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Case Management

Joan J., a Treatment-Naïve Patient Who Isn't Naïve About Treatment Options

Is This Individual a Candidate for Aggressive Suppression Therapy?

October 1997

Joan J. has known for several years that she is seropositive. Her CD4 counts have consistently been above 500 cells/mm3 since her diagnosis, and she has consistently expressed reluctance to begin antiretroviral therapy -- citing data from trials like the Concorde Study that seemed to show no survival benefit to early initiation of therapy.

When she learned that she was HIV-positive, Joan contacted her local AIDS service organization and began the process of educating herself about her disease and her options. On previous office visits she has demonstrated a considerable command of the clinical issues in HIV management, and she has mentioned that she obtains information on HIV disease from a number of sources, among them several Internet sites.

Joan schedules regular visits to the clinic for tests to evaluate her immune status and viral load. During her last visit, one week ago, she announced that she had, after careful consideration, decided to begin antiretroviral therapy. More specifically, she declared that she wanted to begin triple-drug therapy, based on what she had read about its success in suppressing viral replication.

The laboratory data obtained at Joan's last visit indicate that her CD4 count is now 520 and her viral load is 16,500 copies/mL.


The Clinical Questions:

  • What would you recommend as initial therapy?

  • Would you include a protease inhibitor in this regimen? If your answer is yes, which protease inhibitor would you choose, and why?

  • In light of what we now know about protease resistance, what drug combination would you recommend if Joan does develop resistance to the protease inhibitor you have chosen?

The Expert's Recommendations:

Dr. James Kahn, Associate Professor of Medicine, UCSF School of Medicine, and Associate Director of the AIDS Program at San Francisco General Hospital:

What would you recommend as initial therapy?

The evolving paradigm for the treatment of HIV infection is to reduce the patient's viral burden to the lowest possible level, for the longest possible time, with the fewest possible toxicities -- and to do so with a regimen that affords the greatest likelihood of long-term compliance. Joan's rising viral burden -- especially when coupled with her considerable command of the clinical issues in HIV management and her determination to remain compliant with a multidrug antiretroviral regimen -- make her a good candidate for aggressive therapy.

Prospective, double-blind, randomized clinical trials, performed over the past decade, have provided us with a wealth of information on how patients with CD4 counts below 500 cells/mm3 can be expected to respond to various antiretroviral combinations. Unfortunately, these published studies tell us little or nothing about patients like Joan. Her current CD4 count -- 520 cells/mm3 -- places her in a borderline category, where treatment guidelines do not apply.

As recently as two years ago, few clinicians would have encouraged Joan to begin antiretroviral therapy. All that changed with the advent of the HIV RNA assay, which has radically altered our understanding of the pathophysiology of HIV infection and our approach to therapy (see "The HIV RNA Assay: A Valuable New Diagnostic Tool," Vol. 2, No. 2, pages 27-30). When our only method of gauging viral activity was through CD4 counts and other secondary markers of disease progression, it was often assumed that a patient with a CD4 count as high as Joan's was a patient with quiescent viral disease, and the recommendation was that clinicians hold back the handful of antiretroviral agents then at their disposal until the patient's CD4 counts dropped well below 500 cells/mm3.

HIV RNA assays give us a way of assessing a patient's viral load in "real time," and as Dr. David Hardy observes elsewhere in this article, "Detectable HIV RNA, particularly if it is greater than 5,000 copies/mL, is an indication that antiretroviral therapy should begin, irrespective of the patient's CD4 count."

By this yardstick it is time to initiate antiretroviral therapy in this patient, despite Joan's relatively high CD4 count. In the absence of published guidelines for the treatment of this patient, one must rely -- as practitioners so often do in devising therapies for HIV-infected patients -- on personal judgment, clinical experience, and judicious interpretation of information gleaned from unpublished data, anecdotal evidence, and consultation with colleagues.

The first thing to consider, in developing an antiretroviral strategy for Joan, is whether treatment should focus on a single HIV enzyme, reverse transcriptase (RT), or should simultaneously attack both the RT enzyme and the protease enzyme. The first approach involves combining two nucleoside RT inhibitors, with or without the addition of a non-nucleoside RT inhibitor. The options include: ZDV + ddI, ZDV + 3TC, ddI + d4T, d4T + 3TC, and ZDV or d4T+ ddI + nevirapine.

