Objective: To ascertain whether reverse transcriptase polymerase chain reaction (RT-PCR) cycle amplifications until detection, the cycle threshold (Ct), could help inform return to work (RTW) strategies for health care workers (HCWs) recovering from COVID-19 infection. Methods: Sequential Ct data from COVID-19 nasal pharyngeal (NP) RT-PCR testing in all COVID-19 positive HCWs at a single institution. Analysis of Ct in relation to time until negative testing for RTW clearance. Results: Data for 12 employees showed that time elapsed until RT-PCR test-based RTW clearance ranged from 7 to 57 days (median, 34.5 days). Lower initial Ct correlated with the total time elapsed until clearance (r = –0.80; P = 0.002). Conclusion: Considering the RT-PCR Ct, which correlates with the estimated viral load, may help inform RTW planning and decision making beyond solely relying on dichotomized positive/negative results.

We describe a case of opportunistic coinfections with Coccidioides immitis and Pneumocystis jirovecii following treatment with idelalisib, a phosphoinositide 3-kinase inhibitor, for chronic lymphocytic leukaemia. This is the first case of pulmonary coccidioidomycosis reported in association with idelalisib. We review challenges related to diagnosis of opportunistic infections in this context. This report illustrates (1) the uncommon occurrence of two opportunistic infections concurrently or in rapid succession, (2) the importance of maintaining a broad differential diagnosis in the setting of an atypical imaging finding, slow clinical response or when immunomodulatory drugs are used, and (3) the challenges associated with non-invasive serological testing in individuals with haematological malignancy on immunomodulatory therapy.

Author(s): Budak, Jehan Z; Brickman, Cristina E; Abdoler, Emily A; Wallender, Erika K; Mulliken, Jennifer S; Kerkhoff, Andrew D; Lampiris, Harry; Babik, Jennifer M; Koss, Catherine A; Schwartz, Brian S

Abstract Background Burnout in graduate medical education is common and reported in ~70% of Internal Medicine (IM) residents. Most studies have described interventions focused on residency training, but fellowship training suffers from similar challenges and likely similar levels of burnout. After conducting a needs assessment amongst fellows within our Infectious Diseases (ID) fellowship program, we developed a wellness program to address these issues. Methods In Spring 2018, we reviewed the existing literature and consulted with local experts on trainee well-being. Based on our findings, we designed a multi-tiered approach to enhance wellness amongst fellows. An ID Fellowship Well-Being Committee (WBC) was created in September 2018 to lead the intervention. The WBC includes an even mix of fellows and faculty at multiple levels at all three main teaching hospitals associated with the program. Meetings occur every other month, and co-chairs (one faculty and one fellow) report back to the program director quarterly. Topic areas and interventions are described in Table 1. Fellows were sent a qualitative survey to evaluate the impact of the well-being interventions to date. Results Four of 5 first year fellows responded to the survey, and all felt the retreat should be repeated yearly. Themes identified from the survey included benefits of having protected time together, convening in a low pressure and informal setting to provide feedback, and spending quality time in a non-clinical setting with co-fellows. Fellows cited the wellness retreat as a strength at our annual fellowship external program review. Conclusion Burnout is likely high among IM sub-specialty fellows, and interventions are needed to support the well-being of those trainees. We describe a roadmap for the development of a well-being program at a relatively large, academic ID fellowship program led by a mixed fellow and faculty committee. We will continue to monitor data on fellow burnout and make programmatic changes based on feedback. We are hopeful that our work will empower other programs to engage in developing their own well-being programs. Disclosures All authors: No reported disclosures.

