs.

The reduced dose of ritonavir prescribed for Peter serves as a pharmacokinetic tool -- to boost serum levels of saquinavir 40-fold. At this lower dose of ritonavir Peter should experience fewer side effects of this particular protease inhibitor, and that too should promote compliance. The synergistic effect of combining full-dose saquinavir and low-dose ritonavir will more than overcome the 30% decrease in serum levels of saquinavir seen when that drug is taken in combination with nevirapine (see "Nevirapine may prove to be effective when used in combination with protease inhibitors," Vol. 3, No. 1, pages 16-17).

Finally, I have chosen saquinavir as Peter's principal protease inhibitor because the current genotypic laboratory data show relatively little overlap between the resistance patterns of indinavir, to which Peter seems to have developed resistance, and saquinavir. Consequently, his indinavir-resistant HIV isolates should have a 60% or better chance of responding to saquinavir.

If Peter asked you what effect these changes might have on the development of resistance, how would you respond?

Resistance is, ultimately, the Achilles' heel of any antiretroviral regimen that does not achieve full suppression of viral replication (that is, suppression to levels that cannot be detected by the most sensitive of the current RNA assays). Effective antiretroviral exerts selective pressure on any continuously replicating virus in the host, and the goal of aggressive therapy is to suppress replication as completely as possible, in order to eliminate as many emergent resistant strains of HIV as possible.

In theory, multidrug combination therapy is most likely to achieve this goal. The regimen selected for Peter interferes with viral replication at two different sites by three different mechanisms (see the schematic color diagram that is part of "The Rationale for Combination Therapy," the PULL OUT AND SAVE feature in Vol. 2, No. 6, of HIV Newsline). I have chosen to put Peter on three antiretrovirals that he has never taken -- to thwart drug-resistant strains of HIV in this heavily pretreated patient. I have retained d4T because it has an acceptable side effects profile and because resistance to this nucleoside analog has been difficult to detect.

I would endeavor to explain all of these points in discussing my therapeutic recommendations with Peter. I would also tell him that decisions about antiretroviral therapy should be guided by five firm principles:

  • Use the most completely suppressive antiretroviral regime up front -- to achieve the maximal reduction in viral load, avoid resistance, and prolong durability of effect.
  • Do not abandon an antiretroviral therapy prematurely; the full effectiveness of a given therapy may not be seen for 8 to 16 weeks after treatment is initiated.
  • Try to fashion drug regimens that involve as few doses as possible, and as few drug-drug and food-drug interactions as possible, to improve compliance.
  • Never change just one drug in a multidrug regimen, and never add just one drug to such a regimen.
  • Never change an antiretroviral regimen based on a single HIV RNA assay result; this test is not error-free, and all changes in therapy should be based on two or more assays with results that clearly indicate therapeutic failure (i.e., a greater than three-fold increase in viral burden).

Dr. Harold Kessler, Professor of Medicine, Rush Medical College, and member of the editorial advisory board of HIV Newsline:

Would you change Peter's protease inhibitor once again, this time to nelfinavir?

Possibly. The first thing I would want to know is how long Peter has been on indinavir. Has he been taking this protease inhibitor for at least five months, long enough for the drug to achieve maximum effectiveness? And has he been fully compliant with his prescribed dosing regimen throughout this period? I would also want to know if he has had a recent opportunistic infection, because infections can result in transient increases in viral burden. And, finally, I would want to know what adverse reactions Peter had to ritonavir. Some adverse reactions are specific to ritonavir and some are seen with all of the protease inhibitors, and if Peter's problems with ritonavir fall into the latter class there would be no point in switching his therapy.

The answers to these questions, coupled with a follow-up HIV RNA assay to reconfirm that Peter's viral load is indeed rising, would influence my therapeutic decisions. At this point Peter's options are to start nelfinavir, which recently received F.D.A. approval, or to switch to a combination of either saquinavir/nelfinavir or saquinavir/ritonavir, as Dr. Hardy recommends.

Would you make other changes in his drug regimen, and would one of those changes involve adding the non-nucleoside RT inhibitor nevirapine?

Over the past 15 years Peter has taken all of the currently approved nucleoside analogs -- and has presumably developed resistance to several of them -- so his therapeutic options are limited. In a recent phenotypic analysis of patients who were treated with ddI plus d4T for a median of 10.4 months, no changes in susceptibility to either drug were noted. Resistance to these nucleoside analogs seems to develop very slowly, which makes them logical choices in heavily pretreated patients. Of the two drugs, d4T may be the better choice in Peter's case. A recent genotypic analysis of 24 patients who had been on d4T monotherapy for at least two years found no mutations at codons 50 or 75, the codons associated with d4T resistance. These findings confirm the wisdom of Dr. Hardy's decision to select d4T as Peter's nucleoside analog.

Peter does have other therapeutic options, however. He could try d4T plus ddI in combination with saquinavir or nelfinavir, and he could add nevirapine to this regimen. The interactions between nelfinavir and nevirapine have not been studied, but we do know that nevirapine reduces the circulating levels of the other protease inhibitors by approximately 30%, so dosages would have to be adjusted accordingly.

As patients like Peter live longer, they inevitably develop resistance to standard antiretroviral therapies, and clinicians are increasingly challenged to find new drug combinations that will suppress viral replication and preserve the patient's remaining immune function. These decisions must be made in collaboration with the patient, since they can involve largely untested experimental regimens. One option that I might well investigate -- with Peter's permission -- is whether he would qualify for a clinical trial of either of two promising investigational drugs, DMP-266 and 1592-U-89.

If Peter asked you what effect these changes might have on the development of resistance, how would you respond?

What we do know, at this point, is that nelfinavir is not cross-resistant with nucleoside analogs or with non-nucleoside RT inhibitors. This new drug's cross-resistance with other protease inhibitors is not fully known. Nelfinavir does not appear to engender resistance to other drugs in its class when it is given first, but that is not the situation here. As Dr. Hardy points out, there is preliminary evidence to suggest that patients who develop resistance to one of the other protease inhibitors will prove to be cross-resistant to nelfinavir as well. This is the reality of antiretroviral therapy in long-term survivors like Peter, and these facts must be presented to the patient.

Dr. Paul Volberding, director of the AIDS Program at San Francisco General Hospital and editor-in-chief of HIV Newsline:

Although we devote a considerable amount of time to developing recommendations for initial antiretroviral therapy, this case is really much more typical of the problems that clinicians encounter in daily practice. Peter has received, sequentially, each new drug that has become available. He has clearly benefited from all this therapy -- he is alive, he is clinically stable, and he reports that his overall health and outlook are both good. But Peter can now expect to derive less benefit from the newest antiretroviral drugs than he did from their predecessors, because 15 years of constantly evolving therapy have left him with multiple resistance mutations.

Given Peter's long history of drug treatment and his current viral profile, I might consider trying him on the combination of ddI, nevirapine, and nelfinavir, although there are no published data on this particular combination of agents. In the not too distant future we may be able to do phenotypic screening of patients like Peter -- to determine which drugs, and which drug combinations, the patients' viral strains are most susceptible to. For now we must rely on HIV RNA testing, which can tell us in short order and with a high degree of accuracy whether a particular patient is responding to a particular drug combination.

Harvey J. Makadon, M.D., is Vice President and Medical Director of Ambulatory Care and Community Health, Beth Israel Deaconess Medical Center, Boston, MA.




  
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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.
 
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