On 28 March, ENS Paris-Saclay organised its 3rd Sidaction Day, research for HIV prevention. The opportunity, at the time of the official launch of the 25th edition of Sidaction, to review research on infection prevention and treatment of this disease.
"Nothing frightens me more than the symbolic trivialisation of this fight," said Pierre-Paul Zalio, president of the ENS Paris-Saclay, in the preamble to the 3rd edition of the Sidaction Day organised within ENS Paris-Saclay by the Laboratory of Biology and Applied Pharmacology (LBPA - CNRS/ENS Paris-Saclay). While everyone agrees that research has made enormous progress since the first cases of human immunodeficiency virus (HIV) infection appeared in the early 1980s and the subsequent AIDS epidemic, the virus is still there. Today, 37.5 million people are living with HIV worldwide, 75% of whom know their HIV status. Each year, there are nearly two million new infections. In France, we estimate that there are more than 172,700 people carrying the virus, 86% of whom know their status and 76% are on treatment. 24,000 ignore their HIV status. In 2017, more than 6,400 persons discovered it.
A decisive moment
Yet WHO's 2015 recommendations are clear: anyone who has just been diagnosed with HIV infection must be placed on antiretroviral treatment. The benefits, both direct and indirect, are real: at the individual level, the infected person improves his or her quality of life and life expectancy, and at the collective level, his or her viral load becomes undetectable and the infected person no longer transmits the infection to partners. The tritherapies - a combination of three therapeutic molecules - available today are so effective and powerful that, under maintenance treatment, the life expectancy of people living with HIV returns to levels equivalent to those of uninfected people. And "undetectable" is then equivalent to "non-transferable". But the person needs to be tested for HIV before....
"While we nowadays have tools to control the disease, the epidemic is stagnating," said Françoise Barré-Sinoussi, co-discoverer of HIV in 1983 with Luc Montagnier and 2008 Nobel Prize in Medicine, and guest of honour at ENS Paris-Saclay on this special day. "We are currently in a contradictory period. HIV is considered a common infection that can be treated, but getting tested is forgotten or even always scary."
"Today, more than 50% of young people aged 15 to 24 admit not to protect themselves during sexual intercourse, a quarter say they are uninformed about the disease and its modes of transmission, and more than 20% think they can be cured! This is frightening! ", continued Françoise Barré-Sinoussi, who has also been president of the Sidaction association since 2017 (see Focus). The message chosen for the 25th edition of Sidaction, whose official launch is scheduled for April 5, is all the more logical: in 2019, let us not forget that the AIDS virus is still there! "The challenges, whether scientific, societal or political, remain numerous," says the association's president.
On 28 March 2019, many researchers and community workers also took turns at the head of the ENS Paris-Saclay amphitheatre to present the state of progress and current research in the prevention and fight against HIV infection.
HIV cure versus Cancer cure
Olivier Lambotte, Professor of Internal Medicine and researcher at Bicêtre Hospital, explained the physiopathological parallels between remission and even cure in the fields of HIV and cancer, and the importance of a dialogue between oncology and infectiology. "For everyone, the current treatments are very powerful," said the researcher. "The problem lies more in the occurrence of rare events that prevent the complete elimination of the disease: HIV reservoir cells on the one hand, and quiescent cancer cells on the other. Not to mention the failure of the immune system, which malfunctions in both cases."
"And even if the convergences between HIV cure/cancer cure are real, the success of such an approach will depend first and foremost on a better understanding of the pathophysiology of latency and the intrinsic mechanisms of disease persistence, and the crucial role of the immune system. It will also require an in-depth study of tissues, the development of new tools to identify rare events and the combination of several therapeutic strategies."
Towards a reduction in treatments
Anne-Geneviève Marcelin, clinical virologist at the Pitié Salpêtrière Hospital, discussed the various mitigation strategies currently being explored to reduce the strain and weight of drugs taken for life by infected people. Because they are now aging with the virus, they potentially have to take other medications. "This is intended to reduce toxicity and the risk of drug interactions in the long term," she said. Strategies include reducing the number of molecules administered, developing long-acting molecules, and reducing the number of days of treatment per week.
Recent and promising pilot studies on a bitherapy combining dolutegravir and 3TC have shown similar efficacy to standard triple therapy (combining dolutegravir, tenofovir DF and FTC). "We are also looking for molecules with longer half-lives, for weekly or monthly administrations," said Anne-Geneviève Marcelin. And while the ANRS 162-4D pilot trial, launched in France in 2014 with 100 patients to evaluate the efficacy of antiretroviral treatment taken four consecutive days out of seven, showed a therapeutic success of 96%, a new, randomized and larger trial - the Quatuor trial - is expected to yield its results by summer 2019.
