Results from different trials reveal that people with HIV who meet both criteria could potentially benefit from proof-of-concept trials in the cure of HIV
According to three studies presented this week at the 11th International AIDS Society Conference on HIV Science (IAS 2021), which is being held virtually due to the COVID-19 pandemic, people with HIV who initiate the antiretroviral treatment (ART) early and before far-reaching damage to the immune system would have smaller reservoirs of HIV.
HIV infection is inherently incurable with antiretroviral treatment because, although it is possible to completely stop the replication of the virus for long periods, if the treatment is stopped, the replication restarts at the expense of the viral reservoirs on which the drugs cannot act. antiretrovirals.
The latent cell reservoir of HIV forms shortly after the onset of infection and consists primarily of resting CD4 memory T cells. This reservoir of latently infected cells has a half-life of more than 4 years and is the main obstacle to eradication of the virus.
In the first study, Australian researchers analyzed the relationship between CD4 T cell count and viral reservoir size in people who started antiretroviral treatment early in the context of the START trial. This study found that people with HIV had a significantly lower risk of illness and death if they started treatment with a CD4 cell count greater than 500 cells / mm3 rather than waiting for it to drop below 350 cells / mm3, such as established the clinical guidelines at the time this trial was conducted. Thanks to these findings, clinical guidelines around the world began to recommend the initiation of antiretroviral treatment after diagnosis to all people with HIV regardless of the CD4 cell count.
In this substudy, 146 people with HIV participated, of whom 60% were women, the majority black and with a median age of 40 years. The researchers compared the size of viral reservoirs in people who started treatment with a CD4 cell count between 500 and 599 cells / mm3 (36 participants), between 600 and 799 cells / mm3 (60 participants), and with more than 800 cells. / mm3 (50 participants).
After three years of treatment, the researchers collected samples and measured total HIV DNA, HIV DNA of two long terminal repeats (a specific type of HIV DNA), and cell-associated HIV RNA not integrated into CD4 cells. and plasma HIV RNA using an assay capable of detecting a single copy. In addition, three markers of T cell activation were also evaluated: HLA-DR, PD-1 and pSTAT5.
The results show that total HIV DNA was lower in those participants who started treatment with a CD4 count higher than 800 cells / mm3 (16 copies per million cells) than in those who started treatment with 600-799 or 500 -599 cells / mm3 (30 and 68 copies per million cells, respectively). This significant reduction was also recorded for the measurement of plasma HIV RNA in those who started treatment with elevated CD4 counts. However, it was not recorded with HIV DNA with two long terminal repeats or with non-integrated cell-associated RNA. On the other hand, the activation of T cells measured by the HLA-DR marker was also significantly lower in the group of participants who started antiretroviral treatment with a count higher than 800 cells / mm3, however, no differences were recorded in the expression of markers PD-1 and pSTAT5.
Another finding was that older people and women had lower total HIV DNA levels than men and younger people. After adjusting the results for these factors of sex and age and for other variables, the observed association between having a lower level of total HIV DNA and a higher CD4 count at the beginning of treatment was maintained.
In their conclusions, the researchers point out that people with HIV who maintain a CD4 T cell count above 800 cells / mm3 before starting antiretroviral treatment would be endowed with an enhanced ability to kill latently infected cells and may constitute a subgroup that could potentially benefit from strategies evaluated in HIV cure studies.
The second study, conducted by researchers at Gilead Sciences, compared the size and diversity of viral reservoirs and the susceptibility of HIV to broadly neutralizing antibodies (bNAbs) in people who started antiretroviral treatment at different stages of infection. The bNAbs antibodies are able to recognize conserved parts of the virus that change very little between the different strains. These antibodies are currently being studied in HIV treatment, prevention and cure research.
This study included 64 people with HIV, of whom more than 90% were men and had received antiretorviral treatment for three to five years and had elevated CD4 levels, between 700 and 900 cells / mm3. Depending on when they started treatment, they were divided into four cohorts: 16 participants started it at Fiebig stage I or II where HIV RNA and the p24 antigen can be detected; 17 in Fiebig stage III or IV in which HIV antibodies can be detected for the first time; 14 were in late acute infection (three months or less after exposure); and 17 participants in the chronic infection phase (more than six months after infection).
The participants underwent a procedure called leukapheresis in which blood is drawn to obtain white blood cells. The remaining blood is returned to the body. The procedure allowed the researchers to obtain peripheral blood mononuclear cells, that is, T cells and other immune cells. Using an intact proviral DNA assay, a total HIV DNA assay, and a quantitative viral growth assay, the HIV reservoir was measured. HIV susceptibility to elipovimab - a bNAbs being developed by Gilead) - was determined through genotyping of the HIV envelope gene.
The results show that total HIV DNA was lower in patients who started antiretroviral treatment when they were in stage Fiebig I-II and Fiebig III-IV.
Participants who started treatment during late acute infection had a lower level of total HIV DNA than those who started treatment during chronic infection, but the difference did not reach statistical significance. Furthermore, viral diversity was lower in people who started treatment during late acute infection than in participants who did so during chronic infection. People who started antiretroviral treatment earlier also generally had a higher susceptibility to elipovimab.
The researchers note in their conclusions that people with HIV who initiate antiretroviral therapy at Fiebig stages I-IV are an optimal population to benefit from HIV proof-of-concept trials as they have smaller reservoirs of HIV and less diverse.
Source: Aidsmap / Elaboración propia (gTt-VIH)
References: Hudson F et al. (Wright E presenting) Lower HIV reservoir size in individuals who maintain higher CD4+ T cells counts prior to antiretroviral therapy initiation: the Strategic Timing of Antiretroviral Treatment (START) HIV reservoir study. 11th IAS Conference on HIV Science, abstract PEBLB13, 2021.
Moldt B et al. Evaluation of HIV-1 reservoir size and broadly neutralizing antibody (bNAb) susceptibility in individuals who initiated ART during acute and chronic infection. 11th IAS Conference on HIV Science, abstract OAA0405, 2021.