The U.S. Public Health Service has recognized the need for updated
recommendations for antiretroviral treatment and now plans a two-step process
involving two committees. The first is the NIH Panel to Define Principles of
Therapy of HIV Infection, with Charles Carpenter as Chairman. The second
committee is the Panel on Practice Policies for Clinical Care of People with
HIV, which is charged with defining guidelines based on the principles
developed by the NIH panel. The time line is a bit vague, but the NIH Panel
plans a public presentation in January 1997; the Panel on Practice Policies had
its first meeting December 2-3, 1996. The NIH Panel held a public meeting
November 13-14, 1996, and the following is a summary of some of the
presentations.
- David Ho, M.D. HIV Replication Dynamics (Aaron Diamond AIDS
Research Center): Dr. Ho noted that the decrease in HIV plasma concentrations
occurs in two phases. During the first 10-14 days of "triple
therapy,"
decline in viral load is due to a rapid decrease in productive (CD4) cells. The
second phase, occurring after the "inflection point," is marked by a
more gradual decline over a period of weeks or months, which is ascribed
primarily to decay of HIV reservoirs in tissue macrophages. A practical
application of these data is that the impact of initial therapy should be
readily apparent within 10-14 days, although the total impactor nadir may not
be apparent for months.
- Ashley Haase, M.D. Analysis of Tissue Reservoirs (University of
Minnesota): Dr. Haase emphasized that lymph tissue is the major repository of
HIV, accounting for about 98% of the total viral burden. Particularly large
concentrations of HIV are attached to the surface of follicular dendritic
cells. It was noted that antiviral treatment is associated with depletionof
all pools in lymph nodes as well as plasma.
- Angela McLean, Ph.D. and Ronald Gress. T Cell Populations (Institut
Pasteur and NIH): The authors reviewed the T cell repertoire, with attention to
memory cells and "uncommitted" or naive cells. The regeneration
potential is either thymus dependent or reflects peripheral expansion. Memory
cells have a half-life of several months. Regeneration of this population is
largely age-dependent. The implications are that: 1) early intervention is
theo- retically desirable because it avoids the potential problems of target
cell depletion and the depletion of useful clones of memory cells; 2) the
poorer prognosis associated with aging may be explained by the reduced
regenerative capacity of T cells; 3) opportunistic infections correlate best
with the number of T cells rather than any change defined to date with respect
to the T cell repertoire.
- Alvero Munoz, Ph.D. Natural History of T Cell Depletion (Johns
Hopkins University): This presentation concerned modeling of CD4 slopes and
rates of progression in the Multicenter AIDS Cohort Study (MACS).The median
time from seroconversion to AIDS was 9.1 years; the median survival time from a
CD4 cell count <200/mm3 was 2.7 years, and the median survival time after an
AIDS-defining diagnosis was 1.3 years. The estimated proportion that will
survive longer than 12 years from seroconversion is 32- 40%, for 16 years is
19-25% and for 20 years is 10-17%. The slope of CD4 decline for over 1200
patients follow- ed sequentially showed no discrete group with persistently
high CD4 cells, suggesting that virtually all patients will eventually have
progression of disease. As expected, the rate of decline correlated with viral
burden.
- Joseph Margolick, M.D., Ph.D. T Cell Homeostasis (Johns Hopkins
Uni-versity): Analysis of T cells for participants in the MACS cohort showed
that the total number of cells bearing the CD3 marker, which in- cludes both CD4
cells and CD8 cells, remained relatively constant at approximately 1500/mm3
throughout the course of infection until late stage disease. At 1.-2 years
before an AIDS-defining diagnosis there was an "inflection point" in
which the total T cells declined. Thus, there appears to be T cell replacement
without regard to CD4 versus CD8 phenotype until late stage disease.
- David Chernoff, M.D. Quantiplex (bDNA) Assay for HIV-1 RNA (Chiron
Corporation): The diagnostic range of the Chiron bDNA assay expressed as
copies/ml is as follows: first generation: 10,000 to 1,600,000; second
generation: 500 to 1,600,000; third generation: 50 to 1,600,000. This assay
apparently does not detect the O group of HIV, although it is satisfactory for
groups A-F. No diurnal variation was noted.
