icon_folder.gif   Conference Reports for NATAP  
  ICAAC 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
Chicago, Illinois, December 16-19
Back grey_arrow_rt.gif
Therapy Interruptions in HIV
Written for NATAP by Michael Norton, PA, Boriken Family Health Clinic, NYC
Editorial contribution by Jules Levin
  This symposium was divided into four separate talks. The first two dealt with interruptions of therapy and are summarized below.
Philippe Hermans from Brussels, Belgium, delivered the first lecture. Hermanns gave an overview of the rationale behind structured therapy interruptions (STI's) in patients who began HAART during primary HIV infection (PHI). The major rationales are to preserve a full repertoire of T-cells and to prevent viral heterogeneity; virus replicates daily when not under full suppression from therapy, and as virus replicates over time mutations occur, called viral hetrogeneity. He then reviewed the published clinical trial material to date on this subject. Future reports from an ongoing PHI trial entitled Quest should be useful in understanding the utility of STI's in these specific patients.
Steven Deeks from San Francisco, CA delivered the second lecture. Over the past few years, Deeks has done a fair amount of publishing in the arena of advanced patients whose antiretroviral therapy is not fully suppressive due to drug resistance. Deeks noted that he saw 3 options for these patients:
  1. Continue the same therapy even if it is not fully suppressive.

  3. Switch therapy to at least 2 drugs the patient has never seen and has no cross resistant to.

  5. Interrupt therapy, thus allowing the resistant virus to be outgrown by wild type virus, and then restarting therapy.

The second option is not really an option for the vast majority of these salvage patients. Therefore he concentrated on the two remaining options.
The first, continuing on virologically failing HAART. Deeks reports that, in his relatively small cohort, approximately 50% of patients saw their T-cells remain stable over more then 3 years of follow up. He noticed that, in these 50% of patients where T-cells remained stable, it appears that the viral load would rise about 1 log remaining less than 10,000 copies/ml and plateau at that level in some patients, which could last for 2-3 years. He also noted that in other patients viral load could rebound more rapidly. He did note that a downside of this strategy was that more and more drug resistance was acquired with time. Deeks suggested a popular notion that has been recognized for 2 years which might explain the reason cd4s may remain stable while viral load increases, and perhaps why viral load increases to a certain level and stabilizes there for a period of time for certain individuals‹impaired fitness for that virus to replicate. This idea has been discussed with some evidence for supporting research for this idea at the Resistance Workshops that take place annually. But I think some doubt lingers that this is conclusively the explanation.
In the remaining 50% of patients, whose viral load did not plateau but rather was increasing, they tried a structured therapy interruption. The intent of which was to see if allowing the predominance of resistant virus to revert back to wild type translated into clinical and/or virologic benefit. In as fast as two weeks, but a median of 8 weeks, the resistant virus was overtaken by the wild type. Eventually 23 out of 25 patients who underwent this type of STI ended up back on therapy. In 19 out of the 23 resistance to protease inhibitors (PI's) reverted to wild type. In 17 out of 23 resistance to nucleosides (NRTI's) reverted to wild type. After the shift from resistant to wild type a significant increase in viral load was noted as well as a significant decrease in cd4+ T-cells. Thus suggesting that even in these patients with whom virus was rising significantly while on their HAART, HAART was still having a positive effect with respect to the amount of virus and the sustaining of cd4+ T-cells. Also observed was a significant increase in the turnover and activation of (decrease) cd4+ T-cells after the re-emergence of wild type virus. Once again suggesting a beneficial aspect of continuing therapy. During the STI, viral load increased a median of 0.75 log/copies and cd4+ T-cells declined a median of 83 cells/mm3. With regards to successful re-suppression of viremia, once patients restarted HAART, the only predictor of success was the number of active agents prior to the STI. 8 patients were able to fully re-suppress to undetectable, and presumably remain there. Of those eight, five were naive to the NNRTI class and received one of those drugs in their re-started HAART regimen. Deeks reported, not surprisingly given the advanced disease in these patients, that there were many clinical events during both the STI and even after HAART had been re-started.
Editorial note from Jules Levin: the remarkable thing that observers at the conference were taking about was obviously these patients were highly NRTI experienced and had NRTI resistance. But after an interruption and return to wild-type virus, adding one new class of drug, an NNRTI to NRTIs, HIV was resuppressed in these 8 patients. This suggests that the NRTIS had regained activity after the interruption and return to wild-type. However, we don't know how long the suppression will last, as resistance to the NRTIs may return. Research has shown us that even if resistance to s drug may appear to disappear (that is, it cannot be found with a standard resistance test), more sensitive resistance testing techniques can identify resistance. So, the general consensus among researchers is that resistance will re-emerge over time. Over time these individuals who re-suppressed with 1 new drug, an NNRTI, and recycled nukes may see viral load rebound as NRTI resistance returns. If that occurs they will also develop resistance to the NNRTI.
Commentary: What we don't know about Deeks cohort is how many patients, prior to the STI, were on RTV boosted regimens? This might have been another strategy for enhancing the potency of the failing regimens without switching or interrupting therapy. Another question that arises, what would have happened in the 8 patients who reached undetectable if they hadn't had an STI but rather switched immediately to a new regimen? Could they have gained even more benefit by not having a period of presumably high viremia during an STI, or did the reversion to wild type virus in anyway assist in their subsequently reaching undetectable? Due to the fact that this work is not controlled with an arm that immediately switched and another arm that remained on therapy it is difficult to access the benefit if any of these kinds of STI's.