The Body Covers: The 39th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy
Slide Session 69.I: Preservation and Enhancement of Immune System Responses in HIV Disease
September 27, 1999
This study was presented by Dr. Richard Davey from the N.I.H., and looked at the issue of whether HAART can be stopped in patients who have been under excellent virologic control (i.e., undetectable viral load), and what the consequences might be in terms of CD4+ cells and viral load.Abstract: The NoHRT Trial: a Prospective Study of Cessation of HAART in HIV-Infected Patients after Prolonged Viral Suppression (Paper 689)
We are all aware of the pros and cons of using highly active combination therapy directed against HIV. On the one hand, it is possible to gain some measure of control over viral replication, which can lead to stabilization or increase of T-cells, slower progression, and maybe the hope of eventually purging the virus from the body. These "benefits" are counterbalanced by potential toxicities, inconvenience, possible drug interactions, and the overall hassle of having to be constantly aware of and planning for your next date with the medicine cabinet.
One idea that has circulated in the past is the notion of "induction/maintenance", whereby a more intensive regimen used initially might be replaced by a later, simpler, maintenance regimen. Unfortunately, several studies (the COMET trial, Harrigan et al.) have shown this to be a poor choice, and that strategy is not currently recommended. What about just stopping all drugs completely after excellent virologic control is achieved? Would our bodies be able to keep HIV at bay after viral loads were brought to undetectable levels? Unfortunately, the answer seems to be a resounding "NO", and the NoHRT trial results are the clearest answer yet to that question.
This trial enrolled HIV+ patients who had been on HAART for about 12 months. They all had a viral load (VL) of <500 copies/ml for one year, and <50 copies/ml at entry to the study. All had CD4+ counts >350 at entry. Prior treatment with interleukin-2 (IL-2, an immunomodulator) was permitted, because one idea is that IL-2 may have a role in activating some of the human cells that are infected with HIV but not accessible to killing by HAART alone.
In the study, all patients stopped all HIV drugs at once on Day 1. They had lymph node biopsies and spinal taps at baseline and again at 2 months after stopping therapy. The number studied was 18 persons, with an average age of 45. They were all heavily "experienced" in terms of prior therapy, with a mean prior Protease Inhibitor experience of 137 weeks. Twelve (12) patients had prior IL-2 use. Baseline spinal fluid viral load (CSF) was undetectable in 10 of 10 patients checked, as would be expected. Interestingly however, one patient had undetectable HIV at baseline in his PBMC's (a type of cell that harbors hidden HIV).
The mean time to get the viral load >50 was 11 days, and to >500 was 18 days. The CSF VL rebounded early. 3. Use of IL-2 did not matter or effect the results. 4. CD4+ counts dropped about 200 points on average over a few weeks in all groups.
There were two "outlyers" who had somewhat different results. In one, the viral load did not rebound until week 7, and this was the same subject who had undetectable VL in his PBMC's at baseline. Another patient has rebounded but is staying at around 50 copies/ml (they are considering calling him "the Bethesda patient") It is important to note that virus did return in these two, but why their course was different is not well understood.
Fifteen (15) patients promptly restarted HAART after it was clear they were rebounding. It took about 79 days total to regain the starting point VL of <50 copies/ml. Also, the investigators were able to show that the rate of replication of CD4+ and CD8+ cells increased rapidly when HAART was stopped, then slowed when therapy was resumed.
Despite prolonged suppression for an average time of about 2 years, prompt relapse occurs within 2-3 weeks of stopping HAART. This seems to be independent of the extent of baseline viral load suppression. The pool of latently infected CD4+ cells increases rapidly after stopping HAART, then decreases with restarting. Finally, and importantly, restarting HAART led to resuppression of virus with no evidence of resistance with this one cycle of drug interruption.
Many people have raised the idea that perhaps serial drug interruptions (doing what was done here, but over and over, perhaps with changes in the HAART drugs also) might be useful. This study did not look at that issue, but it doesn't seem to support the notion either. The burden of proof that these types of "drug holiday" or "punctuated" treatment schemes will work seems to be on those who advocate the approach.
Authored by: R. Davey, Jr., et al.
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