- Timothy Schacker, M.D. Primary HIV Infection (University of
Min-nesota): The presenter reviewed 72 patients with the acute retroviral
syndrome as indicated by a compatible clinical illness combined with positive
p24 antigen plus negative antibody or HIV seroconversion within 12 months. Most
sought medical attention, but care providers correctly diagnosed only 26%.
Sequential analysis showed a rapid drop in the CD4 cell counts, averaging six
cells/mm3/week for the first six months. There was then a plateau
("inflection
point") with a subsequent loss averaging one cell/mm3/week. Most of the
patients had CD4 cell counts reflecting a selection bias in which most of the
patients had symptomatic disease. It was noted by the authors that six months
were required to reach the "set point," after which quantitative
virology predicted subsequent rates of progression. Poor prognostic findings
included a viral burden exceeding 120,000 copies/ml, clinical symptoms
associated with seroconversion, and age over 31 years.
- Robert Hogg, Ph.D. HIV Treatment in British Columbia, Canada
(Vancouver, British Columbia, Canada): Guidelines for treatment that serve as a
contingency for drug therapy have been established in British Columbia. Before
December 1995, the usual treatment was monotherapy with a nucleoside analog for
patients with a CD4 cell count <500/mm3. Combination treatment was allowed
with a CD4 cell count <350/mm3. In June 1996, the requirement for treatment
was a CD4 cell count <500/mm3 and a viral burden exceeding 5,000 copies/ml.
Use of protease inhibitors required a viral burden exceeding 100,000 copies/ml
or failure with combination treatment. Over 3,000 patients have now received
anti-viral treatment. In December 1995, there was a marked decline in the use
of monotherapy, evolving to the pattern noted in October 1996, in which only
4% of the patients were receiving a single agent. The most common regimen,
accounting for 46% of all treatment regimens, is AZT/3TC. Other common regimens
include d4T/3TC (12%), indinavir/d4T/3TC (8%), AZT/ddC (7%), saquinavir/d4T/3TC
(4%), saquinavir/AZT/3TC (4%) and AZT/ddI (3%); 16% received other regimens.
- Clifford Lane, M.D. and Anthony Kelleher, Ph.D. Treatment Induced
Changes in CD4 Cell Counts (NIH and Australia): The presenters reviewed the
expansion of T cells that accompanies antiretroviral treatment. Expansion of
the T cell pool is largely due to memory cells (CD45 RA). There appears to be
excellent regenerative capacity with IL-2, although functional status of these
regenerated cells is not known. With nucleoside analogs there is a modest
increase in the CD4 cell count, decrease in viral burden, and no change in CD8
cells. With protease inhibitors there is a robust increase in CD4 cell count,
an average two-fold increase in CD8 cells, as well as a major impact on viral
burden. It was noted that the CD4 cell count increase is predominantly composed
of memory cells, with no repair of pre-existing deficits. The mean maximum
increase is 100-150 CD4 cells/mm3 over the initial six months of treatment.
This appears to be a CD4 ceiling, and long term outcome is obviously not known,
but early treatment is recommended to avoid possible accumulation of defects in
the repertoire.
- Emilio Emini, Ph.D. Antiviral Drug Resistance (Merck Research
Lab-oratory): The author provided follow- up data from the trial in patients
receiving combination therapy with indinavir/3TC/AZT. Of those who achieved no
detectable virus (<500 copies/ml), 90% continued to have undetectable viral
load measurements to >75 weeks. Resistance was associated with multiple
mutations, and clinically significant resistance appeared to depend on
multiple mutations. HIV was described as "genetically unforgiving"
in the sense that, once resistance occurred, there was "no going
back."
This was demonstrated in the dose escalation study in which recipients of a
suboptimal dose were switched to high dose treatment but failed to demonstrate any response. The implication of this observation is obviously profound. A question from the Panel concerned recommendations for treatment in a
patient who failed indinavir/3TC/AZT, but no one could provide an answer.
