Mycobacterial spindle cell pseudotumor of the spinal cord: Case report and literature review.

We report the first description of spinal cord mycobacterial spindle cell pseudotumor. A patient with newly diagnosed advanced HIV presented with recent-onset bilateral leg weakness and was found to have a hypermetabolic spinal cord mass on structural and molecular imaging. Biopsy and cultures from blood and cerebrospinal fluid confirmed spindle cell pseudotumor due to Mycobacterium avium-intracellulare. Despite control of HIV and initial reduction in pseudotumor volume on antiretrovirals and antimycobacterials (azithromycin, ethambutol, rifampin/rifabutin), he ultimately experienced progressive leg weakness due to pseudotumor re-expansion. Here, we review literature and discuss multidisciplinary diagnosis, monitoring and management challenges, including immune reconstitution inflammatory syndrome.

Combination of Extended Antivirals With Antiretrovirals for Severe Mpox in Advanced Human Immunodeficiency Virus Infection: Case Series of 4 Patients.

To gauge the safety and utility of extended tecovirimat/cidofovir for severe mpox, here we report our experience caring for 4 patients with mpox and advanced human immunodeficiency virus (HIV) at the Hospitals of the University of Pennsylvania during the 2022 global outbreak. Three patients had recurrent courses complicated by superinfections, coinfections and insufficient nutrition/housing, requiring extended tecovirimat (5-16 weeks) and cidofovir (1-12 doses) with probenecid and fluids. At follow-up, patients had undetectable HIV RNA on antiretrovirals, improved ulcers and stable renal function on antivirals. Serology guided cessation for one 7-month cidofovir course. Overall findings support a comprehensive approach of prolonged tecovirimat/cidofovir with antiretrovirals for severe mpox, while addressing social factors.

Examining virtual driving test performance and its relationship to individuals with HIV-associated neurocognitive disorders.

Significance: Existing screening tools for HIV-associated neurocognitive disorders (HAND) are often clinically impractical for detecting milder forms of impairment. The formal diagnosis of HAND requires an assessment of both cognition and impairment in activities of daily living (ADL). To address the critical need for identifying patients who may have disability associated with HAND, we implemented a low-cost screening tool, the Virtual Driving Test (VDT) platform, in a vulnerable cohort of people with HIV (PWH). The VDT presents an opportunity to cost-effectively screen for milder forms of impairment while providing practical guidance for a cognitively demanding ADL. Objectives: We aimed to: (1) evaluate whether VDT performance variables were associated with a HAND diagnosis and if so; (2) systematically identify a manageable subset of variables for use in a future screening model for HAND. As a secondary objective, we examined the relative associations of identified variables with impairment within the individual domains used to diagnose HAND. Methods: In a cross-sectional design, 62 PWH were recruited from an established HIV cohort and completed a comprehensive neuropsychological assessment (CNPA), followed by a self-directed VDT. Dichotomized diagnoses of HAND-specific impairment and impairment within each of the seven CNPA domains were ascertained. A systematic variable selection process was used to reduce the large amount of VDT data generated, to a smaller subset of VDT variables, estimated to be associated with HAND. In addition, we examined associations between the identified variables and impairment within each of the CNPA domains. Results: More than half of the participants (N = 35) had a confirmed presence of HAND. A subset of twenty VDT performance variables was isolated and then ranked by the strength of its estimated associations with HAND. In addition, several variables within the final subset had statistically significant associations with impairment in motor function, executive function, and attention and working memory, consistent with previous research. Conclusion: We identified a subset of VDT performance variables that are associated with HAND and assess relevant functional abilities among individuals with HAND. Additional research is required to develop and validate a predictive HAND screening model incorporating this subset.

Brief Report: Financial Incentives and Real-Time Adherence Monitoring to Promote Daily Adherence to HIV Treatment and Viral Suppression Among People Living With HIV: A Pilot Study.

