Treatment strategies in 2000: planning first-line (and therefore, second-line) therapy

Theo Smart, for

Perhaps in acknowledgment of the Congress’s new academic sponsors, Stefano Vella, President of the International AIDS Society (IAS), was co-chair of the meeting, while Scott Hammer, MD, of Columbia University, gave the first talk: “Planning First-Line (and Therefore, Second-Line) Therapy”

Finding the best possible first-line antiretroviral regimen to use in a patient has become even more important as the shortcomings of the currently available antiretroviral agents have become apparent. This decision is made more difficult as options for first-line regimens have been increasing. Yet even though the choice of the best first-line regimen was the subject of Dr. Hammer’s talk, he began with a discussion of what he feels to be the most critical decision: when to start treatment.

Although guidelines have been drawn up by experts and published by the IAS and various government health services to help patients and their care providers with this decision, these guidelines are not all in perfect agreement. They are largely educated guesses on this issue because no prospective clinical trial has adequately addressed the question.

Dr. Hammer reviewed the pros and cons of early treatment. For example, early treatment may preserve a more fully functional immune system. Also, if the course of disease is set shortly after infection, earlier treatment may alter the course of disease slowing down progression to symptomatic disease. Also, patients who start treatment with lower viral loads are more likely to achieve viral suppression. Less certain, is that early treatment may prevent transmission of the virus, and thus has public health consequences.

Finally, one of the most compelling reasons to initiate treatment early had been the hope that it might lead to eradication. But this now seems a remote possibility given the persistence of latently infected lymphocytes and evidence for low levels of replication that seems to replenish this reservoir of infected cells despite potent therapy.

The list of reasons to defer treatment seems to be growing alongside the list (and risk of) long-term toxicity such as lipodystrophy, metabolic disorders, and osteoporosis. There are also short-term side effects that can negatively impact on quality of life, particularly in a patient who feels fine before therapy is initiated. Furthermore, Dr. Hammer noted that even though early treatment may preserve immune function, studies have shown that antiretroviral therapy can restore much of the protective immune response in most patients treated during mid-to-late stage disease.

Finally, there is the risk of developing drug resistance, which only increases as a patient has more chances to miss doses over time. Since many of the antiretrovirals share a degree of cross-resistance within their respective classes, drug resistance may not only render the current regimen useless, but may severely limit future options for treatment when one is in danger of becoming symptomatic. So the pendulum has swung towards deferring treatment, but for how long?

“There is consensus that all symptomatic patients should be treated,” said Dr. Hammer. For patients without symptoms who wish to defer treatment, though, Dr. Hammer feels that the decision should be reconsidered when their CD4 cell count falls below 350 or their viral load rises above 30,000 copies/ml. As noted earlier, however, there was a range of opinion on this point, and this issue was addressed by a number of other talks.

Moving back to the subject of which first-line regimen to choose, Dr. Hammer spent only a little time comparing specific regimens head-to-head. Despite the declared “winners and losers” in recent comparative studies, it is often hard to judge which regimen is more potent because of differences in administration „ a comparison of a once-a-day drug versus a three-times a-day drug may merely be comparing adherence not potency. Also, intent-to-treat analyses of trial data may underestimate how well a regimen may perform once clinicians gain experience in dealing with its short-term toxicity.

Dr. Hammer outlined five general options for antiretroviral regimens:

  • A protease inhibitor (PI) (often given with low-dose ritonavir to improve pharmacokinetics (PK)) plus two nucleoside analogues;
  • A non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analogues;
  • Three nucleoside analogues (including abacavir);
  • One to two PIs plus an NNRTI with one to two nucleoside analogues;
  • Two protease inhibitors plus an NNRTI (nucleoside sparing)

The last two options are not as commonly used in clinical practice, mostly because of the fear of losing both potent classes of antiretrovirals at once (should therapy fail and resistance develop). However, there may be circumstances in which such regimens may be best suited to an individual patient. And more than any particular type of regimen, Dr. Hammer stressed this need to tailor a regimen to the individual patient, and to develop a strategic plan for that patient’s treatment that looks beyond the first-line.

Some factors to consider in the selection of the regimen include:

  • Can it suppress viral load to below the level of detection on the most sensitive assay available?
  • How easy will it be for the patient to tolerate?
  • What is the risk that it might cause serious adverse events in the patient? (Which may be confounded by the presence of co-infections such as Hepatitis B & C and concomitant medications)
  • Is it a regimen that this patient will be able to adhere to for a long time?
  • What is the likelihood that a patient could develop a drug resistant strain on this regimen?
  • Does it leave options for future treatment?

This last was, perhaps, the most important consideration to Dr. Hammer, who stressed that clinicians should have clear options for second-line therapy already mapped out when initiating first-line treatment. He listed a number of scenarios where one might switch to a second line regimen such as a switch due to intolerability or toxicity; or a switch to intensify a suboptimal regimen; or a switch due to outright virologic failure. In addition, Dr. Hammer suggested one might pre-plan a switch in order to avoid toxicity or simplify a regimen, for example, if you wish to start treatment with a more potent but less tolerable or more complex regimen in order to suppress a particularly high viral load.

Regardless of the reason for the regimen, “practical alternatives, depending upon the strategy chosen, should already be in hand.” In the event of a less than complete response or virologic failure, the alternative to choose should be directed by drug resistance testing, if possible, to determine whether resistance has developed to one or more of the drugs. Such tests are not always available to clinicians, and Dr. Hammer noted that there is a substantial body of data showing that particular components of regimens appear to be more fragile than others. For example, 3TC resistance seems to occur before resistance occurs to other drugs in PI- or nucleoside analogue-based regimens, although resistance to NNRTIs may occur just as quickly, and sometimes simultaneously when used together.

As new drugs from existing and new classes are developed, the range of options for treating the patient should only increase and improve.

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