Individualized selection of antiretroviral (ARV) therapy is complex, considering drug resistance, comorbidities, drug-drug interactions, and other factors. HIV-ASSIST (www.hivassist.com) is a free, online tool that provides ARV decision support. HIV-ASSIST synthesizes patient and virus-specific attributes to rank ARV combinations based upon a composite objective of achieving viral suppression and maximizing tolerability. To evaluate concordance of HIV-ASSIST recommendations with ARV selections of experienced HIV clinicians. Retrospective cohort study. New and established patients at the Johns Hopkins Bartlett HIV Clinic and San Francisco Veterans Affairs HIV Clinic completing clinic visits were included. Chart reviews were conducted of the most recent clinic visit to generate HIV-ASSIST recommendations, which were compared to prescribed regimens. For each provider-prescribed regimen, we assessed its corresponding HIV-ASSIST “weighted score” (scale of 0 to 10 +, scores of < 2.0 are preferred), rank within HIV-ASSIST’s ordered listing of ARV regimens, and concordance with the top five HIV-ASSIST ranked outputs. Among 106 patients (16% female), 23 (22%) were ARV-naïve. HIV-ASSIST outputs for ARV-naïve patients were 100% concordant with prescribed regimens (median rank 1 [IQR 1–3], median weighted score 1.1 [IQR 1–1.2]). For 18 (17%) ARV-experienced patients with ongoing viremia, HIV-ASSIST outputs were 89% concordant with prescribed regimens (median rank 2 [IQR 1–3], median weighted score 1 [IQR 1–1.2]). For 65 (61.3%) patients that were suppressed on a current ARV regimen, HIV-ASSIST recommendations were concordant 88% of the time (median rank 1 [IQR 1–1], median weighted score 1.1 [IQR 1–1.6]). In 18% of cases, HIV-ASSIST weighted score suggested that the prescribed regimen would be considered “less preferred” (score > 2.0) than other available alternatives. HIV-ASSIST is an educational decision support tool that provides ARV recommendations concordant with experienced HIV providers from two major academic centers for a diverse set of patient scenarios.

Latently infected CD4(+) T cells are the main barrier to complete clearance of HIV infection, but it is unclear what mechanisms govern latent HIV infection in vivo. To address this question, we developed a new panel of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) assays specific for different HIV transcripts that define distinct blocks to transcription. We applied this panel of assays to CD4(+) T cells freshly isolated from HIV-infected patients on suppressive antiretroviral therapy (ART) to quantify the degree to which different mechanisms inhibit HIV transcription. In addition, we measured the degree to which these transcriptional blocks could be reversed ex vivo by T cell activation (using anti-CD3/CD28 antibodies) or latency-reversing agents. We found that the main reversible block to HIV RNA transcription was not inhibition of transcriptional initiation but rather a series of blocks to proximal elongation, distal transcription/polyadenylation (completion), and multiple splicing. Cell dilution experiments suggested that these mechanisms operated in most of the HIV-infected CD4(+) T cells examined. Latency-reversing agents exerted differential effects on the three blocks to HIV transcription, suggesting that these blocks may be governed by different mechanisms.

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Li et al. show that the retinoic acid derivative acitretin activates HIV-1 transcription in latently infected T cells and induces RIG-I signaling, which leads to cell death and suggests an approach to reduce the HIV reservoir. The persistence of latent HIV proviruses in long-lived CD4+ T cells despite antiretroviral therapy (ART)1,2,3 is a major obstacle to viral eradication4,5,6. Because current candidate latency-reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs7,8, new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms4,5,6,9. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell10. Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA11,12,13,14. Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4+ T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir.

This short review of the literature on neuraminidase inhibitor effectiveness on influenza virus concludes that, while randomized clinical trials are lacking, observation data suggest benefit, especially in high-risk patients.

Background: Geriatric syndromes such as falls, frailty, and functional impairment are multifactorial conditions used to identify vulnerable older adults. Limited data exist on these conditions in older HIV-infected adults, and no studies have comprehensively examined these conditions.Methods: Geriatric syndromes including falls, urinary incontinence, functional impairment, frailty, sensory impairment, depression, and cognitive impairment were measured in a cross-sectional study of HIV-infected adults aged 50 years and older who had an undetectable viral load on antiretroviral therapy. We examined both HIV and nonHIV- related predictors of geriatric syndromes including sociodemographics, number of comorbidities and nonantiretroviral medications, and HIV-specific variables in multivariate analyses.Results: We studied 155 participants with a median age of 57 (interquartile range: 54-62) and 94% were men. Prefrailty (56%), difficulty with instrumental activities of daily living (46%), and cognitive impairment (47%) were the most frequent geriatric syndromes. Lower CD4 nadir incidence rate ratio [IRR: 1.16, 95% (confidence interval) CI: 1.06 to 1.26], non-white race (IRR: 1.38, 95% CI: 1.10 to 1.74), and increasing number of comorbidities (IRR: 1.09, 95% CI: 1.03 to 1.15) were associated with increased risk of having more geriatric syndromes.Conclusions: Geriatric syndromes are common in older HIVinfected adults. Treatment of comorbidities and early initiation of antiretroviral therapy may help to prevent development of these agerelated complications. Clinical care of older HIV-infected adults should consider incorporation of geriatric principles.