BACKGROUND: Interventions to promote medication adherence and viral suppression are needed among HIV-positive individuals. We aimed to determine the feasibility, acceptability, and preliminary impact of daily financial incentives linked to real-time adherence monitoring among treatment-experienced individuals. METHODS: At an HIV clinic in Philadelphia, we conducted a pilot randomized trial among treatment-experienced HIV-positive adults with unsuppressed viral loads (>400 copies/mL). Participants randomized to the intervention group were eligible for daily lottery-based financial rewards dependent on antiretroviral therapy (ART) adherence, measured by a wireless-enabled electronic pill bottle. Participants also received a financial incentive for achieving viral suppression at 3 months. The control group received the standard of care. We measured acceptance and feasibility through follow-up survey at 3 months, viral suppression at 3 months, and adherence. RESULTS: Among 29 participants, 28 (93%) completed 3-month follow-up, and 24 (83%) completed a 3-month laboratory visit. Electronic pill bottles were highly acceptable to participants, with most strongly agreeing that they worked well, were reliable, and easy to use. Among those who received the intervention, 77% were very satisfied with their experience. Among those who completed the 3-month laboratory visit, viral suppression was achieved by 40% in the intervention group and 29% in the control group. ART adherence ≥80% was achieved by 36% and 25% in the intervention and control groups, respectively. CONCLUSIONS: Daily financial incentives coupled with real-time adherence monitoring are a promising strategy to support ART adherence among HIV-positive individuals who are not virally suppressed. This novel approach warrants testing in a larger trial.

Novel gRNA design pipeline to develop broad-spectrum CRISPR/Cas9 gRNAs for safe targeting of the HIV-1 quasispecies in patients.

The CRISPR/Cas9 system has been proposed as a cure strategy for HIV. However, few published guide RNAs (gRNAs) are predicted to cleave the majority of HIV-1 viral quasispecies (vQS) observed within and among patients. We report the design of a novel pipeline to identify gRNAs that target HIV across a large number of infected individuals. Next generation sequencing (NGS) of LTRs from 269 HIV-1-infected samples in the Drexel CARES Cohort was used to select gRNAs with predicted broad-spectrum activity. In silico, D-LTR-P4-227913 (package of the top 4 gRNAs) accounted for all detectable genetic variation within the vQS of the 269 samples and the Los Alamos National Laboratory HIV database. In silico secondary structure analyses from NGS indicated extensive TAR stem-loop malformations predicted to inactivate proviral transcription, which was confirmed by reduced viral gene expression in TZM-bl or P4R5 cells. Similarly, a high sensitivity in vitro CRISPR/Cas9 cleavage assay showed that the top-ranked gRNA was the most effective at cleaving patient-derived HIV-1 LTRs from five patients. Furthermore, the D-LTR-P4-227913 was predicted to cleave a median of 96.1% of patient-derived sequences from other HIV subtypes. These results demonstrate that the gRNAs possess broad-spectrum cutting activity and could contribute to an HIV cure.

Attitudes and referral practices for pre-exposure prophylaxis (PrEP) among HIV rapid testers and case managers in Philadelphia: A mixed methods study.

OBJECTIVE: Adoption of pre-exposure prophylaxis (PrEP) to prevent HIV infection has been slow. The purpose of this study was to evaluate knowledge, attitudes and referral practices for PrEP among non-prescribing providers, who may play key role. METHODS: We performed a cross-sectional survey on PrEP knowledge, attitudes, and referral practices among 66 non-prescribing HIV prevention providers (1st August to 31st December, 2016), in Philadelphia, followed by qualitative interviews with 12 of them (5th April to 10th May, 2017). RESULTS: Participants had a mean age of 36 years, with 62% females. Majority were HIV case managers and rapid testers. For half of the respondents, PrEP eligibility screening was part of rapid HIV testing at their organization, 40% never had PrEP training and only 27% indicated personally screening clients for eligibility. Qualitative data revealed that participants held positive attitudes about PrEP and perceived organizational support, but had concerns about potential negative impacts and barriers to routine HIV screening. CONCLUSION: Results highlight the importance of training non-prescribing HIV prevention providers about PrEP, addressing their concerns, and incorporating PrEP screening and referral into routine HIV testing.

