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Study Finds Durable Drug-Free Control of HIV Is Uncommon When Treatment Is Interrupted

January 27, 2016

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Results -- Focus on the Nine Participants Whose Viral Load Rebounded

As mentioned earlier in this report, most participants had their viral load climb well into the detectable range within the first four weeks after interrupting ART. The results below on viral load, the reservoir, T-cells, safety and other issues focus on findings from nine participants whose immune systems were unable to control HIV once ART was interrupted.


Viral Load

On average, the first detectable viral load was 2,125 copies/ml and the second viral load test (to confirm that it was detectable) a week later found that the average viral load had risen to 7,213 copies/ml.


The Viral Reservoir

Since viral load was rising, this indicated that more of the immune system's cells were being infected and that the reservoir would rise. To confirm this change, researchers assessed the reservoir. At the start of the study, the reservoir was estimated to be less than 66 HIV DNA copies per million blood cells. However, once treatment was interrupted, the burden of HIV-infected cells rose: Their reservoir of infected cells was 106 DNA copies per million blood cells. This increase in the size of the reservoir was statistically significant; that is, not likely due to chance alone.


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Changes to T-Cells

Not surprisingly, with all the negative changes that occurred, CD4+ counts quickly began to fall, initially decreasing by an average of 124 cells/mm3. Furthermore, a greater proportion of the immune system's cells became inflamed and activated -- another change that was statistically significant.


Safety

No serious side effects occurred during the study after participants interrupted ART, perhaps in part because their CD4+ counts were generally high (and had never fallen to low levels prior to initiating ART) and the interruption was relatively short. Common adverse effects reported after interruptions were generally of mild or moderate intensity and included the following:

  • headache
  • muscle soreness or pain
  • diarrhea
  • swollen lymph nodes

Viral loads generally decreased rapidly once participants resumed treatment. Four weeks after resumption of ART, eight out of nine participants had a viral load less than 50 copies/ml.

The following happened 24 weeks after resuming ART:

  • Ultrasensitive viral load assays found that seven out of eight participants had a viral load less than 1 copy/ml.
  • On average, the burden of HIV-infected cells (the reservoir) in their blood fell to its pre-interruption level.
  • The average CD4+ count was 823 cells/mm3 (almost 300 less cells than at the start of the study).


Focus on One Person

Researchers are not sure why one person was able to have a relatively low viral load despite interrupting ART for 56 weeks (researchers are still monitoring him). His last viral load test result was 282 copies/ml.  In reviewing his medical history prior to the study, they found that before he initiated ART, his highest-ever viral load was just over 3,000 copies/ml. His lowest-ever CD4+ count (also before initiating ART) was 566 cells/mm3.  Three years before entering Ultrastop, analysis of his blood samples found that his viral load was consistently less than 20 copies/ml.

He does not appear to have any genes associated with decreased susceptibility to HIV.

Despite extensive analyses, researchers could not find an explanation for the man's control of HIV replication in his blood while not taking HIV medications.


Points to Consider

  1. Readers should bear in mind that the participants in this study were very carefully selected. For instance, to be considered for inclusion in Ultrastop, potential volunteers had to have an extremely low level of HIV-infected cells (this represents the reservoir) in their blood -- below the level of detection. Such a level in the French study was less than 66 copies of HIV DNA per million blood cells. The French researchers described such low levels as "a rare event." Additionally, potential volunteers initiated ART when their CD4+ counts were around 500 cells/mm3 and had relatively low pre-treatment viral loads. All of these selection criteria mean that the average HIV-positive person would not have been eligible for this study.
  2. Note that although participants selected for this study were thought to have the best chance for a prolonged drug-free remission from HIV, the time period was remarkably short -- about one month. The French team noted that the short delay in a resurgent viral load in most of the participants was similar to what was seen about 15 years ago when treatment interruptions were first seriously investigated.
  3. The assay used to assess the level of HIV-infected cells in this study has a lower limit of detection of 66 copies of HIV DNA per million blood cells. Tests currently used in research labs to assess the size of the HIV reservoir are imperfect and likely underestimate its true size. Such tests are largely confined to research labs and some studies that seek to test potential therapies to cure HIV infection. However, several research teams are working to develop more accurate ways to assess the HIV reservoir.
  4. The findings from Ultrastop suggest that the interruption of ART, as the sole intervention in an attempt to induce a drug-free remission, is not likely to be done on a large scale in the future. The French researchers were highly selective in their choice of participants, choosing the ones that they hoped had a biomedical profile that would suggest a prolonged drug-free remission was possible. Yet this did not happen.
  5. There were no data reported about analyses of lymph nodes and lymphatic tissues in the French study. Most of the cells (lymphocytes) that HIV infects (98%) are in the lymph nodes and related tissues. As a result, so is most of the HIV in the body. Furthermore, U.S. researchers have found that even when the viral load in the blood is undetectable thanks to ART, HIV can be found infecting cells in the lymph nodes. Hopefully, in the future, researchers will look at these compartments when conducting research on drug-free remission of HIV.