HIV-associated neurocognitive disorders (HANDs) are common, often go undetected, and can impact treatment outcomes. There is limited evidence on how to perform routine cognitive screening in HIV clinical settings. To address this, 44 HIV-positive males were recruited from a Veteran Affairs Infectious Disease clinic and completed the Montreal Cognitive Assessment (MoCA), International HIV Dementia Scale (IHDS), and Depression Anxiety and Stress Scale-21. In all, 50% scored below the MoCA cutoff and 36% scored below the IHDS cutoff. Current CD4 was the strongest predictor of an abnormal MoCA score (P = .007, 95% confidence interval [CI]: 0.987-0.998) and elevated depression was the second strongest predictor (P = .008, CI: 1.043-1.326). Combination antiviral therapy use and age were not significant predictors in this model. The MoCA appeared to be a reasonable screening tool to detect cognitive impairment in HIV-positive patients, and although it is not sufficient to diagnose HAND, it has the potential to provide meaningful clinical data.

IMPORTANCE:Human immunodeficiency virus (HIV)-positive patients treated with antiretroviral therapy now have increased life expectancy and develop chronic illnesses that are often seen in older HIV-negative patients. OBJECTIVE:To address emerging issues related to aging with HIV. Screening older adults for HIV, diagnosis of concomitant diseases, management of multiple comorbid medical illnesses, social isolation, polypharmacy, and factors associated with end-of-life care are reviewed. EVIDENCE ACQUISITION:Published guidelines and consensus statements were reviewed. PubMed and PsycINFO were searched between January 2000 and February 2013. Articles not appearing in the search that were referenced by reviewed articles were also evaluated. FINDINGS:The population of older HIV-positive patients is rapidly expanding. It is estimated that by 2015 one-half of the individuals in the United States with HIV will be older than age 50. Older HIV-infected patients are prone to having similar chronic diseases as their HIV-negative counterparts, as well as illnesses associated with co-infections. Medical treatments associated with these conditions, when added to an antiretroviral regimen, increase risk for polypharmacy. Care of aging HIV-infected patients involves a need to balance a number of concurrent comorbid medical conditions. CONCLUSIONS AND RELEVANCE:HIV is no longer a fatal disease. Management of multiple comorbid diseases is a common feature associated with longer life expectancy in HIV-positive patients. There is a need to better understand how to optimize the care of these patients.

Mr H is a 74-year-old man who was diagnosed with human immunodeficiency virus (HIV) in 1984. He has chronic fatigue and has experienced a 10-lb weight loss over the past 2 years. His current CD4 T-lymphocyte count is 440 cells/ L, with a nadir of 140 cells/ L occurring in 1991. He has never had opportunistic infections. His plasma HIV RNA level (viral load) has been undetectable since 1996. Mr H participated in the original zidovudine (AZT) monotherapy clinical trial in 1988 and subsequently received a total of 7 nucleoside reverse transcriptase inhibitors (NRTIs) and 6 protease inhibitors before starting his current regimen of emtricitabine/ tenofovir and ritonavir-boosted fosamprenavir. He receives treatment at an infectious disease clinic in an urban, tertiary care Veterans Affairs hospital, where his follow-up is led by Dr L and a team that includes an infectious diseases pharmacist, a nutritionist, and a social worker. Mr H vigilantly adheres to his antiretroviral regimen. Even when offered new antiretroviral medications, he prefers to stay with his current regimen. He has hypertension, hyperlipidemia, osteoporosis, depression, atherosclerotic subclavian steal syndrome with stent placement, chronic kidney insufficiency, adenomatous colon polyps, and past anal squamous cell carcinoma. His other medications are rosuvastatin (hyperlipidemia), testosterone (low testosterone level), bupropion (depression), fenofibrate (hypertriglyceridemia), and lorazepam (anxiety; taken as needed). Due to episodic dizziness and fluctuating blood pressure, hydrochlorothiazide and metoprolol were recently discontinued. Mr H was a computer systems analyst until his late 40s when he was diagnosed with HIV. He lives with a partner, but voices concerns for social isolation from the deaths of many HIV-positive acquaintances. He participates in a support group of older adults with HIV run by a psychologist. Mr H is a former smoker and drinks a glass of wine with dinner. He never drank alcohol heavily and never used recreational drugs. He is currently not sexually active. Initial evaluation of his fatigue and weight loss revealed no anemia and his pharmacist found no medication-based association with his symptoms. Dr L discussed testing for malignancy or other disorders causing weight loss, but Mr H initially declined. Mr H retains medical decision-making capacity and has specified that he not receive resuscitation or intubation should he experience a cardiopulmonary arrest.

