Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study.

Background: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer.

Methods: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled.

Brentuximab vedotin with AVD for stage II-IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial.

Background: Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions.

Phase I Trial of the Multi-kinase Inhibitor Cabozantinib, a CYP3A4 Substrate, plus CYP3A4-Interacting Antiretroviral Therapy in People Living with HIV and Cancer (AMC-087).

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamic effects of cabozantinib, a CYP3A4 substrate, in people living with human immunodeficiency virus and cancer receiving antiretrovirals (ARV).

Patients And Methods: Patients received a reduced dose of cabozantinib (20 mg orally daily) with strong CYP3A4 inhibitors (ARV ritonavir or non-ARV cobicistat, stratum A), or a standard 60 mg dose with ARVs that are CYP3A4 inducers (efavirenz or etravirine, stratum B) or noninteracting ARVs (stratum C). Initial dose escalation in stratum A and stratum B was performed on the basis of tolerability.

Construct validity and responsiveness of a health-related symptom index for persons either treated or monitored for anal high-grade squamous intraepithelial lesions (HSIL): AMC-A01/-A03.

Purpose: To determine whether treatment of anal high-grade squamous intraepithelial lesions (HSIL), vs active monitoring, is effective in reducing incidence of anal cancer in persons living with HIV, the US National Cancer Institute funded the Phase III ANal Cancer/HSIL Outcomes Research (ANCHOR) clinical trial. As no established patient-reported outcomes (PRO) tool exists for persons with anal HSIL, we sought to estimate the construct validity and responsiveness of the ANCHOR Health-Related Symptom Index (A-HRSI).

Methods: The construct validity phase enrolled ANCHOR participants who were within two weeks of randomization to complete A-HRSI and legacy PRO questionnaires at a single time point.

HIV post-treatment controllers have distinct immunological and virological features.

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk.

Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer.

Background: The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking.

Plasma extracellular vesicles bearing PD-L1, CD40, CD40L or TNF-RII are significantly reduced after treatment of AIDS-NHL.

Emerging evidence shows that tumor cells secrete extracellular vesicles (EVs) that carry bioactive cell surface markers, such as programmed death-ligand 1 (PD-L1), which can modulate immune responses and inhibit anti-tumor responses, potentially playing a role in lymphomagenesis and in promoting the growth of these cancers. In this study, we investigated the role of EVs expressing cell surface molecules associated with B cell activation and immune regulation. We measured levels of EVs derived from plasma from 57 subjects with AIDS-related non-Hodgkin lymphoma (AIDS-NHL) enrolled in the AIDS Malignancies Consortium (AMC) 034 clinical trial at baseline and post-treatment with rituximab plus concurrent infusional EPOCH chemotherapy.

AMC-070: Lenalidomide Is Safe and Effective in HIV-Associated Kaposi Sarcoma.

Purpose: Kaposi sarcoma (KS), an endothelial cell tumor associated with KS herpesvirus (KSHV), remains among the most common malignancies occurring with HIV infection (HIV-KS). As an oral anti-inflammatory, antiangiogenic, and immunomodulatory agent, lenalidomide is potentially an attractive alternative to standard chemotherapy for KS.

Experimental Design: The primary objectives of this phase I/II trial were to determine the maximum tolerated dose (MTD) and response rates for lenalidomide in HIV-KS.

A Phase 1/2 Randomized, Placebo-Controlled Trial of Romidespin in Persons With HIV-1 on Suppressive Antiretroviral Therapy.

Background: Romidepsin (RMD) is a histone deacetylase inhibitor reported to reverse HIV-1 latency. We sought to identify doses of RMD that were safe and induced HIV-1 expression.

Methods: Enrollees had HIV-1 RNA <40 copies/mL on antiretroviral therapy.

Immune Activation and Microbial Translocation as Prognostic Biomarkers for AIDS-Related Non-Hodgkin Lymphoma in the AMC-034 Study.

Purpose: AIDS-related non-Hodgkin lymphoma (ARL) is the most common cancer in HIV-infected individuals in the United States and other countries in which HIV-positive persons have access to effective combination antiretroviral therapy (cART). Our prior work showed that pretreatment/postdiagnosis plasma levels of some cytokines, such as IL6, IL10, and CXCL13, have the potential to serve as indicators of clinical response to treatment and survival in ARL. The aims of this study were to identify novel prognostic biomarkers for response to treatment and/or survival in persons with ARL, including biomarkers of microbial translocation and inflammation.

Clinical Trials for Treatment and Prevention of HIV-Associated Malignancies in Sub-Saharan Africa: Building Capacity and Overcoming Barriers.

