Description: REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) showed benefits of pitavastatin as preventive therapy for atherosclerotic cardiovascular disease (ASCVD) in people with HIV (PWH). In February 2024, the U.S. Department of Health and Human Services Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (ARV Guidelines Panel) developed statin therapy recommendations for PWH. These recommendations were issued in collaboration with representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), and the HIV Medicine Association (HIVMA). This synopsis summarizes the development process, the recommendations, and how they supplement the AHA/ACC/multisociety cholesterol guidelines and outlines gaps in primary prevention of ASCVD for PWH. Methods: The ARV Guidelines Panel convened a writing group of 10 members (6 members of the Panel with expertise in HIV-related comorbid conditions, biostatistics, and pharmacology and 4 consultants representing ACC, AHA, and HIVMA with cardiometabolic and HIV management expertise). The writing group reviewed REPRIEVE trial data, other studies evaluating the use of statins in PWH, and the AHA/ACC/multisociety cholesterol guidelines to devise recommendations. Recommendations were based on scientific evidence with a rating scheme developed since the 1998 inception of the ARV guidelines. Proposed recommendations were presented to the full ARV Guidelines Panel, rated via vote, and approved by the Panel's voting members. These recommendations were then endorsed by ACC, AHA, and HIVMA. Recommendations: The ARV Guidelines Panel issued a strong recommendation for initiating statin therapy among PWH with a 10-year ASCVD risk score of 5% or higher, whose absolute benefit from statins in REPRIEVE was greatest. For patients with a 10-year ASCVD risk score below 5%, the Panel favored statins but recommended patient-clinician risk discussions considering additional HIV-related factors that can increase ASCVD risk.

The clinical management of people with multidrug-resistant (MDR) human immunodeficiency virus (HIV) remains challenging despite continued development of antiretroviral agents. A 58-year-old male individual with MDR HIV and Kaposi sarcoma (KS) was treated with a new antiretroviral regimen consisting of anti-CD4 domain 1 antibody UB-421 and capsid inhibitor lenacapavir. The individual experienced delayed but sustained suppression of plasma viremia and a substantial increase in the CD4+ T cell count. A longitudinal examination of plasma HIV and infectious isolates showed no evidence of viral evolution or the emergence of UB-421- or lenacapavir-resistant viruses. The individual received three cycles of liposomal doxorubicin and five doses of anti-programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab that resulted in improvement in KS with flattening of lesions. Our data demonstrate that combination therapy with UB-421 could provide sustained virologic suppression in people harboring MDR HIV with limited therapeutic alternatives. An individual with multidrug-resistant HIV and Kaposi sarcoma achieved sustained viral suppression after treatment with an anti-CD4 domain 1 antibody and the injectable long-acting capsid inhibitor, lenacapavir.

BACKGROUND:Increasingly, persons with HIV in Liberia are receiving antiretroviral therapy containing the integrase strand-transfer inhibitor (InSTI) dolutegravir (DTG), but the prevalence of and factors associated with virologic failure and HIV drug resistance (HIVDR) remain unknown. METHODS:Cross-sectional analysis of 2019-2022 enrolment data from 1276 persons with HIV in the HONOR cohort included sociodemographic information, plasma viral loads (pVL), CD4 counts, and HIVDR testing by next generation sequencing in participants with virologic failure (pVL≥1000 copies/mL). RESULTS:Of the 1201 participants with pVL results, 72% are female and median age is 42 (interquartile range [IQR] 35-50) years. All are on ART (median 6.1 [2.1-11] years): 74% on DTG-based and 23% on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Ninety (7.5%) had virologic failure; 970 (81%) are suppressed (<40 copies/mL). Virologic failure is less prevalent with DTG- versus NNRTI-based regimens (5.3% vs. 14%, adjusted prevalence ratio [aPR]=0.3, 95% confidence interval [CI] 0.2-0.5) and is associated with age <50 years, CD4 count <200 cells/µL, and hemoglobin <11 g/dL. In 70 participants with virologic failure and successful sequencing, HIVDR prevalence is 81% for any ARV, 5.7% for InSTIs, 79% for NNRTIs, and 61% for nucleos(t)ide reverse transcriptase inhibitors (NRTIs). Intermediate-to-high resistance to ≥1 NRTI in current ART is less prevalent with DTG+2NRTIs than NNRTI+2NRTIs regimens (aPR = 0.5, 95%CI 0.3-0.8). CONCLUSIONS:Most participants in the cohort are virologically-suppressed. Among those with virologic failure, HIVDR prevalence is high to NRTIs and NNRTIs, but low to InSTIs. Ongoing evaluation is necessary to determine the durability of DTG-based ART.

