A new study explains why antiretroviral treatments in seropositive patients do not definitively cure the infection

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A new study explains why antiretroviral treatments in seropositive patients do not definitively cure the infection

  • The study demonstrates the presence of minimal virus quantities that continue to infect new cells in seropositive patients in spite of taking medications.
  • The results explain why virus blood levels rapidly increase when treatments are interrupted, preventing a definitive cure of the infection.
  • This finding is a first step in re-guiding the design of new therapeutic strategies to eradicate HIV.
  • The results resolve a long-standing medical controversy on the persistence of minimal HIV replicating activity in some patients without apparent virus quantities in the blood, and will be published on March 14 in the Nature Medicine journal.
  • IrsiCaixa has been carrying out five more studies to analyse different ways of intensifying antiretroviral therapy as possible strategies to advance towards eradication. 

The Institute for AIDS Research IrsiCaixa, promoted by the "la Caixa" Foundation and the Department of Health of the Generalitat de Catalunya, is leading a new study, published on March 14, in the North-American scientific journal Nature Medicine, providing very relevant information for the shared objective of eradicating the AIDS virus. The results of this study indicate that in some HIV-infected patients, in spite of the fact that the virus is seemingly under control thanks to antiretroviral treatment, there is a small amount of virus that continues to infect other cells, therefore proving that current drugs are not always able to completely block HIV. This finding has serious clinical implications, given that it could explain why drugs do not permanently cure the infection even though patients remain in therapy over the course of many years. This novel research contributes important information to the design of new therapeutic strategies that will enable total eradication of the HIV virus from the body. 


This project has been led by IrsiCaixa researcher and ICREA research professor Javier Martínez-Picado, in close collaboration with researchers Julià Blanco (IrsiCaixa/IGTP) and Bonaventura Clotet, who is also the director of the Institute for AIDS Research IrsiCaixa, and with the Swedish Institute for Infectious Disease Control and the University of Massachusetts. The research has been conducted within the context of the ambitious HIVACAT research programme, a Catalan consortium dedicated to the development of therapeutic and prophylaptic vaccines against HIV which has the support of Esteve, the “la Caixa” Foundation and the Departments of Health and Universities, Innovation and Enterprise of the Generalitat de Catalunya, and is co-directed by IrsiCaixa and the Infectious Diseases and Aids Service of the Hospital Clínic of Barcelona. 


In order to carry out this study, a team of IrsiCaixa researchers coordinated a clinical study in which 69 patients from the Germans Trias i Pujol, Sant Pau and Clínic Hospitals of Barcelona who were receiving antiretroviral therapy, and in whom the presence of virus in blood had not been detected in a mean time of 5 years, participated.  Their treatment was intensified  by adding a new drug called Raltegravir, which blocks the virus’ infection cycle, specifically in the phase in which viral DNA is integrated into the infected cell’s DNA.  With the use of this new drug researchers were able to apply, for the first time ever, a sophisticated technique for the detection of the presence of HIV.  This technique measures circular viral DNA that is produced when Raltegravir blocks the integration of viral DNA into human DNA and is more sensitive than the one that was routinely carried out. 


The increase of these circular forms in a significant number of patients whose treatment was intensified with Raltegravir, but not in the control group, evidences that active infection phenomena were still taking place in patients before adding Raltegravir and that, after adding this drug, these infection phenomena were blocked. 


Furthermore, the study also analysed the state of the immune system of the patients.  It is a known fact that people with HIV infection have a more activated immune system than healthy people and that his activation is reduced, but does not completely normalize, with antiretroviral treatment.  The results of the study demonstrated that the presence of active infection phenomena is associated with a greater activation of the immune system and that the addition of a new drug sensibly reduces these alterations.  The hypothesis that the virus can maintain certain replication levels in spite of treatment and that this replication can be blocked using therapy intensification strategies is therefore confirmed, representing one more step towards the eradication of HIV.


Regarding antiretroviral therapy 
Antiretroviral therapy is called highly active antiretroviral therapy (HAART) and has been used for the past fifteen years.  This therapy consists of the combination of at least three antiviral drugs in one treatment to minimize the emergence of drug-resistant mutant viruses.  Its efficacy has radically changed the quality of life of thousands of HIV-positive patients by reducing the quantity of virus in the blood to levels that are undetectable by clinically available analysis methods.  This decrease of the virus in blood leads to a significant improvement of the patient’s immune system.  However, current treatments do not permanently cure the infection: in spite of many years of continued and successful treatment, therapy interruption inevitably results in a fast reappearance of the virus in blood and in the associated immune deterioration. 


Is it possible to eradicate HIV-1?
In order to set in motion strategies aimed at curing this disease, we need to understand the sources of the virus that reappears after stopping HAART.  Several research teams have described that these viruses remain encrypted in certain reservoirs, primarily inactive lymphocytes, which contain a copy of the viral genome in their DNA and can start to produce new viruses when activated if treatment is stopped.  However, up until the publication of this article, the belief was that it was unlikely that the virus would continue to actively infect new cells when HAART was being applied. 


Clinical implications
One of the primary challenges that HIV-1 researchers are faced with is to achieve the eradication of a virus that has entailed one of the most dramatic pandemics of the last thirty years.  One of the ways to reach this objective is to search for curative therapeutic strategies that enable the elimination of drugs after a certain time of being taken, without this leading to the reappearance of the virus in blood.  The research conducted by IrsiCaixa researchers evidences for the first time ever that HIV-1 can continue to infect cells in spite of medication. 


These observations will enable a reorientation of treatment strategies towards viral eradication and, therefore, towards a definitive cure for AIDS.


Article published in Nature Medicine:

HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects


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