It's Time to Research TDM

The Time Has Come To Accelerate Research Into Using TDM To Adjust Low Drug Blood Levels For the Purpose Of Improving Viral Load Response to HAART

Dear Community:

There is an issue that I think needs more attention, and ought to be considered for prioritization by the US research community. For several years the HIV community including researchers have been discussing the concept of using Therapeutic Drug Monitoring to evaluate drug blood levels for a patient initiating therapy, and to use this information to adjust dosing for the goal of improving or optimizing the viral load response to the patient's regimen. Of course, another purpose in using TDM is to reduce side efects & toxicities. For example, a recently published paper suggested that efavirenz blood levels were often high in patients with typical neuroplogical EFV- associated side effects. High blood levels may be associated with higher incidence or severity of side effects for a number of patients. And the authors of this paper suggest that blood levels can be reduced and this could achieve a reduction in side effects while maintaining adequate viral load suppression. This needs further exploration.

There have been strong differences of opinion between the American pharmacologists and the Europeans on whether TDM could be used to adjust dosing in individuals with low blood levels of drugs for the purpose of improving their antiviral response to therapy. I think differences of opinion are less when it comes to using TDM to monitor side effects & toxicities. A number of key American researchers, in general, have felt that the difficulties involved in implementing TDM for this purpose may be too prohibitive, although a number of US treating physicians I know have been regularly using TDM for this purpose in their patients. I did not attend this year's Pharmacology Workshop because I started Pegylated Interferon+ribivarin therapy just before the Workshop and was not feeling well enough to attend the meeting. But I have been following the proceedings (NATAP will issue a report on the Conference) and I have been following this area. Europeans have taken the lead in this area of using TDM and are ahead of US researchers and practitionioners in trying to overcome the difficulties associated with using TDM to adjust blood levels and improve virologic outcome. First, the Europeans believe that TDM can be used for this purpose. They also believe that it's possible that resistance testing in combination with monitoring drug levels may also be a useful way to monitor response to therapy. And Charles Boucher, John Schapiro and his colleagues have a study ongoing using genotypic resistance testing & TDM to address this question. Make no mistake about it, there are clear difficult hurdles in trying to harness this concept and use it in the clinic. A number of European investigators are exploring the use of models for addressing some of these difficulties. For example, one of the difficulties is when do you check drug blood levels--at trough, or at some other time point during the dosing period; is one time point measure adequate or do you need several time points during a dosing period; do you need to take blood samples on several consecutive days or is taking one or two samples during one dosing period adequate. Does food intake, which can vary, affect blood levels?

Another difficulty is adherence. What if the patient takes their drugs only for several days before coming in to see the doctor to have their blood levels monitored, but otherwise they are not taking their medications. Clearly, there are hurdles, but for many individuals TDM for the purpose outlined in this paper may be useful. Several European investigators are exploring a model that would use taking one blood sample at any time during a dosing period and they feel they may be able to establish that it as reflective of blood levels during the entire dosing period. This would address some of the hurdles.

At this point in time, it's clear much more research is needed to explore whether or not TDM can be effectively used in general clinical practice to monitor for low drug blood & to adjust dosing. We also need more research to address the numerous hurdles. However, I think the time has come for the US research community to accept the notion that this area ought to receive more research attention. The ACTG has been lagging in getting research off the ground because they have been more discouraged that the hurdles are too prohibitive. Still, some US rsearchers have been studying this concept and believe the hurdles can be ovecome. They include Courtney Fletcher, Steve Piscitelli and others. While European researchers including leadership by Charles Boucher, John Schapiro based in Israel, David Burger, David Back, and Richard Hoetelsmans have moved ahead in this area. They have consistently supported the idea that TDM can be used for this purpose. In their clinics and in other European clinics HIV treating physicians and pharmacologists utilize drug level monitoring for this purpose in managing their patients.

The ability to monitor NRTIs such as AZT, d4T and abacavir with TDM is at this point in time limited. It may be necessary to measure intra-cellular dr ug levels to evaluate NRTIs because that is where they are active (in the cells). But research is looking at correlating blood levels with intracellular levels and we may find that measuring blood levels will reflect intracellular levels. Still, this reflects yet another difficulty in using TDM to evaluate response to HAART. There are 3 or 4 drugs in a regimen so is evaluating blood levels only for the PI or NNRTI truely reflecyive of response to a regimen which also includes 2 NRTIs?

I think it's time for US research establishments to start taking a more emphatic and active role in implementing studies addressing this question. Steve Piscitelli recently left the NIH to head the Virco efforts to conduct studies of this concept. So clearly, a number of efforts are forging ahead to study this question.