Oral second-generation integrase strand transfer inhibitors are now anchor drugs of antiretroviral therapy (ART) globally due to their high resistance barriers. In high-income settings, guidelines recommend routine protease and reverse transcriptase resistance testing before ART initiation but suggest routine integrase resistance testing only for individuals at elevated risk of integrase resistance. Improved characterisation of transmitted integrase resistance, its detection, and its clinical impact will guide future recommendations for clinical decision making. Balancing the need to protect this important drug class against concerns about resource allocation and care complexity presents a substantial challenge. Shifting the responsibility to providers to decide whether and when to test for integrase resistance before ART initiation can be problematic, particularly given the uncertainty around the need to reassess related available recommendations. As our understanding of integrase resistance evolves, prioritising this discussion is essential, and providers, researchers, and policy makers should engage in addressing this important issue.

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective. Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available. Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area.

BackgroundPeople living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking.MethodsWe examined levels of immune activation and exhaustion markers on CD8+ T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay.FindingsThe level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38+/HLA-DR+ (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421.InterpretationOur data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials.FundingDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response. The coronavirus disease 2019 pandemic showcased collaborative successes of academia, federal agencies, and industry but also mistakes and deficiencies. We highlight critical lessons and necessary steps toward a more effective response to ensure the United States and the world are prepared for the next pandemic.

Dietrich, Devon K.; Laidlaw, Elizabeth; Hammoud, Dima A.; Pau, Alice K.; Smith, Bryan R. Author Information

Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIV KGD ) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIV KGD was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC 50 of 130 femtomolar. When cells were exposed to HIV KGD IN–containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS’s putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142–bound HIV KGD ’s PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant–harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.

Abstract While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response.

Objective: Not applicable. Background: A 59-year-old man diagnosed with HIV 26 years prior and a long history of antiretroviral therapy (ART) non-adherence presented with subacute cognitive decline. A neurologic workup including cerebrospinal fluid testing showed no evidence of opportunistic infections. He was admitted to an assisted care facility where he restarted ART. However, he remained viremic and was referred to the National Institutes of Health (NIH). On admission to the NIH, he had an HIV plasma viral load of 28,056 copies/mL and CD4 T-cell count of 5 cells/μL. He was started on a new ART regimen with increased central nervous system penetration (etravirine, dolutegravir, darunavir/cobicistat, tenofovir/emtricitabine). MRI revealed extensive leukoencephalopathy and volume loss, consistent with HIV encephalopathy. Comprehensive neuropsychological testing revealed significant deficits in all cognitive domains, including learning, memory, attention, executive function, and psychomotor speed. The patient was followed for two years, during which time he achieved and sustained viral suppression (<40 copies/mL) and reached a CD4 T-cell count of 197 with ART. A repeat MRI showed profound improvement in the white matter signal abnormality. Repeat neuropsychological testing demonstrated notable improvements in several tests of attention, information processing, and psychomotor speed, but continued difficulty in most other cognitive domains. Design/Methods: Not applicable. Results: Not applicable. Conclusions: While current ART regimens are highly effective in reducing the incidence of HIV-associated neurologic complications, their role in reversing the MRI abnormalities seen in HIV encephalopathy remains unclear. In this case, we tracked HIV encephalopathy in the current era of effective ART with serial MRI evaluations. Our results provide a rare example of dramatic reduction of periventricular white matter hyperintensities and improved performance in a subset of cognitive domains. Providers encountering white matter abnormalities in patients with treated HIV should consider this legacy effect in evaluating whether disease is progressive, or as in this case, improved. Disclosure: Ms. Dietrich has nothing to disclose. Miss Laidlaw has nothing to disclose. Dr. Hammoud has nothing to disclose. Dr. Pau has nothing to disclose. Dr. Smith has nothing to disclose.

In the combination antiretroviral era, there are limited data regarding the pathogenesis of histoplasmosis immune reconstitution inflammatory syndrome (IRIS) in people with human immunodeficiency virus (HIV). We immunologically characterized 10 cases of histoplasmosis, 4 of whom developed histoplasmosis IRIS. CD4+ T cells in histoplasmosis IRIS demonstrated a significant polyfunctional cytokine response to histoplasma antigen.

Background: Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP. Methods: This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5–19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models. Results: Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration–time curve, maximum concentrations (C max ), and concentrations at 24 hours postdose (C 24h ) were reduced by 71%, 41%, and 96% ∼48–72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C 24h concentrations were below the darunavir EC 50 (0.055 µg/mL). Conclusions: Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided.

