December 18, 2001
"Meet the Experts" sessions are different from the typical structured ten-minute presentation of data or the traditional plenary talk. In these sessions, experts, in this case, Ann Collier from the University of Washington, and Patrick Yeni from the Bichat Medical School in France, presented a brief overview of important topics in the management of the treatment-experienced patient. There followed a lively question and answer session. The interaction helps frame problems and focus attention on the types of dilemmas we face.
Much about salvage therapy is controversial. In fact, many even object to the name "salvage" itself. There were few new data at this meeting, or at the last two meetings, that provided clear and simple answers. However, here are some of the issues.
It is important to clarify situations and goals. First failure may be defined as viral breakthrough in a patient on his or her first potent regimen, be it protease inhibitor-based, NNRTI-based, or triple nucleoside. Here, the goal is to achieve complete suppression with the next regimen. Adherence may be the major factor in first failure, and it must be addressed before a new regimen is started.
Data were reviewed reminding us that the patterns of resistance are different depending on the regimen. Patients failing protease inhibitor regimens often fail with only nucleoside mutations (often resistance to 3TC) or with wild-type virus. Those failing NNRTIs often have NNRTI resistance, while those failing abacavir-based regimens usually first develop an M184V mutation which confers 3TC resistance, but if maintained on a failing therapy will develop multiple nucleoside associated mutations (or TAMs) which can jeopardize the whole class.
In second failure, complete suppression may be more difficult. This will depend on the type and number of mutations and the classes of drugs that remain. In late failure, complete suppression is unlikely to be possible. The objective here is to keep the patient healthy and prevent further declines in the immune system. Here, the new paradigm, according to Yeni, may be to find a tolerable regimen that maintains an unfavorable pattern of resistance mutations. This may result in a less fit virus and little or no decline in CD4 count. In this setting, Dr. Yeni suggested, short treatment interruptions have some appeal. Reversion of the virus to wild type in some studies is associated with greater response to subsequent reintroduction of therapy, despite the fact that resistant virus remains in the archival record in the form of infected lymphocytes. The risk posed by treatment interruption is the rapid decline in CD4 count that can occur. If treatment interruption is considered before beginning a salvage regimen, the interruption should be short and the patient watched closely.
Multi-drug regimens, including some recycled drugs known to some as mega-HAART (and to others as mega-toxicities), is a possible strategy. These regimens have been reported to be effective in some patients in late salvage, but their usefulness is limited by toxicity and pill burden.
There was an extensive discussion of sequencing strategies. This area remains controversial, and is made more difficult by our understanding that there is much more cross resistance among virtually all nucleosides than previously appreciated. The good news is that we now better understand protease inhibitor resistance, and cross resistance is not always complete. No optimal strategy for sequencing nucleosides has yet been demonstrated.
Resistance testing is important in salvage therapy, but the discussion here focused on cautions and limitations. The best data confirming the utility of resistance testing comes from patients with first failure, and these are not the most difficult patients to manage. As the complexity of patient experiences and viral mutations increases, the results of resistance tests become increasingly difficult to interpret, and the accuracy of interpretation algorithms decreases. The presenters reminded the audience about the importance of always using treatment history in conjunction with resistance tests. This is particularly important for drugs the person is not currently taking.
It was interesting to see the different approaches to drug levels (therapeutic drug monitoring, or TDM) taken on opposite sides of the Atlantic. In France, according to Dr. Yeni, therapeutic drug monitoring is already readily available and paid for by health insurance. It is considered part of the standard of care, particularly in salvage therapy. In the U.S., however, Dr. Collier explained that the tests are not easily available, and rarely used. However, both agreed that definitive data on the benefit of therapeutic drug monitoring and on target levels are still lacking. The French have chosen to act based on some preliminary studies suggesting benefit, particularly the Athena study (for more information on this study, click here). We Americans seem to have chosen to hold off until there is more convincing evidence. I am not sure who is correct.
Discussion of drug levels is linked to the possible use of new combinations. The greatest interest seems to be in the combination of amprenavir with lopinavir/ritonavir plus saquinavir as well as amprenavir with lopinavir/ritonavir. Conflicting results have been reported at previous meetings, but seem to suggest that amprenavir levels are decreased. A definitive interaction study is clearly needed, and this might be an indication for therapeutic drug monitoring, once laboratory standards and quality control are solved.
New agents with increased activity and boosted regimens are two of the strategies used in managing patients with second failure or multiple failures. Lopinavir/ritonavir and boosted amprenavir have shown some activity in patients with extensive protease inhibitor resistance, but the best results are seen in patients who are also non-nuke-naive. There is less experience using these regimens to rescue patients with multiple protease inhibitor and non-nuke experience. Tenofovir may have a role in salvage, as demonstrated by studies of intensification presented at ICAAC, but when there is very extensive nucleoside resistance, its antiviral activity is diminished. The speakers suggested therefore that perhaps tenofovir should ideally be used somewhat earlier in the sequence.