- Mark Wainberg, M.D. Nevirapine Treatment (Montreal, Canada):
Results of BI 1046 (NVP/AZT/ddI vs. AZT/ddI vs. NVP/AZT for naive patients with
CD4 cell counts of 200-600/mm3), showed all treated with NVP/AZT had resistant
isolates at six months. Among those receiving triple therapy, there was no
detectable virus in 57% at 26 weeks. When quantitative HIV PCR was at
undetectable levels, the HIV recovered from peripheral blood mononuclear cells
was wild type rather than resistant. The presenter concluded that resistance to
nevirapine evolves when the virus is not reduced to undetectable levels. The
utility of nevirapine for nucleoside experienced patients remains vague.
- Scott Eastman, Ph.D. and Thomas Gingeras, Ph.D. Drug Resistant HIV
Variants (Chiron Corporation and Affymetrix): The authors reviewed the
multiple mutations associated with resistance to protease inhibitors. Genotypic
changes show substantial overlap, especially for ritonavir and indinavir. It
was also noted that resistance develops within days of monotherapy with
non-nucleoside RT inhibitors and protease inhibitors. In patients on AZT
monotherapy who had developed the mutation at codon 215 conferring AZT
resistance, reduction in viral burden was noted in one-half after ddI was added,
but the other half had no response. Those who had 3TC added generally
responded. A question from the Panel addressed the utility of measuring in
vitro resistance. Genotypic testing was felt to be unnecessary because with
clinically significant resistance, viral burden increases within two weeks of
measured genotypic changes. The mutant viruses were considered "less
fit"
because sensitive "wild type" HIV returns when antiviral therapy is
discontinued. Such patients have prompt reappearance and dominance of wild type
HIV within 4-5 months. Retreatment results in rapid reappearance of resistant
strains.
- Martin Markowitz, M.D. and Luc Perrin, M.D. Treatment of Primary HIV
Infection (Aaron Diamond AIDS Research Center, New York and Geneva,
Switzerland): Dr. Markowitz provided follow-up information on 24 gay men
treated with AZT/3TC plus either ritonavir or indinavir within months of
seroconversion. At 12 months all patients had viral burdens <500 copies/ml.
Nineteen of 21 patients had viral burdens of <100 copies/ml, and 21 of 21
patients had negative cultures of peripheral blood mononuclear cells. Dr.
Perrin reviewed his experience with AZT/ddI after acute seroconversion and
noted that 8 of 12 had no detectable virus (threshold <200 copies/ml) at
nine months. Lymph node biopsies demonstrated no HIV RNA in 4 of 5 patients.
- Miklos Salgo, M.D., Ph.D. Combination Protease Inhibitors
(Hoffmann-LaRoche): The author reviewed the data for combination therapy with
saquinavir/ritonavir with an 80 week follow-up (study NV 14256). The rationale
for this combination is based on the 20-fold increase in the area under the
curve for saquinavir when ritonavir is given concurrently. Studies of viral
burden showed that 80% had no detectable virus (threshold of 200 copies/ml),
representing nearly a three log decrease. The CD4 cell count increased by a
median of 100/mm3. These results are obviously very promising, although long
term outcome is still unknown.
- Roy Gulick, M.D., Ph.D. Triple Therapy with Indinavir (NYU): The
presenter provided long term follow-up data from the trial of
indinavir/3TC/AZT vs. indinavir (monotherapy) vs. AZT/3TC. Participants had CD4
cell counts of 50-400/mm3, viral burden exceeding 20,000 copies/ml, and more
than six months of AZT prior treatment. Among the 90 participants, the baseline
value for viral burden was 37-43,000 copies/ml, the CD4 cell count was
131-156/mm3, and the duration of prior AZT treatment was 28-31 months. At 52
weeks viral burden had decreased by two logs in recipients of triple therapy,
one log for the indinavir monotherapy group, and had returned to baseline for
recipients of AZT/3TC. In the triple therapy group 80-90% had no detectable
virus, and the median CD4 cell count increased by 100-120/mm3. It was also
noted that 8 of the 60 (13%) indinavir recipients developed nephrolithiasis.
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