Previous human studies suggested that cannabis, to some extent, reduced the related symptoms (anorexia, cachexia, and neuropathic pain) and morbidity/mortality in PLWH [127, 128]. As for immune activation and inflammation in HIV patients, Manuzak et al. clarified that heavy cannabis users had decreased frequencies of HLA-DR+CD38+CD4+ and CD8+ T cell, increased frequencies of classical monocyte subsets (CD14++CD16−), and reduced frequencies of IL-23 and TNF-α producing antigen-presenting cells [129]. Moreover, recent cannabis use was associated with lower levels of inflammatory biomarkers, in both cerebrospinal fluid (CSF) and blood, suggesting its specific antineuroinflammatory effects [130]. Although there are promising benefits of cannabis for HIV/AIDS sufferers, the potential psychoactive side effects (impaired memory, euphoria, anxiety, and paranoia) and minor nonpsychoactive effects (sleepiness, tiredness, dry mouth, and red eyes) continue to be a barrier to its medical use. Also, the similar drug heroin was being tried in PLWH for treating immune activation and cardiovascular risk in HIV ({"type":"clinical-trial","attrs":{"text":"NCT03976258","term_id":"NCT03976258"}}NCT03976258), but no study results were posted to date.

Besides, following treatment of pyridostigmine, an ACh-esterase inhibitor, in 9 treatment-naïve HIV-1 patients with CD4+ T cell count over 300 cells/μL, the fraction of CD69+CD4+ T cells, IFN-γ, and TNF-α was significantly decreased, and Treg was dampened, while IL-4/6/10 were increased compared with placebo [131]. Dipyridamole was demonstrated to inhibit the replication of HIV-1 [132]; however, in virally suppressed persons with HIV on ART, it did not decrease the soluble markers of inflammation levels but modestly reduced the levels of CD8+ T cell activation [133]. Administration of mesalazine to subjects with poor CD4+ T cell gain on virologically suppressive cART did not affect markers of peripheral inflammation [134]. Moreover, leflunomide was proven to reduce the proliferation of activated T cells in vitro [135], but when applied in a small RCT in cART-naive patients, it showed no significant changes in activated CD4+ and CD8+ T cells [136]. Finally, the potential benefits for immune activation/inflammation among HIV-1-infected subjects of other drugs, such as isotretinoin ({"type":"clinical-trial","attrs":{"text":"NCT01969058","term_id":"NCT01969058"}}NCT01969058) and methotrexate ({"type":"clinical-trial","attrs":{"text":"NCT01949116","term_id":"NCT01949116"}}NCT01949116), require additional investigation [137].