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does this mean that drugs are not potent enough?
Feb 29, 2004

Dr. Dave,

You are most definitely the best doctor in this entire site. My question refers to this article. Does this suggest that current meds today are not potent enough, in other words, we need new meds that will be able to fix or improve this situation. Thanks!

Alex Intensification of Antiretroviral Treatment in HIV Patients with Long-term Viral Suppression Does Not Substantially Improve Immune Deficits or Significantly Reduce HIV Latent Reservoir

Patients who start HAART during moderately advanced HIV disease exhibit residual immune abnormalities despite adequate viral load control. These abnormalities do not appear to improve with continued HAART.

The objective of the current study was to ascertain whether antiretroviral (ARV) intensification in patients with controlled viral load leads to improvement in residual immunologic abnormalities and decreases in HIV-1 latent reservoir.

Patients with CD4+ cells < 300, 3TC and protease inhibitor nave, started ZDV, 3TC, and ritonavir. After 72 weeks, if viral load > 1000 copies/mL patients modified HAART. S

Seventeen patients with plasma viral load < 1000 copies/mL for most determinations in the prior 3 years and viral load < 400 copies/mL for the 90 days prior to entry had ARV intensified (ACTG 5136). All added tenofovir and all protease inhibitors were switched to lopinavir/r.

Viral load was assayed using a PCR-based assay (LLD = 50 copies/mL); the latent viral reservoir was measured via limiting dilution assays on highly purified resting CD4+ T cells; the of HIV-producing cells was quantified using flow-based in-situ hybridization (UFISH).

Lymphocyte populations were enumerated after antibody staining using flow cytometry. All summaries are medians; analyses: signed-rank test and rank correlations.

Results

The CD4 at baseline was 538 (30). Forty-eight weeks after intensification, viral load was <50 copies/mL in 10 and <1000 copies/mL in 17 of 17 evaluable subjects.

There was no significant increase in CD4+ cells (+27, p = 0.27). The memory CD4 increased significantly (+5, p = 0.017) while the naive CD4+ cells decreased significantly (-8, p = 0.0027).

There was a significant increase in the CD8 cells (+2, p = 0.029) and memory CD8+ cells (+11,p = 0.0049), while nave CD8 decreased (-6, p = 0.18).

There was no significant change in markers of immune activation or apoptosis in CD4+ or CD8+ cells. Twelve weeks after intensification, the of memory (CD45RO+) CD4+ cells producing HIV declined from 3.2 to 1.2, p = 0.04;

HIV-1 reservoir {Infectious units per million resting cells (IUPM)} was measured in 6 pts with +< 100 copies/mL at entry. Four of these patients maintained viral load < 50 copies/mL throughout the study. IUPM decreased minimally in only one of these patients.

The authors conclude, Intensification of antiretroviral treatment in subjects with long term viral control does not lead to substantial improvement in residual immune deficits or significant reduction in HIV-1 latent reservoirs.

02/27/04

Reference K Y Smith and others. Intensification of Antiretroviral Treatment in Subjects with Long-term Viral Suppression Does Not Lead to Substantial Improvement in Residual Immune Deficits or Significant Reduction in HIV-1 Latent Reservoir. Abstract 228 (poster). Program and Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (11th CROI). February 8-11, 2004. San Francisco, CA.

Response from Dr. Wohl

Dear Alex,

Thanks. This was a small study but does indicate that intensification of therapy does not lead to major changes in some important immune parameters or the pool of latently infected cells.

The intensification here was fairly potent. However, the ability of the therapy to accomplish complete immune reconstitution may not hinge so much on the potency of the regimen. It is conceivable that some of the damage done by HIV occurs earlier during the infection and may be irreversible. Additionally, the impact of HAART on latent virus may be limited as therapies require replicating virus in order to do what they do.

The bigger picture, of course, is that there are other important immune parameters that HIV therapy improves. Adding more HIV therapy appears to not add much.

DW



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