Purpose: The aim of this study was to review the current status of clinical trials for HIV-associated malignancies in people living with HIV in sub-Saharan Africa (SSA) and efforts made by the AIDS Malignancy Consortium (AMC) to build capacity in SSA for HIV malignancy research.

Methods: All malignancy-related clinical trials in 49 SSA countries on ClinicalTrials.gov were reviewed and evaluated for inclusion and exclusion criteria pertaining to HIV status.

Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

Purpose: Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.

Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial).

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle.

Response-adapted therapy with infusional EPOCH chemotherapy plus rituximab in HIV-associated, B-cell non-Hodgkin's lymphoma.

Four cycles of rituximab plus CHOP chemotherapy is as effective as 6 cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with HIV-associated DLBCL and high-grade lymphoma treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy. 106 evaluable patients with HIV-associated DLBCL or high-grade CD20-positive non-Hodgkin's lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH.

Pilot Trial AMC-063: Safety and Efficacy of Bortezomib in AIDS-associated Kaposi Sarcoma.

Purpose: AIDS-related Kaposi sarcoma is often incompletely controlled, requiring serial therapies. Kaposi sarcoma herpesvirus (KSHV) induces transformation of endothelial cells, where it resides in a predominately latent state. We hypothesized proteasome inhibition would have direct antitumor activity, induce lytic activation of KSHV, and inhibit HIV infectivity, improving control of both Kaposi sarcoma and HIV.

Comparison of nylon-flocked swab and Dacron swab cytology for anal HSIL detection in transgender women and gay, bisexual, and other men who have sex with men.

Background: An anal histological high-grade squamous intraepithelial lesion (hHSIL) is an anal cancer precursor. Experts recommend Dacron swab anal cytology as a primary screen for anal hHSILs, especially among human immunodeficiency virus-infected and -uninfected men who have sex with men (MSM). Studies have shown that Dacron cytology inaccurately predicts anal hHSILs and results in unnecessary diagnostic procedures.

Re-boost immunizations with the peptide-based therapeutic HIV vaccine, Vacc-4x, restores geometric mean viral load set-point during treatment interruption.

Background: Vacc-4x, a therapeutic HIV vaccine candidate has previously induced a significant reduction in viral load (VL) set-point compared to placebo upon interruption of combination anti-retroviral therapy (ART) (2007/1 study). This study, (2012/1), explored the potential to maintain Vacc-4x effect by re-boosting eligible 2007/1 study participants.

Methods: Participant inclusion required 2007/1 participants to have completed all Vacc-4x immunizations and interrupted ART for up to 26 weeks.

Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas.

HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL.

Prevalence of HIV in Patients with Malignancy and of Malignancy in HIV Patients in a Tertiary Care Center from North India.

Background And Objectives: People living with HIV/AIDS are at an increased risk of developing cancer. The goals of this study were to obtain data on the prevalence of HIV in the cancer population and vice versa at a major tertiary cancer and HIV center in North India.

Methods: This cross-sectional study was conducted over a 3-year period from July 2013 to June 2016, wherein successive HIV positive patients from an anti-retroviral therapy (ART) center were screened for malignancy.

The Control of HIV After Antiretroviral Medication Pause (CHAMP) Study: Posttreatment Controllers Identified From 14 Clinical Studies.

Background: HIV posttreatment controllers are rare individuals who start antiretroviral therapy (ART), but maintain HIV suppression after treatment interruption. The frequency of posttreatment control and posttreatment interruption viral dynamics have not been well characterized.

Methods: Posttreatment controllers were identified from 14 studies and defined as individuals who underwent treatment interruption with viral loads ≤400 copies/mL at two-thirds or more of time points for ≥24 weeks.

A Randomized Clinical Trial of Infrared Coagulation Ablation Versus Active Monitoring of Intra-anal High-grade Dysplasia in Adults With Human Immunodeficiency Virus Infection: An AIDS Malignancy Consortium Trial.

Background: Anal high-grade squamous intraepithelial lesions (HSILs) ablation may reduce the incidence of invasive cancer, but few data exist on treatment efficacy and natural regression without treatment.

Methods: An open-label, randomized, multisite clinical trial of human immunodeficiency virus (HIV)-infected adults aged ≥27 years with 1-3 biopsy-proven anal HSILs (index HSILs) without prior history of HSIL treatment with infrared coagulation (IRC). Participants were randomized 1:1 to HSIL ablation with IRC (treatment) or no treatment (active monitoring [AM]).

HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers.

HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups.

Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075).

Introduction: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV) or human herpesvirus-8-positive (HHV-8) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART).

Patients And Methods: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV), 1 EBV/HHV-8 primary effusion lymphoma, and 1 unclassifiable NHL.