The integrase strand transfer inhibitor (INSTI) dolutegravir is commonly used in combination antiretroviral therapy regimens and retains strong potency even with primary resistance mutations to some other INSTIs. Acquisition of accessory mutations to primary mutations results in significant increases in dolutegravir resistance. Previously, we reported that addition of the secondary mutation T97A can result in rapid treatment failure in individuals with INSTI mutations at positions 140 and 148. Here, we conducted a detailed case study of one of these individuals and find that T97A-containing HIV emerged from a large replicating population from only a few (≤4) viral lineages. When combined with primary INSTI resistance mutations, T97A provides a strong selective advantage; the finding that T97A-containing variants spread by replication and recombination, and persisted for months after discontinuing dolutegravir, has important implications as dolutegravir is rolled out worldwide.

Background Detailed longitudinal studies of HIV-positive individuals in West Africa are lacking. Here the HIV prevalence, incidence, all-cause mortality, and the proportion of individuals receiving treatment with cART in two cohorts of participants in Ebola-related studies are described. Setting Individuals of all ages were enrolled and followed at four sites in the area of Monrovia, Liberia. Methods Two cohorts identified in response to the Ebola epidemic are described to provide insights into the current state of the HIV epidemic. HIV testing was performed at baseline for participants in both cohorts and during follow-up in one cohort. Results Prevalence and incidence of HIV (prevalence of 3.1% for women and 1.4% for men and incidence of 3.3 per 1,000) were higher in these cohorts compared to 2018 national estimates (prevalence of 1.3% and incidence of 0.39 per 1,000). Most participants testing positive did not know their status prior to testing. Of those who knew they were HIV positive, 7.9% reported being on antiretroviral treatment. The death rate among those with HIV was 12.3% compared to 1.9% in HIV-negative individuals (adjusted odds ratio of 6.87). While higher levels of d-dimer were associated with increased mortality, this was not specific to those with HIV, however lower hemoglobin levels were associated with increased mortality among those with HIV. Conclusion These findings point to a need to perform further research studies aimed at fulfilling these knowledge gaps and address current shortcomings in the provision of care for those living with HIV in Liberia.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

BACKGROUND:Direct oral anticoagulants (DOACs) have become first-line treatment for venous thrombotic events. DOAC prescribing trends among people living with human immunodeficiency virus (PWH) are not well described. The coadministration of DOACs with the antiretroviral (ARV) pharmacokinetic boosters ritonavir (RTV) or cobicistat (COBI) may be complicated by pharmacokinetic interactions.METHODS:A longitudinal cohort study was conducted using the D.C. Cohort Database in Washington, D.C., from January 2011 to March 2017, to describe oral anticoagulant prescribing among PWH ≥ 18 years old and the prevalence of DOAC use with RTV or COBI. Data collection included demographic and clinical characteristics, ARV and anticoagulant prescriptions, and International Classification of Diseases Ninth and Tenth Edition diagnosis codes.RESULTS:Among 8315 PWH, there were 236 anticoagulant prescriptions (96 DOAC, 140 warfarin) for 206 persons. PWH prescribed anticoagulants were predominantly Black (82%) and male (82%), with a mean age at anticoagulant initiation of 56 years. DOAC use increased from 3% of total anticoagulant prescribing in 2011 to 43% in 2016, accounting for 64% of all newly recorded anticoagulant prescriptions by 2016. There were 19 bleeding events recorded among 16 individuals. Despite the Food and Drug Administration label recommendation to avoid rivaroxaban with boosted ARVs, 41% remained on boosted ARVs after rivaroxaban initiation.CONCLUSIONS:DOAC use increased substantially in PWH by 2016. Although rivaroxaban is not recommended with RTV or COBI, concomitant use was recorded in 41% of rivaroxaban recipients in this cohort. As DOAC usage increases, clinicians need to be aware of potential DOAC/ARV interactions in order to select the most appropriate oral anticoagulant and monitoring plan for PWH.

BACKGROUND:Patients living with human immunodeficiency virus (PLWH) with low CD4 counts are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death at antiretroviral therapy (ART) initiation. METHODS:We investigated the clinical impact of IRIS in PLWH and CD4 counts <100 cells/μL starting ART in an international, prospective study in the United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We assessed associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48 with Cox models. RESULTS:We enrolled 506 participants (39.3% were women). Median age was 37 years, and CD4 count was 29 cells/μL. Within 6 months of ART, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at baseline were at higher IRIS risk (hazard ratio [HR], 1.2; P = .004). IRIS was independently associated with increased risk of death after adjustment for known risk factors (HR, 3.2; P = .031). Being female (P = .004) and having a lower body mass index (BMI; P = .003), higher white blood cell count (P = .005), and higher D-dimer levels (P = .044) were also significantly associated with increased risk of death. Decision-tree analysis identified hemoglobin <8.5 g/dL as predictive of IRIS and C-reactive protein (CRP) >106 μg/mL and BMI <15.6 kg/m2 as predictive of death. CONCLUSIONS:For PLWH with severe immunosuppression initiating ART, baseline low BMI and hemoglobin and high CRP and D-dimer levels may be clinically useful predictors of IRIS and death risk.

