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Montreal Researchers Plan to Explore Dolutegravir's Effect on the HIV Reservoir

January 2016

For the past several decades, the laboratory of McGill University professor Mark Wainberg, Ph.D., has been studying HIV and how this virus changes (or mutates) so that it can resist the effect of different anti-HIV drugs.

A research associate at the Wainberg lab, Thibault Mesplède, Ph.D., has become interested in how HIV-infected cells are affected by one particular drug -- dolutegravir (Tivicay and in Triumeq). Wainberg, Mesplède and their associates are conducting experiments in the lab to better understand the interaction between HIV-infected cells and dolutegravir. To do this, they keep cells of the immune system alive and proliferating (making new cells) and add a mix of nutrients, liquids, HIV and dolutegravir. They observe and detect changes in HIV's genetic material over time.

In analysing their experiments, they have found that it is extremely difficult to find HIV that has developed high-level resistance to dolutegravir. Bear in mind that these are the results of carefully controlled lab experiments and not work from studies in HIV-positive people. (Later in this issue of TreatmentUpdate we report on cases of treatment failure with dolutegravir in people.) The findings from laboratory research have spurred Mesplède to design experiments that will use dolutegravir as a probe in order to try to better understand if this drug might have an effect on the body's pool of HIV-infected cells. This pool is also called the reservoir. Researchers in Canada and at leading scientific institutes in other countries are designing experiments that aim to measure the size of the reservoir and uncover ways to shrink the reservoir. It is possible that if Mesplède's initial work is successful dolutegravir could play a role in some of these experiments.


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Resistance and the Reservoir

In some people, HIV has developed the ability to partially or wholly resist the effect of some anti-HIV drugs. This development could have occurred for several reasons, including the use of weak regimens, difficulty absorbing medicines, drug interactions or poor adherence (not taking a regimen exactly as directed). For instance, people who were treated with anti-HIV drugs in the late 1980s and early 1990s would usually have been prescribed and used single-agent therapy (monotherapy), initially with AZT and later with other similar chemically related drugs such as 3TC (lamivudine), ddI (didanosine, Videx), ddC (zalcitabine, Hivid) and d4T (stavudine, Zerit). These drugs are all nucleoside analogues (nukes). They are relatively weak when used by themselves, so people treated with one or two nukes alone tended to develop HIV that could resist these drugs. In those early years of the HIV pandemic, comparatively little was known about how best to use the relatively few drugs available.


A Memory of Resistance

Although more potent drugs (and combinations of potent drugs) became available after 1996, researchers found that if people had HIV that was resistant to one or more drugs in the past, such strains were still present but at relatively low proportions -- even in people whose viral loads in the blood were undetectable. These strains were largely driven out of the blood and, according to researchers, "archived" deep within the body's reservoir of HIV-infected cells, likely residing in the lymph nodes, lymphatic tissues and possibly the brain and reproductive tract. In experiments when people have started taking their old ART on which they previously experienced treatment failure, these archived, drug-resistant strains of HIV quickly emerge into the blood.


HIV in the Body

Based on the results of complex studies of HIV in the lab that Mesplède and colleagues have done, and also the results of experiments with people (carried out by other research teams), Mesplède has developed a theory of what is happening with HIV in the body. He thinks that even in people whose viral load blood tests suggest that HIV is undetectable thanks to potent combination anti-HIV therapy (commonly called ART), HIV is still being produced in the lymph nodes and lymphatic tissues. These parts of the immune system harbour cells that serve as a reservoir for HIV.

The reservoir is an important idea in HIV research. Scientists are refining their methods for assessing the reservoir, or burden, of HIV-infected cells. Such methods will be an important part of efforts to cure HIV, as clinical trials are planned or underway in which researchers hope to shrink the size of the reservoir. If the size of the reservoir can be significantly reduced, then one day it might be possible, in theory, to cure HIV infection.


Focus on Dolutegravir

Mesplède's experiments in the lab, as well as interim results from some studies, support his idea that testing dolutegravir in people who have never previously used ART or who have never previously used integrase inhibitors may prove useful. Specifically, he hopes that dolutegravir-based regimens in those populations could, in theory, interfere with the production of HIV in the reservoir, perhaps even somewhat diminishing it.

Mesplède, Wainberg and colleagues have designed a clinical trial to try to find out the impact of integrase inhibitors on the reservoir of HIV-infected cells. The trial is code-named CTN 294 (and nicknamed LAHDGA) and will be sponsored by the CIHR HIV Clinical Trials Network; it will be observational in design. In this study, researchers hope to enroll 60 HIV-positive adults who are already on ART and whose viral load is less than 50 copies/mL.

Participants taking the following specific regimens will be enrolled:

  • dolutegravir-based regimen -- 20 participants
  • elvitegravir (in Genvoya and Stribild)-based regimen -- 20 participants
  • a regimen without integrase inhibitors -- 20 people

This study should be viewed as a pilot to test an interesting idea. If Mesplède and colleagues find evidence to support their theory, a larger prospective clinical trial will be needed to confirm their results. Although the CTN has sponsored the LAHDGA study, Mesplède, Wainberg and colleagues still need to raise funds to conduct it.


Acknowledgement

We thank Thibault Mesplède, Ph.D., McGill University, for his expert review and research assistance.


References

  1. Liang J, Mesplède T, Oliveira M, et al. The combination of the R263K and T66I resistance substitutions in HIV-1 jntegrase is incompatible with high-level viral replication and the development of high-level drug resistance. Journal of Virology. 2015 Nov 15;89(22):11269-74.
  2. Mesplède T, Wainberg MA. Resistance against integrase strand transfer inhibitors and relevance to HIV persistence. Viruses. 2015 Jul 7;7(7):3703-18.
  3. Gubavu C, Prazuck T, Niang M, et al. Dolutegravir-based monotherapy or dual therapy maintains a high proportion of viral suppression even in highly experienced HIV-1-infected patients. Journal of Antimicrobial Chemotherapy. 2016; in press.
  4. Walmsley S, Baumgarten A, Berenguer J, et al. Brief Report: Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 jnfection in antiretroviral therapy- naive patients: Week 96 and week 144 results from the SINGLE randomized clinical trial. Journal of Acquired Immune Deficiency Syndromes. 2015 Dec 15;70(5):515-9.
  5. 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.
  6. 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.
  7. 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.
  8. 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
  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. Osman N, Mesplède T, Quashie PK, et al. Dolutegravir maintains a durable effect against HIV replication in tissue culture even after drug washout. Journal of Antimicrobial Chemotherapy. 2015 Oct;70(10):2810-5.


Related Stories

Is Dolutegravir Alone Enough to Control HIV?
Why Dolutegravir Might Get Us Closer to Ending AIDS: Next Step, Further Research
Dolutegravir: A Powerful Drug Entering Different Research Paths
Caution Needed When Interpreting the Results of Simplification Studies



This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.
 

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