"But in 10% of infected patients, the virus is already resistant to at least one antiretroviral agent. In others, it is multi-resistant, and patients are then in therapeutic failure. We therefore need to develop new molecules," said Anne-Geneviève Marcelin.
HIV and integration
The mechanisms of HIV-1 resistance to dolutegravir (DTG) are the focus of Clémence Richetta’s research at the Laboratory of Biology and Applied Pharmacology. She is particularly interested in the integration of HIV genome into host genome, a key step of the infection. "The existence of non-integrated forms of viral DNA that accumulate in the infected cell has been identified." Dolutegravir, used in triple therapy, is an integrase inhibitor, the enzyme responsible for integration. "In some patients, resistance to DTG has been reported when there were no mutations of the integrase." Researchers’ work has uncovered a possible new model of the virus replication cycle, independent of viral DNA integration, and where non-integrated forms would explain DTG resistance.
The evolution of HIV prevention, while waiting for a vaccine
For his part, Bruno Spire, a doctor, a researcher and former president of the AIDES association, presented the range of prevention tools currently available: while prevention based on systematic condom use has made it possible to stabilize the epidemic, today, new biomedical tools are available to populations in an attempt to control the epidemic. PrEP - pre-exposure prophylaxis - is one way to treat HIV-negative people to prevent potential exposure to HIV. This drug, in the form of a tablet - it is a bitherapy - is to be taken before any situation of potential risk of HIV acquisition, either daily over the long term or just at the time of sexual intercourse. "If condoms are not systematically used, then PrEP is an alternative. With it, you are more than 99% guaranteed that you will not get HIV", says Bruno Spire. But the real challenge is elsewhere: too few people are regularly tested for HIV. "90% of HIV-positive people should be tested within a year of infection and start antiretroviral treatment to control the HIV epidemic. The time between infection and diagnosis is too long, it is important to go frequently for testing!", Bruno Spire hammered.
For, as Anaïs Chapel, of the HIV, inflammation and persistence unit at the Institut Pasteur, confirmed, there are still many obstacles to the creation of an HIV preventive vaccine and the trials are encountering serious failures. "HIV is forcing us to return to the fundamentals of immunology. We need to review our empirical approach to vaccination", warned Françoise Barré-Sinoussi.
Focus: A few words with Françoise Barré-Sinoussi
Being President of Sidaction today, after all these years of research, is part of my philosophy, which is not new. I cannot stand it when I or other researchers try to give the best of ourselves to advance knowledge and the development of tools for the benefit of patients, and they do not receive the benefit as soon as possible. It's totally unbearable, and so I'm trying to react, to change that, by working with Act-up, Sidaction, AIDES, etc. One day, representatives of the associative community gave me the most beautiful compliment anyone has ever given me in my life : they told me that I was an activist researcher!
I started working with AIDES in 1984, as soons as it was created. At the time, I was completely helpless when I saw patients arriving in my office at the Pasteur Institute who were not well at all, sometimes from foreign countries, who did not have social security coverage, and who obviously needed to be hospitalised as soon as possible.
It was then, in the 1980s, that I realized how essential the relationship between researcher - medical staff - patient was if we wanted to make progress. Before, I was, like many others, a researcher locked in her laboratory, who had never seen a patient before in her life. I then understood the vision of this great man who was Louis Pasteur: to work with and for the people.
The discovery of the AIDS virus finally changed my life and my research: it was done for and with patients. This is the first disease where there have been so many implications for researchers and people living with the disease.
As President of Sidaction, I’m thinking, with others, about the future of the association, and on ways to improve its strategy and visibility in order to attract new donations. The associative field as a whole is not as well as it was at one time. Financing is becoming increasingly difficult to obtain, there are fewer donations. Economic and political reasons explain this: recent tax changes and the increase in the generalized social contribution (CSG) for pensioners have driven donors away. Last year, we raised just over 4 million euros during the Sidaction. In 2018, approximately €3 million was used to support research and young researchers. Today, we are at a turning point in the field of HIV, we see that the epidemic is stagnating: to improve prevention and patient care, these must be integrated into an overall improvement in countries' health and health systems, as in the case of tuberculosis and malaria.
By Véronique Meder.