Timing of hepatitis C treatment initiation and retention in office-based opioid treatment with buprenorphine: a retrospective cohort study.

BACKGROUND: This study examined associations between receipt of hepatitis C (HCV) treatment and retention in office-based opioid treatment (OBOT) care. METHODS: We conducted a retrospective cohort study of HCV-infected patients who initiated OBOT treatment between December 2015 and March 2021 to characterize HCV treatment and assess associations with OBOT retention. HCV treatment was characterized as no treatment, early treatment (< 100 days since OBOT initiation) or late treatment (≥ 100 days). We evaluated associations between HCV treatment and cumulative days in OBOT. A secondary analysis using Cox Proportional Hazards regression was done to determine the rate of discharge over time when comparing those who did versus did not receive HCV treatment as a time-varying covariate. We also analyzed a subset of patients retained at least 100 days in OBOT care and evaluated whether HCV treatment during that period was associated with OBOT retention beyond 100 days. RESULTS: Of 191 HCV-infected OBOT patients, 30% initiated HCV treatment, of whom 31% received early treatment and 69% received late treatment. Median cumulative duration in OBOT was greater among those who received HCV treatment (any: 398 days, early: 284 days and late: 430 days) when compared to those who did not receive treatment (90 days). Compared to no HCV treatment, there were 83% (95% CI: 33-152%, P < 0.001), 95% (95% CI: 28%-197%, p = 0.002 and 77% (95% CI: 25-153%, p = 0.002) more cumulative days in OBOT for any, early and late HCV treatment, respectively. HCV treatment was associated with a lower relative hazard for discharge/drop-out, although results did not meet statistical significance (aHR = 0.59;95% CI: 0.34-1.00; p = 0.052). Among the subset of 84 patients retained in OBOT at least 100 days, 18 received HCV treatment during that period. Compared to those who did not receive treatment within the first 100 days, those who received treatment had 57% (95% CI: -3%-152%, p = 0.065) more subsequent days in OBOT. CONCLUSIONS: A minority of HCV-infected patients received HCV treatment after initiating OBOT treatment, but those who did had better retention. Further efforts are needed to facilitate rapid HCV treatment and evaluate whether early HCV treatment improves OBOT engagement.

Barriers and facilitators to implementing a Pharmacist, Physician, and Patient Navigator-Collaborative Care Model (PPP-CCM) to treat hepatitis C among people who inject drugs.

BACKGROUND: Direct-acting antivirals (DAAs) offer an unprecedented opportunity to eliminate hepatitis C virus (HCV) infection, yet barriers among people who inject drugs (PWID) remain. Having pharmacists provide care through collaborative drug therapy agreements (CDTAs) offers a promising solution. We developed and piloted a Pharmacist, Physician, and Patient Navigator-Collaborative Care Model (PPP-CCM) which utilized pharmacists to directly deliver HCV care at community organizations serving PWID. We conducted formative evaluation of the PPP-CCM pilot to characterize implementation experiences. METHODS: The PPP-CCM was implemented from November of 2020 through July of 2022. Formative evaluation team members observed implementation-related meetings and conducted multiple site visits, taking detailed fieldnotes. Fieldnotes were iteratively reviewed to identify barriers and facilitators to implementation and used to inform 7 key informant interviews conducted with programmatic staff at the end of the pilot. All data were analyzed using a Rapid Assessment Process (RAP) guided by the Consolidated Framework for Implementation Research (CFIR). The formative evaluation team shared results with program stakeholders (pharmacists, physicians, and other site staff) to verify and expand on learnings. RESULTS: Evaluation of PPP-CCM revealed 5 themes, encompassing all CFIR domains: 1) PPP-CCM was feasible but challenging to deliver efficiently; 2) the pharmacist role and characteristics (e.g., being flexible, available, and patient-centered) were key to PPP-CCM successes; 3) the PPP-CCM team met challenges engaging patients over time, but some team-based strategies helped; 4) community site characteristics (e.g., existing trusting relationships with PWID and physical space that enabled program visibility) were important contributors; and 5) financial barriers may limit PPP-CCM scale-up and sustainability. CONCLUSION: PPP-CCM is a novel and promising approach to HCV care delivery for PWID who may previously lack engagement in traditional care models, but careful attention needs to be paid to financial barriers to ensure scalability and sustainability.

Production of a dendritic cell-based vaccine containing inactivated autologous virus for therapy of patients with chronic human immunodeficiency virus type 1 infection.

In preparation for a pilot clinical trial in patients with chronic human immunodeficiency virus type 1 (HIV-1) infection, a novel dendritic cell (DC)-based vaccine is being manufactured. The trial will test the hypothesis that isolated endogenous virus presented by DCs serves as a potent immunogen for activation of CD8(+) and CD4(+) T cells specific for a broad range of autologous HIV-1 antigens. Production of the vaccine under good manufacture practice conditions involves (i) autologous virus isolation; (ii) superinfection of CD4(+) T cells with the virus; (iii) inactivation of the virus in CD4(+) T cells, T-cell apoptosis, and coincubation of T cells with autologous DCs; and (iv) product testing and release. Endogenous virus was isolated from peripheral blood-derived CD4(+) T cells of three HIV-1-positive subjects by coincubation with autologous OKT-3-stimulated CD4(+) T cells. CD4(+) T-cell supernatants were tested for p24 levels by enzyme-linked immunosorbent assay (>25 ng/ml) and for the 50% tissue culture infective doses (TCID(50); which ranged from 4,642 to 46,416/ml on day 19 of culture). Autologous CD4(+) T cells that were separated on immunobeads (>95% purity) and superinfected with virus-expressed p24 (28 to 54%) had TCID(50) of >400/ml on days 5 to 10. Virus inactivation with psoralen (20 microg/ml) and UVB irradiation (312 nm) reduced the TCID(50) of the supernatants from 199,986 to 11/ml (>99%). 7-Amino-actinomycin D-positive, annexin V-positive CD4(+) T cells were fed to autologous DCs generated by using the Elutra cell separation system and the Aastrom system. Flow analysis showed that DC loading was complete in 24 h. On the basis of these translational results and experience with the generation of DCs from HIV-1-infected patients in a previous clinical trial, the Investigational New Drug application for clinical vaccination was submitted and approved by the FDA (application no. BB-IND-13137).

