For over 20 years, the advances made in clinical research have considerably improved the quality of life of patients infected by HIV: control of viremia, life expectancy of patients with low-level viremia comparable to that of the general population, decrease in treatment-related side effects, and so forth.
Despite these major advances, questions remain: How do some patients control HIV infection? How can the size of viral reservoirs be reduced? Is it possible to de-escalate treatment in patients with low-level viremia?
Some patients control their HIV infection, either spontaneously or after interruption of antiretroviral treatment started very early after the infection. Through its research, the ANRS is trying to understand how this control is possible. What are the virological and immunological mechanisms at play? How does treatment initiated early contribute to this control? What are the factors associated with this control after discontinuation of treatment?
ANRS CO21 CODEX, A UNIQUE COHORT
The cohort ANRS CO21 Codex includes three profiles of patients who show control of HIV infection. By studying such patients, we can explore different ways of understanding the mechanisms of such control. This understanding could in time lead to the development of an effective therapeutic vaccine. The three patient profiles are as follows:
- patients who are asymptomatic long term: infected by HIV long ago, these patients, in the absence of treatment, have a stable CD4 cell count, regardless of viral load.
- long-term nonprogressors: infected by HIV for at least 5 years, these patients are asymptomatic and have a viral load below 400 copies/mL, whatever the CD4 cell count and in the absence of antiretroviral treatment.
- post-treatment controllers: these patients, still sometimes called “VISCONTI patients,” control their infection after discontinuation of antiretroviral treatment taken at primary infection.
Some patients, given antiretroviral treatment right from the start of primary infection, control their infection after discontinuation of treatment. Can this be reproduced by implementation of treatment soon after infection?
ANRS 169 OPTIPRIM 2
This randomized multicenter trial in patients with primary HIV-1 infection is assessing the impact on the viral reservoir of a combination of tenofovir/emtricitabine and darunavir/cobicistat. The aim, through very early treatment, is to limit the quantity of virus in the reservoirs and to discontinue treatment. Will these patients control their infection after discontinuation of drugs, like post-treatment controllers?
The ANRS is studying the feasibility of treatment de-escalation in patients who experience viral control on triple-drug therapy and who show no drug resistance. The aims are to improve their quality of life and to limit the risk of drug-related toxicity.
REDUCE THE NUMBER OF DRUGS
Two clinical trials are studying whether it is possible to maintain viral control when patients switch from triple-drug therapy to dual therapy.
ANRS 163 ETRAL: This trial is evaluating the capacity of a dual therapy (raltegravir plus etravirine) to maintain viral control till 48 weeks in patients infected by HIV-1 and receiving first-line triple-drug therapy.
ANRS 167 LAMIDOL: This trial is evaluating the virological efficacy of dual therapy with dolutegravir and lamivudine in patients infected by HIV-1 in whom viral control is achieved with triple-drug therapy.
REDUCE DOSING FREQUENCY
One ANRS trial is assessing whether a treatment taken daily is as effective when it is taken less frequently.
ANRS QUATUOR: This trial is examining whether the 4 days/7 strategy is non-inferior to the 7 days/7 strategy, in other words whether, for the same efficacy, the patients in the treatment de-escalation group experience secondary benefits (fewer side effects, better adherence …).
This new trial follows on from encouraging results (ANRS press release July 2016) in ANRS 162 4D, a trial assessing maintenance of viral control by an antiretroviral treatment strategy of 4 consecutive days out of 7, following on from treatment 7 days out of 7, in patients infected by HIV-1 who have had an undetectable viral load for at least 12 months.
"This therapeutic success was maintained, despite the decrease in drugs, throughout the trial. Most people said they felt they had much better control over their health, and chose to take their treatment for four days, not including the weekend. This allows them to visit friends without necessarily having to take their medication." Pierre de Truchis - France info.fr – 19.07.2016
Treatment de-escalation also applies to reducing the doses of certain drugs. One ANRS trial is studying maintenance of efficacy of antiretroviral treatment when halving the dose of darunavir.
ANRS 165 DARULIGHT: This trial in patients infected by HIV-1, with a viral load undetectable under treatment comprising darunavir 800 mg/day (combined with two nucleoside reverse transcriptase inhibitors), is seeking to keep the viral load below 50 copies/mL when the darunavir dose is halved to 400 mg/day.
DE-ESCALATING TREATMENT IN PREGNANT WOMEN
In France, triple-drug therapy comprising a protease inhibitor is recommended in pregnant women. However, several studies have shown that there is a high risk of treatment-associated prematurity, cardiac anomalies in the child, and toxicity for the mother. Treatment de-escalation is a potential way to limit this risk.
ANRS 168 Monogest: This trial is evaluating whether a treatment without protease inhibitor limits the risk of toxicity for the child, while avoiding mother-to-child transmission.