The second approach involves combining one of the two-drug combinations listed above with ritonavir, indinavir, or nelfinavir -- or with the combination of saquinavir and ritonavir. (When these two protease inhibitors are combined, the latter is prescribed for pharmacokinetic rather than pharmacologic reasons: When ritonavir is administered in combination with saquinavir, it boosts serum concentrations of saquinavir 40-fold.)

Any multidrug antiretroviral regimen that includes a protease inhibitor should normally exclude either of the currently approved non-nucleoside RT inhibitors, because of the unpredictable impact of this class of drugs on the bioavailability and the pharmacokinetic profiles of protease inhibitors (see Dr. David Hardy's comments on this subject). Coadministration of these two drug classes requires a clear understanding of the pharmacokinetics of both drug classes and extensive experience with combination antiretroviral regimens.

It is clear to me that Joan has given a good deal of thought to the issue of when, and how, to initiate antiretroviral therapy. I note that her clinician did not rush Joan into making decisions about her treatment, and I commend that approach. Clinicians who treat people with HIV infection have the luxury of time to educate those patients, to create a sense of trust and a feeling of support, and to develop a coherent, long-term strategy for achieving maximal viral suppression while maintaining maximal adherence to therapy -- all before treatment is initiated. (The exceptions to this rule are cases of primary HIV infections and post-exposure prophylaxis. In these situations therapy must begin immediately.)

Would you include a protease inhibitor in this regimen? If your answer is yes, which protease inhibitor would you choose, and why?

Given what I know about Joan's depth of commitment to aggressive antiretroviral therapy -- therapy which requires sustained, high-level adherence to achieve optimal results and avoid the emergence of drug-resistant viral strains -- I would encourage Joan to begin therapy with dual-enzyme inhibition. This approach would call for her to begin therapy with two nucleoside RT inhibitors and one or two protease inhibitors.

In many cases the decision to prescribe a protease inhibitor is the easy part. The hard part is deciding which protease inhibitor to prescribe. To make that decision, I need to know more about the circumstances of Joan's life. Does she have a refrigerator at home and at work? If she doesn't, ritonavir -- which must be kept chilled until it is taken or it loses its potency -- is not an option for her. Is Joan going to be able to adhere to a dosing regimen that calls for her to take pills three times a day rather than twice a day? If that prospect worries her at the outset, it's a good bet that she will have trouble with adherence to a thrice-daily dosing schedule -- and in that case she cannot be assigned indinavir or nelfinavir.

Last but not least, there is the question of self-hydration. Patients who cannot remember to drink six full glasses of water during the course of each day are poor candidates for indinavir therapy, even if they are capable of complying with that drug's thrice-daily dosing regimen.

My preference is to start patients like Joan on either d4T + ddI or d4T + 3TC as the initial RT inhibitors, and to combine these drugs with nelfinavir, indinavir, or the combination of saquinavir and ritonavir (for the reasons described above). If Joan wants her regimen to include the drug with the greatest antiretroviral efficacy, based on published studies, I would choose indinavir. If she wants the convenience of twice-a-day dosing, I would choose saquinavir plus ritonavir. If she shies away from either of these choices -- because she fears that she will have trouble remaining compliant with the strictures of indinavir therapy, or because she doesn't want to try the two-drug combination until there are more published data on the combination's effectiveness -- I would recommend nelfinavir.

In light of what we now know about protease resistance, what drug combination would you recommend if Joan does develop resistance to the protease inhibitor you have chosen?

There are no guidelines for how to treat HIV-positive patients after they develop resistance to one or more antiretroviral agents -- and that is why it is so important to consider the full range of treatment options before therapy is initiated. The best antiretroviral effects are achieved with the initial therapy; subsequent treatments have significantly smaller, and less durable, effects. My expectation is that Joan will do very well for an extended period on combination therapy, but if she does develop resistance to her chosen protease inhibitor, she will need a new regimen.

The current recommendation is that any change of therapy should involve switching at least two of the components of the failing regimen. These general guidelines may help clinicians make those choices:

  • If the initial regimen included two RT inhibitors, switch both of them.

