Facts and Issues [International Conference on AIDS (11th: 1996: Vancouver, Canada)]

Most of these therapies can be used as prophylaxis or as treatment. Some doctors will
reserve certain therapies as treatment, and use others for prophylaxis.Thus rifabutin is
often used for the prevention of MAC, with clarithromycin and azithromycin reserved for
treatment. Many doctors recommend that dual combination therapy be used to treat
MAC; others recommend three or four drugs as treatment.
Other Important Terms and Concepts
Throughout the week of the Conference, certain key concepts will be presented as part
of scientific papers, particularly in Track B: Clinical Science. Many of these concepts are
fundamental to understanding what's new and what's exciting in the field of HIV treatments.
These concepts include viral load as a surrogate marker, drug resistance and viral variability.
CD4 Counts and Viral Load Measures: Surrogate Markers to Determine Drug Efficacy
Traditionally researchers used "time-to-death" or "time-to-illness" or progression of illness
to determine the effectiveness of drugs.These are referred to as "clinical outcomes"outcomes that can be measured through observation by a clinician. In AIDS, however, it has
become evident that the efficacy of drugs may be determined before waiting until someone
becomes outwardly ill or dies.This is particularly important given the shortened lifespan of
a person living with HIV
Instead, researchers have found substitute or "surrogate" markers to determine if HIV
disease is progressing.The tools to make these evaluations are virological and immunological
measurements.These lab measurements are used to give a rapid indication of drug activity
It would take a much longer period of time to actually monitor whether the treatment
reduces disease progression or the chance of early death.
Virological markers include viral load and p24 antigen (a component of HIV), while
immunological markers include CD4 cell count, neopterin (a substance produced by activated monocytes and macrophages) and 32-microglobulin (a molecule present on the surface
of B and T immune cells). Plasma viral load or CD4 cell count are the most commonly used
surrogate markers. Researchers assert that a drug is beneficial when it lowers plasma viral
load and increases CD4 cell counts. By using a combination of both measures, it is believed
that a highly predictive assessment of clinical benefit may be made.
Drug Resistance
Each time HIV replicates, some of the new viruses are slightly different genetically to the
old ones, in that parts of a particular gene may be missing or changed.Thus during each
reproductive cycle, new virus is made which has, for example, a slightly different enzyme to
previous viruses. Drugs tend to target just one area of an enzyme and, on some occasions,
the particular enzyme of the new HIV is so different to the old one that it is no longer
affected by the current inhibitor drugs.These different viruses therefore continue to reproduce,
as they are outside the drug's influence. Eventually these different viruses become the majority,
and viral replication starts to increase rapidly again. When the virus population reaches this
stage it is said to be resistant to the drug being used.
Protease inhibitors target different parts of the virus than the NRTIs.Thus to become
resistant to both a protease inhibitor and a reverse transcriptase inhibitor, the new virus
must have changes on both the protease and reverse transcriptase genes.The likelihood
of this is less than the likelihood of a virus having changes on just one of those genes. In
addition, for resistance to occur to some protease inhibitors, one genetic change to the
protease is not enough; for example, a minimum of three changes are required for the
virus to become resistant to indinavir and ritonavir.Thus there are two major ways to
minimise resistance:
* use a combination of therapies which act against different parts of the virus or viral lifecycle
* suppress virus replication as much as possible so that not enough of the changed viruses
can be produced