Special Articles25 September 2020Convalescent Plasma for the Treatment of COVID-19: Perspectives of the National Institutes of Health COVID-19 Treatment Guidelines PanelFREEAlice K. Pau, PharmD, Judith Aberg, MD, Jason Baker, MD, MS, Pamela S. Belperio, PharmD, Craig Coopersmith, MD, Page Crew, PharmD, MPH, Birgit Grund, PhD, Roy M. Gulick, MD, MPH, Carly Harrison, MS, Arthur Kim, MD, H. Clifford Lane, MD, Henry Masur, MD, Virginia Sheikh, MD, MHS, Kanal Singh, MD, MPH, Jinoos Yazdany, MD, MPH, and Pablo Tebas, MD, for the National Institutes of Health COVID-19 Treatment Guidelines Panel*Alice K. Pau, PharmDNational Institutes of Health, Bethesda, Maryland (A.K.P., P.C., H.C.L., H.M., K.S.), Judith Aberg, MDIcahn School of Medicine at Mount Sinai, New York, New York (J.A.), Jason Baker, MD, MSHennepin Healthcare/University of Minnesota, Minneapolis, Minnesota (J.B.), Pamela S. Belperio, PharmDDepartment of Veterans Affairs, Los Angeles, California (P.S.B.), Craig Coopersmith, MDEmory University School of Medicine, Atlanta, Georgia (C.C.), Page Crew, PharmD, MPHNational Institutes of Health, Bethesda, Maryland (A.K.P., P.C., H.C.L., H.M., K.S.), Birgit Grund, PhDUniversity of Minnesota, Minneapolis, Minnesota (B.G.), Roy M. Gulick, MD, MPHWeill Cornell Medicine, New York, New York (R.M.G.), Carly Harrison, MSLupusChat, New York, New York (C.H.), Arthur Kim, MDMassachusetts General Hospital/Harvard Medical School, Boston, Massachusetts (A.K.), H. Clifford Lane, MDNational Institutes of Health, Bethesda, Maryland (A.K.P., P.C., H.C.L., H.M., K.S.), Henry Masur, MDNational Institutes of Health, Bethesda, Maryland (A.K.P., P.C., H.C.L., H.M., K.S.), Virginia Sheikh, MD, MHSU.S. Food and Drug Administration, Silver Spring, Maryland (V.S.), Kanal Singh, MD, MPHNational Institutes of Health, Bethesda, Maryland (A.K.P., P.C., H.C.L., H.M., K.S.), Jinoos Yazdany, MD, MPHUniversity of California, San Francisco, San Francisco, California (J.Y.), and Pablo Tebas, MDUniversity of Pennsylvania, Philadelphia, Pennsylvania (P.T.), for the National Institutes of Health COVID-19 Treatment Guidelines Panel*Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-6448 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Currently, no Food and Drug Administration (FDA)–approved therapeutics exist for coronavirus disease 2019 (COVID-19). In this context, the pandemic has put considerable pressure on health care providers to prescribe treatments despite limited information about their safety and efficacy. This pressure has exacerbated the tension between the importance of practicing evidence-based medicine and the urgency of providing access to promising therapies before their safety and efficacy are established.As members of the National Institutes of Health COVID-19 Treatment Guidelines Panel (the Panel) (1), we are charged with providing guidance for U.S. clinicians on the treatment of COVID-19 by reviewing current scientific evidence and providing real-time recommendations based on the strength and quality of the data.On 23 August 2020, the FDA issued an Emergency Use Authorization (EUA) for convalescent plasma for treating COVID-19 (2). An EUA does not constitute drug approval by the FDA. Rather, an EUA allows the FDA to facilitate the availability and unapproved uses of medical products during a public health emergency (3). The criteria for issuing an EUA for medical products include the following: The public health concern must be serious or life threatening; sufficient evidence must exist that the product “may be effective”; the known and potential benefits of the product, when used to diagnose, prevent, or treat the identified disease or condition, outweigh the known and potential risks of the product; and no adequate, approved alternatives to the product are available (3).A strong scientific rationale and historical precedents exist for the study of passive immunotherapeutic approaches for viral infections (4). Concentrated, virus-specific immunoglobulin preparations are FDA approved for the postexposure prophylaxis of such viral infections as hepatitis B, varicella, and rabies (5). Recently, a randomized controlled trial (RCT) demonstrated the efficacy of 2 different monoclonal antibody products for treating Ebola virus disease (6).The situation is less clear regarding the safety and efficacy of convalescent plasma, which has been used to treat viral infections from the 1918 influenza pandemic to the recent epidemics of severe acute respiratory syndrome (SARS), H1N1 influenza, Middle East respiratory syndrome, and Ebola virus disease (7–10). The only RCT demonstrating efficacy of convalescent plasma for an infectious disease was conducted more than 40 years ago, for treating Argentine hemorrhagic fever (11).Early in the COVID-19 pandemic, convalescent plasma was used in China to treat hospitalized patients with COVID-19 (7). Shortly thereafter, RCTs evaluating convalescent plasma in patients with COVID-19 began in several countries, including the United States (12). In March 2020, the FDA authorized expanded access to convalescent plasma for treating severe or life-threatening COVID-19 under individual-patient emergency Investigational New Drug applications. The Mayo Clinic's Expanded Access Program (EAP) was developed in parallel to provide broader access to convalescent plasma; however, it was not designed to generate definitive data on safety or to evaluate efficacy (13). One of the requirements for an EAP is that it not interfere with pivotal trials (14). Adequately powered RCTs of convalescent plasma in the United States have been slow to enroll patients.Given the lack of data from properly powered RCTs, and the need to inform regulatory decision making regarding continued access to convalescent plasma, both the FDA and the Mayo Clinic performed retrospective, indirect evaluations of efficacy by using EAP data, hypothesizing that patients who received plasma units with higher titers of neutralizing antibodies would have better clinical outcomes. The results of the analyses were used as supporting evidence for the EUA.The FDA analysis included 4330 patients, and donor neutralizing antibody titers were measured by the Broad Institute, using a SARS coronavirus 2 (SARS-CoV-2) neutralization assay (15). The analysis revealed no difference in 7-day mortality between the patients who received high-titer and those who received low-titer plasma in the overall population or in the subset of patients who were intubated. However, among nonintubated patients (approximately two thirds of those analyzed), 11% of those who received high-titer plasma died within 7 days of transfusion compared with 14% who received low-titer plasma (P = 0.03) (16). In a post hoc analysis of nonintubated patients who were younger than 80 years and treated within 72 hours of diagnosis, 7-day mortality for those who received high- versus low-titer plasma was 6.3% and 11.3%, respectively (P = 0.0008) (15).A similar efficacy analysis by the Mayo Clinic included 3082 participants who had received a single unit of plasma among the 35 322 participants who had received plasma through the EAP by 4 July 2020 (17). Antibody titers were measured by using the VITROS anti–SARS-CoV-2 IgG assay (Ortho Clinical Diagnostics), and outcomes were compared among patients receiving low- (lowest 18%), medium-, and high-titer (highest 17%) plasma. After adjusting for baseline characteristics, the 30-day mortality rate was 29.1% in the low-titer group and 24.7% in the high-titer group. This difference did not reach statistical significance. The Mayo Clinic post hoc subgroup analyses also suggested a benefit of high-titer plasma in patients who received plasma within 3 days of COVID-19 diagnosis (17).The FDA concluded that the totality of data, including additional data from small randomized trials and nonrandomized, observational, and animal studies, met the criteria for EUA issuance.Despite clearly meeting the “may be effective” criterion for EUA issuance, the analyses of the EAP data are not sufficient to establish the efficacy or safety of convalescent plasma because of the lack of an untreated control group. For example, the possibility that differences in outcomes are attributable to harm from low-titer plasma rather than benefit from high-titer plasma cannot be excluded. In addition, the EAP data may be subject to several confounders, including regional differences and temporal trends in COVID-19 management. There is no widely available and generally agreed-upon best test for measuring neutralizing antibodies, and the antibody titers in convalescent plasma from patients who have recovered from COVID-19 are highly variable. In addition, the analyses focused on early mortality, which may not be clinically meaningful in the context of the prolonged disease course of COVID-19. The efficacy analyses rely on a subset of EAP patients and thus represent only a fraction of patients who received plasma through the EAP (17). In this regard, additional analyses