    If ddI is one component of this new pair of RT inhibitors, consider adding hydroxyurea to the patient's regimen, based on laboratory evidence of enhanced antiretroviral activity when hydroxyurea is combined with ddI.

  • If a protease inhibitor was part of the initial regimen, consider adding a non-nucleoside RT inhibitor rather than another protease inhibitor, because the resistance data we have seen to date suggest that patients who develop resistance to one protease inhibitor tend to develop at least partial resistance to other drugs in this class.

The goals of treatment for those who have failed initial therapy are identical to the goals of treatment for those who are beginning therapy, but the options are reduced and the implementation of effective therapy is more difficult.

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:

What would you recommend as initial therapy?

One of the best indications for initiating antiretroviral therapy in a seropositive patient is not simply falling CD4 counts or rising HIV RNA levels but the patient's willingness to begin therapy. Joan is clearly ready to commit herself to combination therapy, with all its complexity and demands, and her decision to begin antiretroviral therapy after several years of apparently stable CD4 counts is one that her care providers should wholeheartedly endorse.

Joan's desire to start treatment with a three-drug regimen reflects how well informed she is about the benefits and risks of such therapy. We know that adherence to therapy is better in patients who understand the rationale for multidrug antiretroviral therapy (see "The Rationale for Combination Therapy," the Pull Out and Save section of Vol. 2, No. 6, and "Compliance: How You Can Help," Vol. 3, No. 3). Joan is an exceptionally well-informed individual, and the fact that she has done her homework bodes well for her response to treatment.

It has not yet been definitively established, through clinical-outcome studies, that starting patients like Joan on protease inhibitor-containing three-drug regimens is superior to starting them on two-drug regimens. However, a recently published clinical trial, ACTG 320, did conclusively demonstrate that patients treated with the three-drug combination of indinavir, 3TC, and ZDV (or d4T) experience statistically significant reductions in disease progression and death compared to patients treated with the two-drug combination of 3TC and either ZDV or d4T.

All of the participants in ACTG 320 had been extensively pretreated with ZDV but had not previously been treated with 3TC or one of the protease inhibitors, and all had CD4 counts of less than 200 cells/mm3. Significantly, it was the patients with the most advanced disease, those with CD4 counts below 50 cells/mm3, who exhibited the greatest benefit from triple-drug therapy.

Whenever a clinician is considering the initiation of antiretroviral therapy for a particular patient, several factors should come into play:

  • The regimen chosen should be potent, as demonstrated by its ability to produce significant reductions in viral load, and significant increases in CD4 count, in the majority of treated patients.

  • The components of this regimen should have no known antagonistic effects with one another, and there should be a high degree of probability that the chosen agents do not have deleterious drug-drug interactions -- interactions that might compromise the efficacy of the antiretroviral regimen or the effectiveness of a concomitant prophylaxis regimen.

  • Food-drug interactions should also be taken into account when the clinician is considering which agents to include in a multidrug regimen. Patients with poor fasting tolerance and those who eat whenever they feel hungry, rather than at scheduled meal times, may find it hard to comply with the daily dosing schedule for indinavir -- although the dozens of low-fat and no-fat snacks listed in the pull out and save section of this issue should help to alleviate this potential impediment to adherence.

  • The regimen should be designed to elicit the highest possible degree of compliance from the patient -- which means that the new regimen must be tailored to the patient's daily routine. Individuals whose work schedules, dietary habits, and sleep cycles are highly irregular are poor candidates for regimens that require thrice-daily dosing on a fixed schedule, for instance.

Another important consideration, when a clinician is weighing whether it is time to initiate antiretroviral therapy in a patient like Joan, is the patient's viral load. In patients whose HIV RNA levels are greater than 100,000 copies/mL, a three- or four-drug regimen that contains at least one protease inhibitor will almost certainly be necessary to suppress such high-level viral replication. For a patient like Joan, with a viral load of 16,500 copies/mL, it may be possible to achieve suppression of viral replication with a less complex regimen.

Serial CD4 counts remain an important means of evaluating a patient's risk of developing AIDS-related opportunistic infections, and clinicians should continue to use this marker of disease progression as a yardstick for determining when to begin prophylaxis against PCP and other OIs. As a parameter for deciding when to initiate antiretroviral therapy, however, the CD4 count has taken a back seat to viral-load quantification. Detectable HIV RNA, particularly if it is greater than 5,000 copies/mL, is an indication that antiretroviral therapy should begin, irrespective of the patient's CD4 count.

Would you include a protease inhibitor in this regimen? If your answer is yes, which protease inhibitor would you choose, and why?

Because Joan's CD4 count is within the normal range by most lab standards (520 cells/mm3) and her viral load is relatively low (16,500 copies/mL), I would not recommend that her initial therapy include a protease inhibitor. Rather, I would start Joan on the three-drug combination of ZDV, ddI, and nevirapine. If Joan is concerned about the dietary restrictions imposed by ddI therapy or by the gastrointestinal side effects sometimes seen with such therapy, I would either substitute 3TC for ddI or use d4T and 3TC for the nucleoside analog component of her regimen.

My recommendation is based on several important considerations:

  • The data from the INCAS trial (BIRG 1046) established that antiretroviral-naïve patients treated with standard doses of ZDV, ddI, and nevirapine experience drops in viral load of 1.5 to 1.8 log and rises in CD4 count of 100 to 125 cells/mm3. Moreover, more than 70% of the triple-drug recipients had their viral burdens fall below the detection level (500 copies/mL) of the assay used in this study -- an effect that endured for 52 weeks or longer in up to 72% of these patients.

    One noteworthy finding of this trial was that patients who achieved good to excellent compliance with therapy were much more likely to have their viral loads fall to undetectable levels, and these same patients were much less likely to develop phenotypic resistance to any of the drugs in this regimen. This is the first time that adherence to therapy has been so closely correlated with reduction of viral load and with a reduced likelihood that viral isolates from therapy-compliant patients will develop resistance to the components of a multidrug regimen.

  • Nevirapine is an appealing alternative to the protease inhibitors in patients like Joan. One attraction is its simplicity: patients take only two pills a day, one in the morning and one in the evening. Other attractions are the drug's high bioavailability, which is roughly 90%, and its CNS penetration, which is 95% to 98% of unbound drug in the plasma.

  • Because Joan's viral load is relatively low, the potency of a protease inhibitor is probably not needed to achieve suppression of viral replication -- and this class of drugs can therefore be reserved for future use as needed.

The primary side effect of nevirapine therapy is a macropapular rash that occurs in 17% to 20% of treated patients, usually within the first month of therapy. The rash is typically mild to moderately pruritic, and it characteristically begins on the trunk and spreads centrifugally. It can generally be treated symptomatically with antihistamines. Patients rarely have to discontinue therapy due to this adverse reaction, although Stevens-Johnson reactions have occurred in approximately 1% of treated patients. To reduce the chance that a therapy-limiting rash will develop, nevirapine is initiated at 200 mg once a day for 14 days, and then the dose is increased to 200 mg twice a day as the medication induces its own metabolism via the cytochrome P450 system.

The combination of nevirapine plus two nucleoside analogs offers patients like Joan -- who are antiretroviral-naïve and have relatively high CD4 counts and relatively low viral loads -- the opportunity to begin therapy with a potent three-drug regimen that has the virtue of twice-daily dosing and that is unlikely to cause drug-drug or drug-food interactions.

As Dr. James Kahn has noted elsewhere in this article, nevirapine lowers plasma concentrations of both saquinavir and indinavir -- by a significant 28% to 35%. Its effect on ritonavir is negligible (> 11%), and while coadministration with nelfinavir causes AUC levels to drop by 15% to 18%, dose modifications are not required when these protease inhibitors are administered concurrently with nevirapine.

In light of what we now know about protease resistance, what drug combination would you recommend if Joan does develop resistance to the protease inhibitor you have chosen?

If Joan insists that her therapy include a protease inhibitor, I would recommend the triple-drug combination of ZDV, 3TC, and nelfinavir (at a dose of 750 mg t.i.d.) as initial therapy. I recognize that we have, at this point, only limited data on the efficacy of this particular combination -- and we have no data at all comparing various three-drug antiretroviral regimens that include a protease inhibitor, although studies are in progress -- but what information we do have is encouraging.

