NIH Panel to Define Principles
of Therapy of HIV Infection

By John G. Bartlett, M.D.
The Hopkins HIV Report:
A bimonthly newsletter for healthcare providers
Volume 9, Number 1, January 1997

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.

This article is from The Johns Hopkins University AIDS Service,
The Hopkins HIV Report: A bimonthly newsletter for healthcare providers.