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Abstract: Despite the burden of chronic pain in sickle cell disease (SCD), nonpharmacological approaches remain limited. This multisite, randomized trial compared digital cognitive behavioral therapy (CBT) with a digital pain/SCD education program (“Education”) for managing pain and related symptoms. Participants were recruited virtually from seven SCD centers and community organizations in the United States. Adults (aged ≥18 years) with SCD-related chronic pain and/or daily opioid use were assigned to receive either CBT or Education for 12 weeks. Both groups used an app with interactive chatbot lessons and received personalized health coach support. The primary outcome was the change in pain interference at six months, with secondary outcomes including pain intensity, depression, anxiety, quality of life, and self-efficacy. Of 453 screened participants, 359 (79%) were randomized to CBT (n = 181) or Education (n = 178); 92% were Black African American, and 66.3% were female. At six months, 250 participants (70%) completed follow-up assessments, with 16 (4%) withdrawals. Engagement with the chatbot varied, with 76% connecting and 48% completing at least one lesson, but 80% of participants completed at least one health coach session. Both groups showed significant within-group improvements in pain interference (CBT: −2.13; Education: −2.66), but no significant difference was observed between them (mean difference, 0.54; P = .57). There were no between-group differences in pain intensity, depression, anxiety, or quality of life. High engagement with health coaching and variable engagement with digital components may explain the similar outcomes between interventions in this diverse, hard-to-reach population.

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.

BACKGROUND:Identifying pre-ART factors associated with the emergence of HIV-1 drug resistance is critical for optimizing strategies to prevent virologic failure. A previous study reported that lower pre-ART HIV-1 pol diversity was associated with higher risk of virologic failure in HIV-1-infected children. To investigate this association in adults, we measured HIV-1 diversity with deep sequencing in pre-ART samples from adults with well-characterized virologic outcomes in a study (A5142) of initial ART conducted by the AIDS Clinical Trials Group (ACTG). METHODS:We identified 22 cases in ACTG A5142 who experienced virologic failure with drug resistance mutations in RT and 44 matched controls who did not experience virologic failure. cDNA was synthesized from plasma HIV-1 RNA. Each cDNA molecule was tagged with a unique primer ID and RT codons 41-103 were amplified and deep sequenced. Sequences with the same tag were aligned and a consensus was generated to reduce PCR and sequencing errors. Diversity was calculated by measuring average pairwise distance (APD) of the consensus sequences. An exact conditional logistic regression model with percent APD as the risk factor estimated the odds ratio for VF and the corresponding 95% confidence interval. RESULTS:Consensus single-genome sequences and diversity estimates of pol were obtained for pre-ART samples from 21 cases and 42 controls. The median (IQR) pre-ART percent APD was 0.71 (0.31-1.13) in cases and 0.58 (0.32-0.94) in controls. A possible trend was found for higher diversity being associated with greater risk of virologic failure in adults (OR = 2.2 per one percent APD increase, 95% CI = [0.8, 7.2]; p = 0.15). CONCLUSIONS:This study in adults suggests there is a positive association between higher pre-ART pol diversity and the risk of virologic failure in adults rather than an inverse relationship reported in children.

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.

Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART.