Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-02-22
2001-06-12
Brusca, John S. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S024300
Reexamination Certificate
active
06245511
ABSTRACT:
FIELD OF THE INVENTION
The invention generally relates to techniques for monitoring the effectiveness of medical therapies and dosage formulations, and in particular to techniques for monitoring therapy effectiveness using viral load measurements.
BACKGROUND OF THE INVENTION
It is often desirable to determine the effectiveness of therapies, such as those directed against viral infections, including therapies involving individual drugs, combinations of drugs, or other related therapies. One conventional technique for monitoring the effectiveness of a viral infection therapy is to measure and track a viral load associated with the viral infection, wherein the viral load is a measurement of a number of copies of the virus within a given quantity of blood, such per milliliter of blood. The therapy is deemed effective if the viral load is decreased as a result of the therapy. A determination of whether any particular therapy is effective is helpful in determining the appropriate therapy for a particular patient and also for determining whether a particular therapy is effective for an entire class of patients. The latter is typically necessary in order to obtain FDA approval of any new drug or medical device therapy. Viral load monitoring is also useful for research purposes such as for assessing the effectiveness of new antiviral compounds determine, for example, whether it is useful to continue developing particular antiviral compounds or to attempt to gain FDA market approval.
A test to determine the viral load can be done with blood drawn from T-cells or from other standard sources. The viral load is typically reported either as an absolute number, i.e., the number of virus particles per milliliter of blood or on a logarithmic scale. Likewise, decreases in viral load are reported in absolute numbers, logarithmic scales, or as percentages.
It should be noted though that a viral load captures only a fraction of the total virus in the body of the patient, i.e., it tracks only the quantity of circulating virus. However, viral load is an important clinical marker because the quantity of circulating virus is the most important factor in determining disease outcome, as changes in the viral load occur prior to changes in other detectable factors, such as CD4 levels. Indeed, a measurement of the viral load is rapidly becoming the acceptable method for predicting clinical progression of certain diseases such as HIV.
Insofar as HIV is concerned, HIV-progression studies have indicated a significant correlation between the risk of acquiring AIDS and an initial HIV baseline viral load level. In addition to predicting the risk of disease progression, viral load testing is useful in predicting the risk of transmission. In this regard, infected individuals with higher viral load are more likely to transmit the virus than others.
Currently, there are several different systems for monitoring viral load including quantitive polymerase chain reaction (PCR) and nucleic acid hybridization. Herein, the term viral load refers to any virological measurement using RNA, DNA, or p24 antigen in plasma. Note that viral RNA is a more sensitive marker than p24 antigen. p24 antigen has been shown to be detectable in less than 50% asymptomatic individuals. Moreover, levels of viral RNA rise and fall more rapidly than levels of CD4+ lymphocytes. Hence, changes in infection can be detected more quickly using viral load studies based upon viral RNA than using CD4 studies. Moreover, viral load values have to date proven to be an earlier and better predictor of long term patient outcome than CD4-cell counts. Thus, viral load determinations are rapidly becoming an important decision aid for anti-retro viral therapy and disease management. Viral load studies, however, have not yet completely replaced CD+ analysis in part because viral load only monitors the progress of the virus during infection whereas CD4+ analysis monitors the immune system directly. Nevertheless, even where CD4+ analysis is effective, viral load measurements can supplement information provided by the CD4 counts. For example, an individual undergoing long term treatment may appear stable based upon the observation of clinical parameters and CD4 counts. However, the viral load of the patient may nevertheless be increasing. Hence, a measurement of the viral load can potentially assist a physician in determining whether to change therapy despite the appearance of long term stability based upon CD4 counts.
Thus, viral load measurements are very useful. However, there remains considerable room for improvement. One problem with current viral load measurements is that the threshold level for detection, i.e., the nadir of detection, is about 400-500 copies per milliliter. Hence, currently, if the viral load is below 400-500 copies per milliliter, the virus is undetectable. The virus may nevertheless remain within the body. Indeed, considerable quantities of the virus may remain within the lymph system. Accordingly, it would be desirable to provide an improved method for measuring viral load which permits viral load levels of less than 400-500 copies per milliliter to be reliably detected.
Another problem with current viral load measurement techniques is that the techniques are typically only effective for detecting exponential changes in viral loads. In other words, current techniques will only reliably detect circumstances wherein the viral load increases or decreases by an order of magnitude, such by a factor of 10. In other cases, viral load measurements only detect a difference between undetectable levels of the virus and detectable levels of the virus. As can be appreciated, it would be highly desirable to provide an improved method for tracking changes in viral load which does not require an exponential change in the viral load for detection or which does not require a change from an undetectable level to a detectable level. Indeed, with current techniques, an exponential or sub-exponential change in the viral load results only in a linear change in the parameters used to measure the viral load. It would instead be highly desirable to provide a method for monitoring the viral load which converts a linear change in the viral load into an exponential change within the parameters being measured to thereby permit very slight variations in viral load to be reliably detected. In other words, current viral load detection techniques are useful only as a qualitative estimator, rather than as a quantative estimator.
One reason that current viral load measurements do not reliably track small scale fluctuations in the actual number of viruses is that a significant uncertainty in the measurements often occurs. As a result, individual viral load measurements have little statistical significance and a relatively large number of measurements must be made before any statistically significant conclusions can be drawn. As can be appreciated it would be desirable to provide a viral load detection technique which can reliably measure the viral load such that the statistical error associated with a single viral load measurement is relatively low to permit individual viral load measurements to be more effectively exploited.
Moreover, because individual viral load measurements are not particularly significant when using current methods, treatment decisions for individual patients based upon the viral load measurements must be based only upon long term changes or trends in the viral load resulting in a delay in any decision to change therapy. It would be highly desirable to provide an improved method for measuring and tracking viral load such that treatment decisions can be made much more quickly based upon short term trends of measured viral loads.
As noted above, the current nadir of viral load detectability is at 400-500 copies of the virus per milliliter. Anything below that level is deemed to be undetectable. Currently the most successful and potent multi-drug therapies are able to suppress viral load below that level of detection in about 80-90 perce
Brusca John S.
Kim Young
Kukkonen, III Carl A.
Mallery Daniel C.
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