Therapeutic immunization with human immunodeficiency virus type 1 (HIV-1) peptide-loaded dendritic cells is safe and induces immunogenicity in HIV-1-infected individuals.

Treatments for human immunodeficiency virus type 1 (HIV-1)-positive individuals that augment HIV-1 suppression and have potential for achieving long-term control of HIV-1 viremia in the absence of antiretroviral therapy (ART) are urgently needed. We therefore conducted a phase I, clinical safety trial of a dendritic cell (DC)-based vaccination strategy as immunotherapy for HIV-1-positive individuals on ART. We studied 18 HIV-1-positive subjects on ART who underwent leukapheresis to obtain peripheral blood mononuclear cells for DC generation from monocytes cultured with cytokines. Mature DC were pulsed with three HIV-1 HLA*A0201 Gag, Env, and Pol peptides and one influenza A virus matrix protein peptide. The vaccine was administered to donors randomized to receive two vaccinations, either intravenously or subcutaneously. The primary end points were safety and tolerability of two doses of peptide-DC vaccine (3 million versus 10 million). Secondary end points included gamma interferon (IFN-gamma) enzyme-linked immunospot assay responses and clinical correlates of an immune response to vaccination. Autologous DC-peptide vaccine was safe, well tolerated, and feasible for use in all participants. Adverse events were rare. Although the trial was not powered to assess an immunologic response, a significantly increased frequency of HIV-1 peptide-specific IFN-gamma-positive cells was observed 2 weeks following the second vaccine, with three individuals responding to all four peptides. DC vaccination was safe, was feasible, and showed promise of immunogenicity in ART-treated, HIV-1-positive individuals. Additional studies of DC immunization strategies for HIV-1 infection are warranted.

Treating HIV-1 infection with dendritic cells.

The orchestration of a coordinated immune response by dendritic cells (DCs) make them an attractive target for pathogens to exploit to evade host immunity, as well as for use in therapeutic strategies to overcome this exploitation. Because HIV-1 infection is predominantly a disease of the immune system, targeting DCs for therapeutic strategies to counter the effects of HIV-1 on DCs and other immune effector cells is a timely and extremely dynamic endeavor. Our knowledge of DC function and the interaction between HIV-1 and DCs is rapidly increasing. This review focuses on HIV-1-DC interactions, the impact of these on DC therapeutics for the treatment of HIV-1-infected individuals and the current status of DC-based therapeutic vaccines for HIV-1 infection.

CD27 and CD57 expression reveals atypical differentiation of human immunodeficiency virus type 1-specific memory CD8+ T cells.

The failure of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells to control chronic HIV-1 infection could be due to the progressive loss of their capacities to undergo normal memory effector differentiation. We characterized and compared the expressions of CD27, CD28, CD57, and CD62L by Epstein-Barr virus (EBV)-, cytomegalovirus (CMV)-, and HIV-1-specific CD8+ T cells by six-color, eight-parameter flow cytometry. In contrast to the maturation of EBV- and CMV-specific memory CD8+ T cells, we found that HIV-1-specific CD8+ T cells did not display coordinated down-regulation of CD27 and up-regulation of CD57 and accumulated in an atypical CD27(high) CD57(low) subset. Moreover, the accumulation of CD27(high) CD57(low) HIV-1-specific CD8+ T cells was positively correlated with HIV-1 plasma viremia. The differentiation of HIV-1-specific CD8+ T cells to an effector subset is therefore impaired during chronic HIV-1 infection. This lack of normal CD8+ T-cell differentiation could contribute to the failure of cellular immune control of HIV-1 infection.

Proinflammatory cytokines in HIV disease-a review and rationale for new therapeutic approaches.

Antiretroviral drugs currently in use for treating HIV-1 infection are very effective at maintaining low viral loads and clinical stability, but have been limited by their inability to eradicate virus in infected individuals, resulting in the need for indefinite therapy. The inability of antiretroviral drug therapy to eliminate HIV-1 infection is thought to be due to incomplete restoration of host immunity to the virus. New strategies to improve control of HIV-1 infection during antiretroviral therapy should target enhancement of host immunity. Proinflammatory cytokines are the central mediators of both innate and adaptive immunity, and modulation of these cytokines has been shown to alter anti-HIV-1 reactivity in vitro. Modulation of proinflammatory cytokines could therefore be utilized in strategies for immunotherapy of HIV-1 infection. The ultimate goal is to find regimens that could more durably suppress viral replication and potentially eliminate the need for indefinite antiretroviral therapy. This review presents what is known about the dysregulation of proinflammatory cytokines in HIV-1 infection, highlighting newly available immune-based therapies that could augment antiretroviral drug therapies.