Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy.

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus.

BACKGROUND: Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART). METHODS: AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. RESULTS: Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (P = .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; P = .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]). CONCLUSIONS: In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART. CLINICAL TRIALS REGISTRATION: NCT02475655.

Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption.

BACKGROUND: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 µg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).

Leveraging Cancer Therapeutics for the HIV Cure Agenda: Current Status and Future Directions.

Despite effective antiretroviral therapy (ART) and undetectable HIV RNA in the plasma, latent replication-competent HIV persists indefinitely in long-lived cells. Cessation of ART results in rebound of HIV from these persistent reservoirs. While this was thought to be an insurmountable obstacle to viral eradication, recent cases suggest otherwise. To date one patient has been "cured" of HIV and several others have been able to interrupt ART without viral rebound for prolonged periods. These events have sparked renewed interest in developing strategies that will allow eradication of HIV in infected individuals. We review the current knowledge of HIV latency and the viral reservoir, describe the potential utility of emerging cancer therapeutics in HIV cure research with an emphasis on pathways implicated in reservoir persistence, and outline opportunities and challenges in the context of the current clinical trial and regulatory environment.

NRTI backbone in HIV treatment: will it remain relevant?

Nucleoside reverse transcriptase inhibitors (NRTIs) remain a critical component of therapy for HIV-infected patients. The drugs are effective, relatively inexpensive and an important component of antiretroviral therapy (ART), particularly in areas where the introduction of effective therapy has been delayed. They are an essential part of initial therapy for HIV and for prevention of mother-to-child transmission; however, toxicities and resistance may limit their use. The role for pre-exposure prophylaxis (PrEP) to reduce sexual transmission of HIV is still undefined, but this use may have a significant impact on NRTI resistance worldwide, most particularly in areas where subtype C predominates. With increasing prevalence of resistant HIV, the approval of new agents that are effective against resistant virus, and those that use novel cellular targets, are essential. Large studies are now in progress examining the safety and efficacy of NRTI-sparing regimens, but results are not currently available. NRTIs may lose relevance in the not distant future unless steps are put in place to reduce the development and spread of NRTI-resistant viruses, and new NRTIs with minimal toxicity are developed that have a novel resistance profile. This article describes the principal NRTIs, their mechanism of action, and resistance and selected toxicities of the class and of the individual drugs.

Determination of total potentially available nucleosides in human milk from Asian women.

OBJECTIVE: The objective was to measure the total potentially available nucleosides (TPAN) in breast milk from Asian women. METHODS: One hundred sixty milk samples were collected from 135 healthy, lactating women in Hong Kong, the Philippines, and Singapore at four stages of lactation: colostrum (1 to 3 days postpartum), transitional (7 to 10 days postpartum), early mature (28 to 35 days postpartum), and late mature (90 to 100 days postpartum). Samples were pooled by site and stage of lactation before analysis. RESULTS: The mean TPAN concentration was 203 microM/L (69.4 mg/L corrected for recovery). Average TPAN concentrations were 171.9 microM/L in colostrum, 208.1 microM/L in transitional milk, 221.6 microM/L in early mature milk, and 210.6 microM/L in late mature milk, with no notable differences between countries. The major sources of nucleosides were RNA (43.3% of TPAN) and free nucleotides (39.9% of TPAN). The average percentages of cytidine, uridine, guanosine, and adenosine monophosphates were 44.5%, 23.1%, 16.5%, and 16.1% of TPAN, respectively. The sources of nucleosides and percentages of nucleotide bases were similar for all stages of lactation. Over 91% of the TPAN was present in the non-cellular component except in colostrum. CONCLUSIONS: The average TPAN level in Asian women is similar to that in European and American women, and free nucleotides in human milk represent less than half of the TPAN.

Tolerancia gastrointestinal de una nueva formula lactea infantil en bebes sanos: estudio multicentrico realizado en Mexico / Gastrointestinal tolerance of a new infant formula

El siguiente estudio fue diseñado para probar la hipótesis de que la alimentación infantil con ingredientes dietéticos específicos juega un rol protagonico en la tolerancia gastrointestinal del lactante. El objetivo primario fue comparar la tolerancia gastrointestinal de niños sanos a la leche humana y a otras fórmulas infantiles. De los 1.453 sujetos evaluados, 134 recibieron leche humana; 267 leche humana más la nueva fórmula infantil, Similac Advance, NF; 83 leche humana más otra fórmula; 787 NF y 191 otra fórmula (principalmente NAN de Nestle, N o SMA de Wyeth, S). Los niños alimentados con NF tuvieron una consistencia de heces más blanda que los que recibieron otra fórmula (p=0.001); y menos regurgitación que los alimentados con N ó S (p<0.01). Igualmente, los niños alimentados con la nueva fórmula infantil tuvieron una menor incidencia de intolerancia general, regurgitaciones, evacuaciones duras, flatulencia y/o cólicos que los niños alimentados con otras fórmulas infantiles; y estos resultados fueron estadísticamente significativos. En conclusión, NF fue bien tolerada en lactantes sanos y los resultados de las evacuaciones fueron similares a las de los niños alimentados con leche humana; cosa que no se consiguió en los lactantes alimentados con otras fórmulas