Dear Nelson and Friends,
I read with interest the attached excellent review of treatment strategies for PRN Notebook by Dr’s Charles Farthing and Athe Tsibris. I believe and feel strongly that two incorrect conclusions might be drawn from the studies presented in article that could adversely effect treatment strategy in individual patients.
1. Firstly, the conclusion is drawn from the tipranavir (Aptivus) and darunavir (Prezista) trials that “Salvage therapy is best undertaken when at least two active drugs are available.” Although the data presented from the tipranavir and darunavir trials show that two active drugs are better than one active drug for patients starting a new salvage regimen the results in my mind are pretty poor even when two new actives agents are used. MY CONCLUSION IS THAT 3 not 2 ACTIVE DRUGS SHOULD BE STARTED IF AT ALL POSSIBLE IN A SALVAGE REGIMEN.
Starting just two drugs is not quite as bad as starting one new drug but similarly risks exposing patients to sequential therapy and blowing sometimes the last remaining treatment options. In fact starting two new “active agents” in salvage therapy instead of one active agent risks blowing two drugs which is worse that blowing one active drug.
For example, the clinical trial presented on tipranavir shows that only 34% of pts given tipranavir and enfurvitide (Fuzeon) sustained an undetectable viral load at 96 weeks. That means that 66% of patients probably ended up resistant to Fuzeon and Aptivus and possibly components of their “optimized” background.
So the question needs to be posed when is it worth the risk of failing therapy and using up two active agents instead of waiting for three active agents?. Unfortunately, none of the studies presented provide much help in answering this question.
In the Resist studies with tipranavir the average CD4 cell count at entry was 196 with only 20% of the patients studied starting with less than 50 T cells. Thus easier to treat patients with higher T cells are mixed in with more difficult to treat patients. Although patients with higher CD4 cells may have a lot of resistance they are often viral disconnect patients who maintain stable CD4 cells sometimes for years despite drug resistance. (more on this later)
The consequences of more sequential therapy for these patients is less dire than for more advanced patients with very low CD4 cells whose lives may depend on the success of a salvage regimen using new meds.
Unfortunately the consensus in my profession as reflected in this article and the DHHS treatment guidelines is to start two new drugs. Perhaps this is why Nelson has correctly described patients truly in need of salvage rx as the “invisibles” in an important Wall Street Journal article on the plight of HIV infected patients in need of better therapies.
It seems wrong to me that the standard of care for easier to treat naive patients is to get three fully active drugs in combination when much more difficult to treat patients are told the standard is to get just two new active drugs.
I believe patients with very low CD4 cells and multidrug resistance and who have or at risk of suffering from AIDS complications are in a different category than healthier patients with MDR-HIV who are usually asymptomatic. These patients sometimes desperately need three fully active drugs in their salvage regimen.
In addition as Nelson correctly points out on his website salvagetherapies.org patients are getting exposed to sequential therapy who participate in clinical trials of new drugs where patients are randomized to drug or placebo and less than 3 fully active drugs are given.
There needs to be a pooled treatment registry tracking the outcomes of all salvage patients treated in clinical trials to learn what approaches lead to the best outcomes including what constitutes the best Optimized Background regimen for patients who must start a substandard regimen with only one or two active drugs if the clinical situation dictates an urgent treatment change,
Drug companies like BI, Merck and Tibotec deserve great credit for developing new drugs and bringing them to market. However it is important for the HIV medical community and patient community to realize that the focus of drug companies is to gain accelerated FDA approval based on a multidrug resistance based indication and win market share for their new drug. How to best use their drug with other active agents is often left to private investigators in post approval studies.
In summary Dr’s Farthing and Tsibris conclude that “when using tipranavir or darunavir be sure to combine it with at least one new active agent.” I believe that this is a mistake and should specify using tipranavir or darunavir with at least 2 active drugs. The current second wave of HAART can make this reality a possibility with two new protease inhibitors, a new non nucleoside, Maraviroc, an integrase inhibitor and Fuzeon. The challenge that we face now is how to treat patients who have already developed resistance to several of these products since their approval or in EAPs and phase III studies.
2. My second point regards what I believe can be a wrong conclusion drawn from a study referenced in the article entitled “Rate of Viral evolution and risk of losing future drug options in heavily pretreated patients remaining on a stable partially suppressive regimen” by H Hatano.
Farthing raises concerns that patients who are stable but elect to continue their meds rather than starting new drugs could lose active drugs due to resistance due to progressive resistance and cross resistance. This supports the notion that patients with viral breakthrough and drug resistance should if possible be put on maximally suppressive regimens to avoid using up future drug options.
While this is a reasonable concern, there is in my mind little evidence in the actual paper supporting this concern. In addition, there is no evidence in the Hatano paper that patient outcomes are compromised by the strategy of maintaining an MDR-HIV patient who has a viral disconnect response.
In fact only 4% of patients followed in this study developed evidence of new resistance to tipranavir which could compromise a future salvage regimen. This is a complicated study but in my opinion after careful review if anything it shows the opposite: that it is reasonably safe to continue a regimen that is maintaining a good immune response despite ongoing viral replication (viral disconnect) from the standpoint of preserving good future treatment options
In fact, a recent study published in JAIDS in September 2004 entitled “Effect of Persistent Moderate Viremia on Disease Progression During HIV Therapy” shows that patients with less than 20,000 copies/ml have similar outcomes as patients with less than 400 copies /ml in patients on treatment when followed up several years later. Presumably some of the patients with ongoing viremia followed in this study also developed some additional resistance mutations which did not impact on outcomes. Of note patients with viral loads >than 20,000 had worse outcomes.
The issue of how to strategically address treatment in healthier patients with drug resistance is a complicated one and requires the careful individualized application of principles of therapy including drug toxicity concerns not just drug resistance concerns. More research is needed in these patients that tracks clinical outcomes.
Its great news that finally new HIV drugs with new mechanisms of action are becoming available to patients. Let’s make sure we make the best possible use these new drugs by strategically applying what we have learned about principles of antiviral therapy such as combination therapy with three active drugs (whether treatment naive or experienced) and by tracking actual patient outcomes.
Dr. Paul Bellman
New York City
Surviving Antiretroviral Drug Resistance: Strategies for Optimal Use of Therapeutic Agents