The development of HIV-1 integrase strand transfer inhibitors (INSTIs) has been a major therapeutic breakthrough in the management of HIV-1 infection. The first HIV-1 integrase inhibitor, raltegravir, was licensed in 2007 and was subsequently approved for use in treatment-naive patients. Since then, newer members of the INSTI class have been developed, including elvitegravir (EVG), which is in advanced clinical development and is being developed for use in both treatment-naive and treatment-experienced patients. EVG utilizes pharmacokinetic boosting to achieve adequate serum levels with once-daily dosing. Boosting agents with which it is being studied include ritonavir and cobicistat. In addition, EVG is being studied as a once-daily INSTI in a coformulated fixed-dose combination pill with the agents tenofovir disoproxil fumarate, emtricitabine and cobicistat (QUAD pill), which has the additional potential benefit of convenient once-daily dosing. The in vitro activity, pharmacokinetic and pharmacodynamic properties, results of Phase I–III clinical trials, resistance profile and drug–drug interactions of EVG will be reviewed in this article.

HIV infection is associated with increased colonic epithelial cell proliferation, mucosal inflammation and immunodeficiency, all of which may contribute to the development of colorectal cancer. Several population-based cohort studies and endoscopic studies have suggested that colorectal neoplasia and colorectal cancer is increased during chronic HIV infection. The incidence of colorectal neoplasia during surveillance colonoscopy has not been reported.

Although commercial tests are approved for detection of HIV-1 plasma viral loads ≥20 copies per milliliter (ml), only one specialized research assay has been reported to detect plasma viral loads as low as 1 copy/ml. This manuscript describes a method of concentrating HIV-1 virions from up to 30 ml of plasma, which can be combined with a commercial viral load test to create a widely available, reproducible assay for quantifying plasma HIV RNA levels less than 1 copy/ml. Using this pre-analytically modified assay, samples with a known level of 0.5 copy/ml were detected in 8 of 12 replicates (mean 0.47 copy/ml; 95% confidence interval (CI) 0.14–0.81 copy/ml) and samples with a known level of 1.0 copy/ml were detected in 13 of 13 replicates (mean 1.96 copy/ml; 95% CI 1.42–2.50 copy/ml). By concentrating virus from 30 ml of plasma, HIV RNA could be measured in 16 of 19 samples (84%) from 12 of 12 subjects (mean 2.77 copy/ml; 95% CI 0.86–4.68 copy/ml). The measured viral load correlated inversely (r = −0.78; p = 0.028) with the total duration of viral suppression (viral load < 40 copies/ml).

BACKGROUND Some human immunodeficiency virus (HIV)-infected individuals are not able to achieve a normal CD4(+) T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size. METHODS Thirty treated subjects with CD4(+) T cell counts of <350 cells/mm(3) despite viral suppression for ≥ 1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in peripheral blood mononuclear cells (PBMCs). RESULTS The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue. CONCLUSIONS Low-level viremia is not likely to be a significant cause of suboptimal CD4(+) T cell gains during HIV treatment. CLINICAL TRIALS REGISTRATION NCT00631449.

Background:Although integrase inhibitors are highly effective in the management of drug-resistant HIV, some patients fail to achieve durable viral suppression. The long-term consequences of integrase inhibitor failure have not been well defined. Methods:We identified 29 individuals who exhibited evidence of incomplete viral suppression on a regimen containing an integrase inhibitor (23 raltegravir, 6 elvitegravir). Before initiating the integrase inhibitor-based regimen, the median CD4+ T-cell count and plasma HIV RNA levels were 62 cells/mm3 and 4.65 log10 copies/mL, respectively. Results:At the first failure time-point, the most common integrase resistance pattern for subjects taking raltegravir was wild-type, followed in order of frequency by Q148H/K/R+G140S, N155H, and Y143R/H/C. The most common resistance pattern for subjects taking elvitegravir was E92Q. Long-term failure was associated with continued viral evolution, emergence of high-level phenotypic resistance, and a decrease in replicative capacity. Conclusions:Although wild-type failure during early integrase inhibitor failure is common, most patients eventually develop high-level phenotypic drug resistance. This resistance evolution is gradual and associated with declines in replicative capacity.