Being Alive 1996 Sep 5: 6
Although good news from the International AIDS Conference in
Vancouver has inspired renewed hope within the hiv/aids arena,
there is a growing concern that prevention efforts may begin to
wane once people believe that a "cure" is at hand.
A vital question demands further exploration: What are the
options for the growing population of hiv+ people who are
unable to tolerate currently available protease inhibitors?
Even among individuals who can tolerate the side effects of
protease inhibitors, a significant percentage will still fail
therapy due to non-compliance (leading to viral drug
resistance), or from rare "breakthroughs" despite strict
adherence to the prescribed three-drug combination. Preliminary
data from the "Crixivan plus Two Nucleosides Study" suggest
that, after 60 weeks of treatment, a persistent, "undetectable"
viral load exists among 80-p;90% of study participants;
10-p;20% of study participants have detectable levels of hiv in
circulation. The significance of this finding is still unclear.
If the goal of triple combination anti-retroviral therapy is to
achieve long term viral clearing, the idea of a safety net is
very attractive. It has been estimated that 12 anti-retroviral
drugs will be available for general use by the end of 1996,
thus broadening treatment options. The next generation of
anti-hiv agents approaching Phase III trials may be categorized
Improvement of Existing Classes of Drugs
Nucleoside Analogues: 1592U89 from Glaxo-Wellcome is a
nucleoside analogue with potent in vitro (test-tube) activity
against hiv-1. Like other agents in this class, 1592U89
inhibits the enzyme reverse transcriptase, thus preventing
viral replication. The valuable features of this drug are: good
absorption when taken orally (the drug may be taken with food);
capability of reducing viral load by two log-fold when used by
itself; ability to increase (on average) CD4 cell count by 100
cells/mm^3 after four weeks; no rapid resistance seen in vitro;
excellent central nervous system penetration.
Lobucavir (BMS) is another promising nucleoside analogue
currently in development. In addition to good oral absorption
and potency against hiv, Lobuvacir is active along a "broad
spectrum" (i.e., it is active against CMV, Herpes simplex and
Herpes zoster, Hepatitis B virus, and Epstein-Barr virus).
Protease Inhibitors: Nelfinavir (Viracept) from Agouron
Pharmaceuticals appears to be one of the most potent protease
inhibitors available. One study examining the relationship
between nelfinavir in combination with AZT and 3TC showed an
average decrease in hiv-RNA by 3.6 log. Interestingly, the
development of resistance to nelfinavir still allows
susceptibility to indinavir, ritonavir, saquinavir and VX-478
(a new and highly potent protease inhibitor compound from
Glaxo-Wellcome), thus potentially making nelfinavir the first
line protease inhibitor.
New Classes of Antiretroviral Drugs
Nucleotide Analogues: Adefovir dipivoxil (Gilead Sciences,
Inc.) is one of the first nucleotide-class drugs being
developed for the treatment of hiv. Unlike nucleoside analogues
which only penetrate uninfected cells, adefovir dipivoxil is
capable of penetrating both infected and uninfected cells, and
a principal benefit is its ability to stay inside a cell for a
long period of time. Adefovir dipivoxil is a broad spectrum
antiretroviral agent, active against CMV, Herpes viruses,
Hepatitis B virus, and HIV.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's):
Nevirapine is the first drug within the NNRTI classification to
be approved by the Food and Drug Administration (FDA) for use
in combination therapy. Nevirapine acts by directly inhibiting
the enzyme reverse transcriptase, unlike nucleoside-class drugs
which act upon the same enzyme via a different mechanism (i.e.,
prevention of hiv-DNA chain growth).
DMP-266 (Dupont Merck) is a new NNRTI with good oral
absorption. DMP-266 has a high specificity for hiv-1 reverse
transcriptase and is effective on AZT-resistant viral strains,
making it a very potent agent. In vitro (i.e., test tube)
studies with DMP-266 show resilience against the development of
Biological Immune Modulators
Interleukin-2 is a natural cytokine released by T-cells and has
powerful effects on the growth and differentiation of immune
cells (including T-cells, B-cells, and natural killer cells).
Preliminary data indicate that Interleukin-2 is capable of
stimulating dramatic increases in CD4 cell counts in people
with early hiv infection. Although Interleukin-2 is generally
well-tolerated, some people develop a flu-like illness with
each infusion. This form of infusion approaches the reality of
"immune reconstitution" (i.e., the ability to restore a damaged
immune system to normal function).
HBYO97, mentioned at the Vancouver conference, is an intriguing
compound designed to prompt hiv-1 genetic mutation and cause
the virus to be less virulent. Other novel cytokines, e.g. "C-C
chemokines" (a substance produced by CD4 cells, CD8 cells,
T-cells, and macrophages), can stop hiv replication in vitro
and prevent HIV from entering into human cells.
(Tom Baholyodhin, MD is an HIV specialist who is actively
involved in clinical research at Kraus Medical Partners. For
additional information, contact the KMP Research Hotline at