of the EAP cohort and completion of the current RCTs will be of critical importance.Taking everything into account, the Panel has determined that currently the data are insufficient to recommend for or against convalescent plasma for treating COVID-19 (18). Prospective, well-controlled, and adequately powered RCTs are needed to determine whether convalescent plasma and other passive immunotherapies are effective and safe for COVID-19 treatment. Although providers have access to this therapy, the Panel cannot recommend it as a standard of care for treating COVID-19 at this time. This is consistent with the language of the convalescent plasma EUA Fact Sheet (19).The COVID-19 pandemic has intensified the tension between providing rapid access to promising therapies and generating the scientific evidence needed to establish whether those therapies are safe and effective. This tension was also noted during the West African Ebola outbreak in 2014 to 2016, when several therapies, including convalescent plasma, were claimed to be of benefit. A National Academies of Sciences, Engineering, and Medicine review of that response noted that RCTs are critical during an outbreak, because they are the quickest way to identify effective therapies (20). Experience with convalescent plasma, hydroxychloroquine, and other interventions has taught us that large observational cohorts, EAPs, and EUAs can have a profound impact on our ability to conduct the properly designed RCTs necessary to provide definitive evidence of safety and efficacy. Conversely, the lack of access to large RCTs at many health care centers during the COVID-19 pandemic may exacerbate issues of equity in access to care. Expanded Access Programs continue to be an important mechanism to provide promising therapies for patients who do not otherwise have access to them (that is, through clinical trials). Balancing this tension is challenging but imperative to maintaining the ability to generate rigorous and convincing evidence during a public health crisis.Despite the challenges of the COVID-19 pandemic, conducting well-controlled, adequately powered RCTs is possible. Two such trials, ACTT (Adaptive COVID-19 Treatment Trial) and RECOVERY (Randomized Evaluation of COVID-19 Therapy), recently demonstrated the efficacy of remdesivir and dexamethasone, respectively, for treating COVID-19 (21, 22). Collaboration and partnership among governmental agencies, industry, academia, and the public are needed to establish and carry out a robust and coordinated emergency research response, including the rapid development, deployment, and analysis of high-caliber RCTs. This approach is the quickest and most efficient way to generate the answers needed to provide the best evidence-based patient care.Appendix Table. National Institutes of Health COVID-19 Treatment Guidelines Panel Members*References1. National Institutes of Health. COVID-19 Treatment Guidelines. Appendix A, Table 1. COVID-19 Treatment Guidelines Panel Members. Accessed at www.covid19treatmentguidelines.nih.gov/panel-roster on 7 September 2020. Google Scholar2. U.S. Food and Drug Administration. Convalescent plasma letter of authorization. Accessed at www.fda.gov/media/141477/download on 6 September 2020. Google Scholar3. U.S. Food and Drug Administration. Emergency Use Authorization of Medical Products and Related Authorities: Guidance for Industry and Other Stakeholders. Accessed at www.fda.gov/media/97321/download on 31 August 2020. Google Scholar4. Fischer JC, Zänker K, van Griensven M, et al. The role of passive immunization in the age of SARS-CoV-2: an update. Eur J Med Res. 2020;25:16. [PMID: 32404189] doi:10.1186/s40001-020-00414-5 CrossrefMedlineGoogle Scholar5. Centers for Disease Control and Prevention. ACIP Vaccine Recommendations and Guidelienes. Accessed at www.cdc.gov/vaccines/hcp/acip-recs/index.html on 7 September 2020. Google Scholar6. Mulangu S, Dodd LE, Davey RT, et al; PALM Writing Group. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381:2293-2303. [PMID: 31774950] doi:10.1056/NEJMoa1910993 CrossrefMedlineGoogle Scholar7. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al; Convalescent Plasma Study Group. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015;211:80-90. [PMID: 25030060] doi:10.1093/infdis/jiu396 CrossrefMedlineGoogle Scholar8. Beigel JH, Tebas P, Elie-Turenne MC, et al; IRC002 Study Team. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med. 2017;5:500-511. [PMID: 28522352] doi:10.1016/S2213-2600(17)30174-1 CrossrefMedlineGoogle Scholar9. Ko JH, Seok H, Cho SY, et al. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. Antivir Ther. 2018;23:617-622. [PMID: 29923831] doi:10.3851/IMP3243 CrossrefMedlineGoogle Scholar10. van Griensven J, Edwards T, de Lamballerie X, et al; Ebola-Tx Consortium. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med. 2016;374:33-42. [PMID: 26735992] doi:10.1056/NEJMoa1511812 CrossrefMedlineGoogle Scholar11. Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome. Lancet. 1979;2:1216-7. [PMID: 92624] CrossrefMedlineGoogle Scholar12. National Institutes of Health. List of randomized trials of convalescent plasma. ClinicalTrials.gov. Accessed at www.clinicaltrials.gov/ct2/results?term=convalescent+plasma&cond=Covid19&intr=Randomized on 7 September 2020. Google Scholar13. Mayo Clinic. Expanded Accesss to Convalescent Plasma for the Treatment of Patients With COVID-19 [Protocol]. Version 10.0. Accessed at www.uscovidplasma.org/physicians-protocol on 6 September 2020. Google Scholar14. U.S. Food and Drug Administration. Title 21. Chapter 1. Part 312. Subpart I. Expanded Access to Investigational Drugs for Treatment Use. Section 312.305(a)(3). Google Scholar15. U.S. Food and Drug Administration. EUA 26382: Emergency Use Authorization (EUA) Request. Accessed at www.fda.gov/media/141481/download on 6 September 2020. Google Scholar16. U.S Food and Drug Administration. Decisional memo. Accessed at www.fda.gov/media/141480/download on 6 September 2020. Google Scholar17. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. medRxiv. 2020. [PMID: 32817978] doi:10.1101/2020.08.12.20169359 CrossrefMedlineGoogle Scholar18. National Institutes of Health. The COVID-19 Treatment Guidelines Panel's Statement on the Emergency Use Authorization of Convalescent Plasma for the Treatment of COVID-19. Accessed at www.covid19treatmentguidelines.nih.gov/statement-on-convalescent-plasma-eua on 7 September 2020. Google Scholar19. U.S. Food and Drug Administration. Fact Sheet for Health Care Providers. Emergency Use Authorization (EUA) of COVID-19 Convalescent Plasma for Treatment of COVID-19 in Hospitalized Patients. Accessed at www.fda.gov/media/141478/download on 6 September 2020. Google Scholar20. National Academies of Sciences, Engineering, and Medicine. Integrating Clinical Research into Epidemic Response: The Ebola Experience. National Academies Pr; 2017. Google Scholar21. Beigel JH, Tomashek KM, Dodd LE. Remdesivir for the treatment of COVID-19 - preliminary report. Reply [Letter]. N Engl J Med. 2020;383:994. [PMID: 32649078] doi:10.1056/NEJMc2022236 CrossrefMedlineGoogle Scholar22. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19 - preliminary report. N Engl J Med. 2020. [PMID: 32678530] doi:10.1056/NEJMoa2021436 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Daniel ArkfeldKeck School of Medicine27 September 2020 Convalescent Plasma for Covid 19-that is the question. It is with great interest I read this state of the art review on convalescent plasma for covid 19. Waiting for controlled trials to show efficacy seems to be the best practice. saying that since i have underlying lung disease due to HAPE and asthma, i would personally take this therapy if infected, and it appears earlier treatment would be best. Keeping my fingers crossed that this will be beneficial like antivirals and dexamethasone. Dr.Wahby Gerisnone25 September 2020 About suggested new therapy for Covid 19 I suggest to investigate the role of "Sulfamethoxazole and Trimethoprim" in Covid-19. Author, Article, and Disclosure InformationAuthors: Alice K. Pau, PharmD; Judith Aberg, MD; Jason Baker, MD, MS; Pamela S. Belperio, PharmD; Craig Coopersmith, MD; Page Crew, PharmD, MPH; Birgit Grund, PhD; Roy M. Gulick, MD, MPH; Carly Harrison, MS; Arthur Kim, MD; H. Clifford Lane, MD; Henry Masur, MD; Virginia Sheikh, MD, MHS; Kanal Singh, MD, MPH; Jinoos Yazdany, MD, MPH; Pablo Tebas, MDAffiliations: National Institutes of Health, Bethesda, Maryland (A.K.P., P.C., H.C.L., H.M., K.S.)Icahn School of Medicine at Mount Sinai, New York, New York (J.A.)Hennepin Healthcare/University of Minnesota, Minneapolis, Minnesota (J.B.)Department of Veterans Affairs, Los Angeles, California (P.S.B.)Emory University School of Medicine, Atlanta, Georgia (C.C.)University of Minnesota, Minneapolis, Minnesota (B.G.)Weill Cornell Medicine, New York, New York (R.M.G.)LupusChat, New York, New York (C.H.)Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts (A.K.)U.S. Food and Drug Administration, Silver Spring, Maryland (V.S.)University of California, San Francisco, San Francisco, California (J.Y.)University of Pennsylvania, Philadelphia, Pennsylvania (P.T.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-6448.Corresponding Author: Alice K. Pau, PharmD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Room 11C103, Bethesda, MD 20892; e-mail, apau@niaid.nih.gov.Author Contributions: Conception and design: J. Aberg, J. Baker, P.S. Belperio, C.M. Coopersmith, P. Crew, B. Grund, C. Harrison, A.Y. Kim, H.C. Lane, A.K. Pau, V. Sheikh, K. Singh, P. Tebas, J. Yazdany.Analysis and interpretation of the data: J. Aberg, A. Adimora, J. Baker, L.M. Baumann Kreuziger, R. Bedimo, P.S. Belperio, T. Burgess, D. Campbell, S.V. Cantrill, C.M. Coopersmith, P. Crew, E.S. Daar, S. Davis, A. Dzierba, L. Evans, J. Francis, J.J. Gallagher, R. Gandhi, D.V. Glidden, B. Grund, R.M. Gulick, E.J. Hardy, C. Harrison, C. Hinkson, B.L. Hughes, S.C. Johnson, M. Keller, A.Y. Kim, S.S. Kuriakose, H.C. Lane, J.L. Lennox, A.M. Lerner, M.M. Levy, G.S. Martin, H. Masur, S. Naggie, M. Nason, A.K. Pau, A.T. Pavia, N. Seam, V. Sheikh, S.Q. Simpson, K. Singh, S. Swindells, P. Tebas, P. Tien, T.M. Uyeki, A. Waghmare, R. Walker, K.C. Wilson, J. Yazdany.Drafting of the article: J. Aberg, J. Baker, P.S. Belperio, C.M. Coopersmith, P. Crew, B. Grund, C. Harrison, A.Y. Kim, H.C. Lane, A.K. Pau, V. Sheikh, K. Singh, P. Tebas, J. Yazdany.Critical revision for important intellectual content: J. Aberg, A. Adimora, J. Baker, L.M. Baumann Kreuziger, R. Bedimo, P.S. Belperio, T. Burgess, D. Campbell, S.V. Cantrill, C.M. Coopersmith, P. Crew, E.S. Daar, S. Davis, A. Dzierba, L. Evans, J. Francis, J.J. Gallagher, R. Gandhi, D.V. Glidden, B. Grund, R.M. Gulick, E.J. Hardy, C. Harrison, C. Hinkson, B.L. Hughes, S.C. Johnson, M. Keller, A.Y. Kim, S.S. Kuriakose, H.C. Lane, J.L. Lennox, A.M. Lerner, M.M. Levy, G.S. Martin, H. Masur, S. Naggie, M. Nason, A.K. Pau, A.T. Pavia, N. Seam, V. Sheikh, S.Q. Simpson, K. Singh, S. Swindells, P. Tebas, P. Tien, T.M. Uyeki, A. Waghmare, R. Walker, K.C. Wilson, J. Yazdany.Final approval of the article: J. Aberg, A. Adimora, J. Baker, L.M. Baumann Kreuziger, R. Bedimo, P.S. Belperio, T. Burgess, D. Campbell, S.V. Cantrill, C.M. Coopersmith, P. Crew, E.S. Daar, S. Davis, A. Dzierba, L. Evans, J. Francis, J.J. Gallagher, R. Gandhi, D.V. Glidden, B. Grund, R.M. Gulick, E.J. Hardy, C. Harrison, C. Hinkson, B.L. Hughes, S.C. Johnson, M. Keller, A.Y. Kim, S.S. Kuriakose, H.C. Lane, J.L. Lennox, A.M. Lerner, M.M. Levy, G.S. Martin, H. Masur, S. Naggie, M. Nason, A.K. Pau, A.T. Pavia, N. Seam, V. Sheikh, S.Q. Simpson, K. Singh, S. Swindells, P. Tebas, P. Tien, T.M. Uyeki, A. Waghmare, R. Walker, K.C. Wilson, J. Yazdany.Statistical expertise: D. Glidden, B. Grund, M. Nason.Obtaining of funding: H.C. Lane.Administrative, technical, or logistic support: P. Crew, S.S. Kuriakose, A.M. Lerner, A.K. Pau, K. Singh.This article was published at Annals.org on 25 September 2020.* For members of the National Institutes of Health COVID-19 Treatment Guidelines Panel, see the Appendix Table. 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A Comparative StudyEmergency Approvals for COVID-19: Evolving Impact on Obligations to Patients in Clinical Care and ResearchHolly Fernandez Lynch, JD, MBE, Alison Bateman-House, PhD, MPH, and Steven Joffe, MD, MPHHas Convalescent Plasma Therapy Hesitancy Increased COVID-19 Mortality?Attenuating the Effects of Novel COVID-19 (SARS-CoV-2) Infection-Induced Cytokine Storm and the ImplicationsConvalescent Plasma for the Prevention and Treatment of COVID-19: A Systematic Review and Quantitative AnalysisUpdate in COVID-19 in the intensive care unit from the 2020 HELLENIC Athens International symposiumSeven days in medicine: 23-29 September 2020 January 2021Volume 174, Issue 1 Page: 93-95 Keywords Antibodies Blood plasma COVID-19 Food and Drug Administration Infectious diseases Mortality Prevention, policy, and public health Safety SARS coronavirus Treatment guidelines ePublished: 25 September 2020 Issue Published: January 2021 Copyright & PermissionsCopyright © 2020 by American College of Physicians. 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HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as "defective" by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant "graveyard" of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4+ T cells and T cell-cloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication.