The gold salt auranofin may be a promising addition to antiretroviral therapy (ART) to target individuals categorized as latent viral reservoirs of HIV-1, according to study results published in the International Journal of Antimicrobial Agents.
Antiretroviral therapy (ART) is the treatment of choice in people with HIV-1 or AIDS and is composed of a combination of 3 antiretroviral drugs. However, ART does not affect latent HIV-1 genomes in individuals who are viral reservoirs, and thus can be re-infected once treatment is suspended, highlighting the fact that HIV-1 cannot be eradicated by ART.
Although many clinical trials have attempted to target the HIV-1 reservoir, only 2 individuals have been eradicated of HIV-1, underscoring the unmet medical need for an HIV-1 cure. Gold salts have an anti-lymphoproliferative effect that has been well-documented in rheumatologic diseases and may benefit chronic viral diseases like HIV-1. The gold salt auranofin has previously been shown to induce decay of viral DNA in peripheral blood of macaques with HIV infection when used in combination with intensified ART. Additionally, auranofin can induce lymphocyte differentiation especially in the memory compartment that encompasses the viral reservoir and may further limit proliferative potential.
These observations make auranofin a promising potential addition to ART to achieve HIV-1 cure. Therefore, this study provided an estimate of the effect of auranofin on HIV-1 reservoirs in humans and detailed the effects of the first use of a gold compound with ART in a clinical setting (ClinicalTrials.gov identifier: NCT02961829).
A total of 30 individuals who demonstrated viral load suppression with ART and did not have an active AIDS-defining condition were included and randomly assigned to 1 of 6 groups: (1) continuation of ART; (2) intensified ART (ART + dolutegravir + maraviroc); (3) intensified ART and nicotinamide (1000 mg once daily); (4) intensified ART and auranofin (oral, 3 mg twice daily); (5) partially intensified ART (dolutegravir) + dendritic cell vaccine; and (6) partially intensified ART + nicotinamide + auranofin + dendritic cell vaccine. The antiretroviral drugs were administered at dosages that followed standard clinical guidelines and auranofin was used for the first 24 weeks.
The study is ongoing and the results presented are an interim analysis of the effect of auranofin on the viral reservoir; therefore, groups 3 and 6 are not included in the results. The primary outcome of this interim analysis was the measurement of viral reservoir markers at 5 months of treatment (ie, the time point at which the effects of auranofin are maximal). Plasma viral load was quantified every 4 weeks and DNA from peripheral blood mononuclear cells was isolated and quantified.
The results suggested that auranofin may have an effect on DNA dynamics via an antiproliferative effect. Compared with ART-only regimens, patients in auranofin-treated regimens experienced a significant decrease in viral DNA (P =.0365) and induced a decrease in integrated viral DNA. In addition, resulted showed that both groups treated with intensified ART (group 2) and intensified ART + auranofin (group 4) displayed decreases in CD4+ CD38+ cells (group 2, P =.046; group 4, P =.0082).
To assess the effect of auranofin on viral DNA composition, the nef gene of the HIV-1 DNA obtained from peripheral blood mononuclear cell samples from 3 participants in either group 2 or 4 were sequenced and the evolution of viral sequences over time was analyzed for a decrease in the number of proliferating clones after treatment. Compared with the ART-only patients, the auranofin-treated patients showed significantly different clustering sequences (P =.0416), suggesting that the bulk of the original proviral sequences were decreased or depleted by auranofin treatment. Further, in the auranofin-treated regimens, the proliferation rate of the viral reservoir decreased from 1.4 day-1 to 0.56 day, -1 which translates to a viral reservoir decay of 37% of the original level upon auranofin treatment. Despite a transient decrease in CD4+ T-cells at weeks 8 and 12, there were no serious adverse events from auranofin treatment.
Overall, the study authors concluded that, “Despite the limited number of patient-derived sequences available in this study, phylogenetic analyses of nef sequences support the idea that auranofin may impact on the viral reservoir.”
Diaz RS, Shytaj IL, Giron LB, et al. Potential impact of the antirheumatic agent auranofin in proviral HIV-1 DNA in individuals under intensified antiretroviral therapy: results from a randomised clinical trial [published online August 5, 2019]. Int J Antimicrob Agents. doi:10.1016/j.ijantimicag.2019.08.001