Investigating the distribution of HIV-1 Tat lengths present in the Drexel Medicine CARES cohort.

Human immunodeficiency virus type 1 (HIV-1) encodes for Tat, a multi-functional regulatory protein involved in transcriptional enhancement and in causing neurotoxicity/central nervous system (CNS) dysfunction. This study examines Sanger sequencing of HIV-1 subtype B Tat from 2006 to 2014 within the Drexel University College of Medicine CNS AIDS Research and Eradication Study (CARES) Cohort to investigate Tat length in patients. The Los Alamos National Laboratory (LANL) database was used as a comparator. Miscoded stop codons were present in the CARES Cohort and LANL and protein variability was highly similar. Tat proteins in CARES and LANL were predominantly 101 residues. There was no observed correlation between Tat length and clinical parameters within the CARES Cohort. Unique Tat lengths found in the CARES Cohort and not in LANL were 31, 36, and 39 residues. When CARES patients were longitudinally examined, sequence lengths of 101 had a low probability of reducing to below 48, and sequences had a high probability of increasing to above 86 residues during their next visit, when below 48 residues in length. This suggests that Tat length is conserved to retain the majority of the proteins function highlighting its importance in viral replication.

Drawing from the Theory of Planned Behaviour to examine pre-exposure prophylaxis uptake intentions among heterosexuals in high HIV prevalence neighbourhoods in Philadelphia, Pennsylvania, USA: an observational study.

Background Research surrounding attitudes and intentions concerning pre-exposure prophylaxis (PrEP) among at-risk heterosexuals, women and ethnic and racial minorities is needed to inform programs to scale this effective HIV prevention intervention among these populations. METHODS: The study sample includes 192 HIV-negative heterosexuals recruited from HIV testing sites operating in high HIV prevalence neighbourhoods in a mid-Atlantic city. Participants received brief educational sessions on PrEP and completed a self-administered survey assessing sociodemographic factors, HIV risk behaviours and theoretical determinants of PrEP uptake, based on the Theory of Planned Behaviour. RESULTS: Participants were majority persons of colour (86%), with a median age of 43 years. Compared with Whites, a higher percentage of Black and Brown persons had more than five sex partners (75.0%), used condoms inconsistently (85.6%) and engaged in transactional sex (84.4%). Most expressed positive PrEP attitudes and indicated intention to adopt PrEP, especially if recommended by their doctor. In a multivariable model, willingness to take PrEP if suggested by a healthcare provider (aOR: 4.17; 95% CI: 1.42-12.24) and willingness to take PrEP even if it caused side-effects (aOR: 1.98; 95% CI: 1.01-3.90) were both associated with greater PrEP adoption intentions. CONCLUSIONS: A diverse at-risk population was identified through community-based HIV testing. Low perceived HIV risk, as well as PrEP-related attitudes, subjective norms and perceived behavioural control were associated with PrEP use intentions. These factors are potential targets for interventions to increase PrEP adoption among diverse heterosexual samples.

Heterosexual Men Anticipate Risk Compensatory Behaviors With Future Preexposure Prophylaxis Initiation: Findings From an Exploratory Cross-Sectional Study.

Among 146 urban heterosexuals screening negative for human immunodeficiency virus, one third anticipated increased sexual risk taking with human immunodeficiency virus preexposure prophylaxis. Men (vs. women) and black (vs. white) participants had increased odds for anticipating decreased condom use. Men and persons reporting transactional sex expected to increase sexual partnerships. Risk compensation could affect reproductive health and disease control.

An Update on the Current Role of High Resolution Anoscopy in Patients With Anal Dysplasia.