For the Future

Interruption of ART will probably be included in some studies in the future that seek to cure HIV or induce a period of drug-free remission for ART users. Such studies will need to find ways to bolster the immune system's ability to detect and kill HIV-infected cells and to reduce the HIV reservoir. Only after such steps are first taken might researchers reconsider treatment interruption.

Other research teams are working on ways to better predict which HIV-positive people might experience a virological rebound once ART has been interrupted.

Many exciting studies lie ahead -- some will include bone marrow transplantation, drugs to help reduce the HIV reservoir and strengthen the immune system, and gene therapy. It is important that HIV-positive people volunteer for these studies, as they will greatly help scientists understand the complex consequences of HIV infection and find ways to refine approaches to ART-free remission or a cure.


References

  1. Calin R, Hamimi C, Lambert-Niclot S, et al. Treatment interruption in chronically HIV-infected patients with an ultralow HIV reservoir: results from the Ultrastop study. AIDS. 2016; in press.
  2. Assoumou L, Weiss L, Piketty C, et al. A low HIV-DNA level in peripheral blood mononuclear cells at antiretroviral treatment interruption predicts a higher probability of maintaining viral control. AIDS. 2015 Sep 24;29(15):2003-7.
  3. Calin R, Fourati S, Schneider L, et al. Very early ART resulting in the absence of HIV-1 antibodies and in a sustained undetectable plasma HIV-1-RNA and proviral-DNA in an HLA-B*5701 and Δ32 heterozygote HIV-1-infected patient was not associated with functional cure. Journal of Antimicrobial Chemotherapy. 2015 Jan;70(1):317-9.
  4. Churchill MJ, Deeks SG, Margolis DM, et al. HIV reservoirs: what, where and how to target them. Nature Reviews Microbiology. 2016 Jan;14(1):55-60.
  5. Martin AR, Siliciano RF. Progress toward HIV eradication: Case reports, current efforts, and the challenges associated with cure. Annual Review of Medicine. 2016 Jan 14;67:215-28.
  6. Hurst J, Hoffmann M, Pace M, et al. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nature Communications.  2015 Oct 9;6:8495.
  7. Procopio FA, Fromentin R, Kulpa DA, et al. A novel assay to measure the magnitude of the inducible viral reservoir in HIV-infected individuals. EBioMedicine. 2015 Jun 27;2(8):872-81.
  8. Cockerham LR, Hatano H. Elite control of HIV: is this the right model for a functional cure? Trends in Microbiology. 2015 Feb;23(2):71-5.
  9. Rothenberger MK, Keele BF, Wietgrefe SW, et al. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proceedings of the National Academy of Sciences. 2015 Mar 10;112(10):E1126-34.
  10. Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proceedings of the National Academy of Sciences.  2014 Feb 11;111(6):2307-12.
  11. Santangelo PJ, Rogers KA, Zurla C, et al. Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nature Methods. 2015 May;12(5):427-32.
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This article was provided by Canadian AIDS Treatment Information Exchange. Visit CATIE's Web site to find out more about their activities, publications and services.
 

 

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