Being Alive 1995 Feb 5: 9
Combination treatment with AZT (zidovudine) plus 3TC
(lamivudine) produces the most pronounced and prolonged
effect of any anti-HIV drug regimen yet studied in
suppressing HIV replication and increasing CD4 counts,
according to study results presented last November, at the
Second International Congress on Drug Therapy in HIV
Infection in Glasgow, Scotland. The promising results have
prompted Glaxo, the developer of 3TC, to announce that the
company intends to file in the first half of 1995 for FDA
approval of 3TC in combination with AZT.
The two Phase II/III studies of 352 people reported at the
Glasgow Conference were designed to evaluate the effect of
the AZT/3TC combination on laboratory markers of HIV disease
progression, such as viral load and CD4 counts, not clinical
endpoints, such as opportunistic infections and survival
time. No clinical data on the effects of the AZT/3TC double
combination were presented in Glasgow.
Effect on CD4 Counts
Professor Christine Katlama of the H�pital Piti� Salp�ti�re
in Paris reported on a study of 129 HIV+ patients with CD4
counts between 100 and 400 cells who had no previous anti-HIV
threapy. Participants taking the AZT/3TC combination had an
average gain of 85 CD4 cells after 8 weeks of therapy and
sustained an 80 cell increase above baseline at week 24.
Participants who stayed on the combination experienced a 49
CD4 cell increase over baseline at week 48. The patients who
received AZT alone experienced a drop of 7 CD4 cells at week
24. However, those in the AZT monotherapy group who switched
to the combination regiment showed an average increase of 40
CD4 cells above baseline at week 48.
Effect on HIV Levels in Blood Cells
Professor Katlama reported that participants taking the
AZT/3TC combination experienced a 99% decrease below baseline
of HIV levels in blood cells at week 24, as measured by
cultures of peripheral blood mononuclear cells (PMBC). For
participants who continued the combination regimen, the 99%
reduction in virus levels was sustained at week 48. Among
patients taking AZT alone, HIV levels in blood cells fell 70%
at week 4, but returned to within 11% of baseline by week 24.
Patients on AZT alone who switched to the combination at week
24 also experienced a 99% reduction in HIV levels in blood
cells at week 48.
Effect on HIV Levels in Blood Plasma/Serum
As measured by quantitative PCR HIV RNA testing, levels of
HIV in the bloodstream (viral load) of participants taking
the AZT/3TC combination were reduced by 92% below baseline at
week 2 and were sustained at 86% by week 24 and at 91% by
week 48, according to Professor Katlama. HIV levels in those
taking AZT alone were reduced by 76% at week 2, but by week
24 had reached 36% below baseline. Patients who switched from
AZT monotherapy to combination therapy at week 24 experienced
a 92% decrease in HIV levels from baseline by week 48.
Early studies of 3TC as a single agent in HIV infection,
showed that HIV rapidly develops resistance to the drug.
Because of this, it quickly became apparent that 3TC
monotherapy did not have a promising role in fighting HIV
The rationale for combining 3TC with AZT was the discovery
that the two drugs were synergistic in their anti-HIV
activity. Researchers also theorize that 3TC, when used in
combination with AZT, may help to prevent or significantly
delay the development of HIV resistance to AZT. In fact, this
may explain in part the ability of the AZT/3TC combination to
reduce viral load more effectively and for a more sustained
period of time than AZT alone.
German Study of AZT/3TC Combination
At the Glasgow Conference, Schlomo Staszewski, MD, of Goethe
University in Frankfurt, Germany, reported results of a
second study of combination treatment with AZT plus 3TC. That
study compared 2 doses of 3TC in combination with AZT and AZT
alone. Two hundred twenty-three HIV+ patients with 100-400
CD4 cells and with at least 24 weeks of prior AZT therapy
took either 150 or 300 mg 3TC twice daily in combination with
600 mg/day AZT, or 600 mg/day AZT alone.
After 4 weeks, both doses of combination therapy increased
CD4 cell counts from baseline by an average of 33 cells
(high-dose combination) and 36 cells (low-dose combination).
At week 24, participants on both combination regimens
experienced an average increase of 33 CD4 cells. On average,
patients taking AZT alone experienced decreases of 8 CD4
cells below baseline at week 24. The effect of the
combination on CD4 counts beyond 24 weeks is not yet known.
In addition, viral load data from the German study was not
presented in Glasgow.
Adverse Side Effects
Overall, the combination of AZT and 3TC was well tolerated by
patients, according to the investigators. Nausea and vomiting
were reported in 26% of participants in the French study and
in 15% of those in the German study. Headache was reported in
9% of patients in both studies. Neutropenia and anemia
affected 4% and 5%, and 3% and 2% of patients in the French
and German studies, respectively.
Access to 3TC
3TC is currently available free to HIV+ individuals through
an Open Label Compassionate Use protocol. To be
eligible,individuals must have failed or be intolerant to
standard anti-HIV therapy (AZT, ddI, ddC, d4T) and have fewer
than 300 CD4 cells. To enroll patients in the Open Label
protocol, physicians may call Glaxo at 1.800.248.9757.
The data from the French and German studies are extremely
promising. The French data, in particular, demonstrate
clearly that the AZT/3TC combination significantly reduces
HIV levels and significantly increases CD4 counts over a
48-week period. The AZT/3TC combination appears to have a
more profound effect on decreasing viral load and increasing
CD4 counts than the double combination of either AZT plus ddI
or AZT plus ddC, or than the triple combination of AZT plus
ddC plus saquinavir (a protease inhibitor drug). In addition,
the beneficial effects of the AZT/3TC double combination on
laboratory markers persisted for a year, without showing any
sign of falling off.
These data strengthen the notion that combination treatment
with certain nucleoside analogues is more effective than
single agent therapy in increasing CD4 counts and reducing
HIV levels in blood cells and in the bloodstream. Although
these studies evaluated changes in laboratory markers, not
clinical endpoints, there is a growing consensus among
researchers that reduction of viral load correlates with
clinical benefit. Trials to assess the clinical benefit of
combination treatment with AZT/3TC will begin in North
America and Europe in early 1995, according to Glaxo.
Implications of Study Results
The release of these data comes at an important moment in
AIDS research. The results of these and other studies showing
that the two and three drug combinations of anti-HIV agents
can significantly reduce viral load add considerable weight
to the argument that combination treatment offers the current
best hope for slowing HIV disease progression.
After reviewing the promising data from the AZT/3TC
combination studies, two questions immediately come to mind:
(1) what would be the effect on laboratory and clinical
markers of a triple combination using AZT plus 3TC plus a
protease inhibitor? (2) what would be the effect of a
four-drug combination using AZT plus 3TC plus a protease
inhibitor plus nevirapine or a second protease inhibitor? It
is hoped that the Inter-Company Collaboration of
pharmaceutical firms will design short-term studies in the
near future that can help to provide the answers to these
questions. (This article is reprinted from the December 1994
issue of BETA, Bulletin of Experimental Treatment for AIDS,
with the permission of the San Francisco AIDS Foundation. For
subscription information, call 1.800.959.1059.)