This regimen has been shown to achieve a significant reduction of viral load (1.8 to 2.4 logs) and to cause CD4 counts to rise by 125 to 150 cells/mm3. Even after 40 weeks of treatment, 85% of those receiving this three-drug combination had viral loads below 1,200 copies/mL, which was the lower limit of detection of the assay used in the study (Chiron bDNA, second generation). The researchers who conducted this small trial reported a 10% to 17% incidence of mild-to-moderate diarrhea as the most significant side effect of therapy.

It should be noted that compliance with this regimen may be a challenge for Joan, because nelfinavir must be taken three times a day. However, this protease inhibitor should be taken with food and can be dosed t.i.d. -- rather than at eight-hour intervals.

Finally, studies of phenotypic resistance suggest that HIV isolates from patients first treated with nelfinavir retain sensitivity to all of the other protease inhibitors. (By contrast, the limited data we have on HIV isolates taken from patients first treated with the other protease inhibitors show that only about 60% retain sensitivity to nelfinavir.) This initially favorable cross-resistance profile improves the patient's therapeutic options.

Should resistance develop to the triple-drug combination of ZDV, 3TC, and nelfinavir, I would recommend that Joan switch to d4T, ddI, and nevirapine or to d4T, ddI, and ritonavir + saquinavir, depending on the level of her breakthrough viral load.

Dr. Howard Libman, Assistant Professor of Medicine, Harvard Medical School, and Co-Director, HIV Intake and Consultation Unit, Beth Israel Deaconess Medical Center:

What would you recommend as initial therapy?

I believe that starting antiretroviral therapy in an asymptomatic patient with a normal CD4 count can be supported by what is known about the pathophysiology of HIV disease. However, at our current level of understanding this is very much an individualized decision, one that takes into account the patient's attitude toward taking medications and the patient's reliability.

Before initiating therapy I would first determine to my satisfaction that Joan understands that there are as yet no data from clinical trials showing that early therapy in asymptomatic patients delays disease progression or prolongs life. This is important, because while some patients are willing to start drug treatment if there is even a slim possibility that it will help, others want assurance that medication will benefit them in a tangible way. From her history, it appears that Joan is interested in aggressive therapy and would be compliant with a multidrug regimen.

Would you include a protease inhibitor in this regimen? If your answer is yes, which protease inhibitor would you choose, and why?

I would recommend the combination of zidovudine (ZDV), lamivudine (3TC), and nelfinavir as initial therapy. In general, this has proven to be a well-tolerated regimen, with the most common side effects being nausea and diarrhea. Importantly, none of these drugs requires an empty stomach for absorption. A follow-up visit, four weeks after the initiation of therapy, would enable me to determine how well Joan was tolerating therapy, and a repeat CD4 count and viral-load measurement would allow me to assess how she was responding to that therapy.

Given that Joan's viral load is relatively low, it might also be reasonable to initiate combination therapy with two reverse transcriptase inhibitors. At this stage all of the goals of antiretroviral therapy -- suppression of viral load below the detection limits of the available assays; maintaining or restoring immunologic function, as measured by CD4 counts; and providing a regimen with a minimum of side effects -- could probably be attained using two nucleoside analogs. However, this approach is contrary to clinical experience -- which has shown us that maximal viral suppression is achieved only with three-drug regimens that include a protease inhibitor. As importantly, it is contrary to Joan's wishes.

In light of what we now know about protease resistance, what drug combination would you recommend if Joan does develop resistance to the protease inhibitor you have chosen?

I would modify Joan's antiretroviral regimen if her viral load titer started to rise, her CD4 count fell, or she developed clinical evidence of disease progression on the combination of ZDV, 3TC, and nelfinavir. In general, if a regimen is failing I make at least two changes concurrently, so as not to expose the resistant viral strains to what would, in effect, be "monotherapy" with the one new agent. These new agents should be chosen on the basis of the patient's medication history, and any drugs the patient has received in the past 12 months should be specifically avoided.

One reasonable option in such a situation would be to substitute d4T for the ZDV and indinavir for the nelfinavir. With any change of therapy, as with the initiation of therapy, I schedule a follow-up visit and lab tests for four weeks after the patient starts new medications, to assess the combination's effectiveness.

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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