• What to Start With and What to Include? Should Compounds With Non Cross-Resistance Profiles Be Preferentially Used in Initial or Late Therapy?
  Authored by Julio Montaner (Vancouver, Canada)
  Abstract PL1.2

Background

When the Glasgow Conference began some 10 years ago, there was an extremely limited choice of antiretroviral agents with only realistically AZT (zidovudine, Retrovir) and ddI (didanosine, Videx) being available to individuals. Now, both physicians and patients are almost spoilt for choice on which drugs to start with, with six nucleosides and one nucleotide, three non-nucleosides and six protease inhibitors to choose from. Clearly there are a myriad of possible regimens available. Regimens are chosen based on the available antiretroviral therapies and on the results of efficacy from clinical trials and known toxicities which occur with the agents.

In addition, it is becoming clearer that the majority of individuals who fail therapy may be non-adherent to their therapies, and so choosing a therapy to fit into a patient's lifestyle is equally important. Both the International AIDS Society and the British HIV Association have issued guidelines on when to start therapy. The International AIDS Society suggests commencing therapy when the CD4 count falls below 350. While the British HIV Association's view on when to start is slightly different, it still recommends that therapy commence before the CD4 count falls below 200.

Aim

The aim of this plenary was to discuss available antiretroviral therapy options, and how to choose therapy.

Results

Both the International AIDS Society and British HIV Association guidelines suggest a starting regimen of either two nucleosides and a protease inhibitor, preferably a boosted protease inhibitor, or two nucleosides and a non-nucleoside reverse transcriptase inhibitor. In addition, both suggest the possibility of commencing threapy with a triple nucleoside analogue (e.g., Trizivir), although these have been shown to be potentially less potent -- there is a fall off in success when using triple nucleoside analogues in individuals with high viral load. This lower success must be weighed against the benefit in ease of administration when selecting a therapy. Although both cohorts and clinical trials have shown that the percentage of patients reaching full virological success is increasing in the short-term, we still see virological failure, particularly in the long-term, secondary to toxicity and adherence problems. The increase in treatment success over the last few years has been attributed to simpler and better tolerated regimens, rather than an increase in the power of the available drugs.

Adherence to regimens is an extremely important factor in continuing virological success. Former U.S. Surgeon General C. Everett Coop stated that drugs won't work if people don't take them. Alternatively, we now have such a choice of drugs, that we can say drugs do work if people do take them.

Dr. Margaret Fischl has demonstrated, in data from a prison population, that when adherence reaches 100 percent -- due to the introduction of directly observed therapy where prisoners with HIV are given each dose as prescribed -- then treatment success is also extremely high.

In addition, it has been proposed that patients entering clinical trials with enhanced follow up and regular adherence support, will reach approximately 80 percent of treatment success, which may be greater than the general clinic population. More recent data has shown the importance of adherence in patients with very low CD4 counts. In patients who have started therapy with a CD4 count of less than 50 the survival is 75 percent if adherent, compared with only 35 percent with patients who are not. This clearly may be impacted upon by the illnesses that individuals may be suffering from, which clearly will impact on the potential for adherence, and clearly no one would counsel a patient to wait to start therapy with such a low CD4 count.

Although patients are often blamed for being non-adherent to their regimen, the importance of doctor experience cannot be understated. Doctors who dabble in HIV, with less than five HIV patients, can expect approximately 68 percent of their patients who commence therapy late to survive, compared to 86 percent survival for doctors treating more than five patients.

An important point put forward by Dr. Montaner is the price of drugs. Several drugs within the different classes are more expensive than others, but appear to have little advantage especially in individuals who are commencing therapy. Dr. Montaner proposed that if we were to use cheaper drugs, then the cost savings could be redirected into improving adherence support and adherence research, with greater benefit for the majority of patients over time.

Conclusion

The conclusion from Dr. Montaner's brief summary, is that although we now have multiple drug regimens to choose from, it may be more important how easily drugs can be adhered to than which drugs are more effective. It is also clearly imperative that doctors do not just give out drugs and leave the patients to their own resources, but that full adherence support is given.