The incidence of anal squamous cell carcinoma (ASCC) in the U.S. is increasing, particularly in immunocompromised patients. Preventative screening is used to monitor precancerous dysplasia known as anal intraepithelial neoplasia (AIN), which can progress to ASCC. High Resolution Anoscopy (HRA) is one screening procedure that uses a colposcope with acetic acid and Lugol's iodine solution to visualize the anal epithelium for AIN. HRA has offered potential in managing AIN, but as more evidence emerges it is unclear whether HRA provides definitive benefit. This narrative review updates readers on the efficacy of HRA in screening AIN, compares HRA to other techniques, compares the use of HRA in various high-risk populations, and offers practical information on the use of HRA. Keyword searches were conducted using MEDLINE, Web of Science, and Cochrane Library. Current literature is mixed regarding the utility of HRA. Further randomized controlled trials are needed to definitively assess the role of HRA.

"I Don't Need PrEP Right Now": A Qualitative Exploration of the Barriers to PrEP Care Engagement Through the Application of the Health Belief Model.

The Health Belief Model has been useful for studying uptake of HIV prevention behaviors and has had limited application to understanding utilization of pre-exposure prophylaxis (PrEP), a biomedical strategy to reduce HIV acquisition. We recruited 90 persons undergoing HIV screening and educated them about PrEP. We followed up with 35 participants approximately 3 weeks later and quantitatively assessed PrEP uptake. No participant had initiated PrEP. We conducted in-depth interviews with 15 participants to explore situational factors impacting this decision. In this paper we provide an overview of PrEP-related engagement using qualitative data to contextualize (in)action. While participants perceived PrEP as beneficial, perceived benefits did not outweigh real- and perceived barriers, such as financial and time-related constraints. In order to promote PrEP uptake, cues to action that increase the benefits of PrEP during seasons of risk, and interventions that reduce real and perceived barriers are needed.

Broad-Spectrum and Personalized Guide RNAs for CRISPR/Cas9 HIV-1 Therapeutics.

The clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 system has been used to excise the HIV-1 proviral genome from latently infected cells, potentially offering a cure for HIV-infected patients. Recent studies have shown that most published HIV-1 guide RNAs (gRNAs) do not account for the diverse viral quasispecies within or among patients, which continue to diversify with time even in long-term antiretroviral therapy (ART)-suppressed patients. Given this observation, proviral genomes were deep sequenced from 23 HIV-1-infected patients in the Drexel Medicine CNS AIDS Research and Eradication Study cohort at two different visits. Based on the spectrum of integrated proviral DNA polymorphisms observed, three gRNA design strategies were explored: based on the patient's own HIV-1 sequences (personalized), based on consensus sequences from a large sample of patients [broad-spectrum (BS)], or a combination of both approaches. Using a bioinformatic algorithm, the personalized gRNA design was predicted to cut 46 of 48 patient samples at 90% efficiency, whereas the top 4 BS gRNAs (BS4) were predicted to excise provirus from 44 of 48 patient samples with 90% efficiency. Using a mixed design with the top three BS gRNAs plus one personalized gRNA (BS3 + PS1) resulted in predicted excision of provirus from 45 of 48 patient samples with 90% efficiency. In summary, these studies used an algorithmic design strategy to identify potential BS gRNAs to target a spectrum of HIV-1 long teriminal repeat (LTR) quasispecies for use with a small HIV-1-infected population. This approach should advance CRISPR/Cas9 excision technology taking into account the extensive molecular heterogeneity of HIV-1 that persists in situ after prolonged ART.

Evidence of Divergent Amino Acid Usage in Comparative Analyses of R5- and X4-Associated HIV-1 Vpr Sequences.

Vpr is an HIV-1 accessory protein that plays numerous roles during viral replication, and some of which are cell type dependent. To test the hypothesis that HIV-1 tropism extends beyond the envelope into the vpr gene, studies were performed to identify the associations between coreceptor usage and Vpr variation in HIV-1-infected patients. Colinear HIV-1 Env-V3 and Vpr amino acid sequences were obtained from the LANL HIV-1 sequence database and from well-suppressed patients in the Drexel/Temple Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. Genotypic classification of Env-V3 sequences as X4 (CXCR4-utilizing) or R5 (CCR5-utilizing) was used to group colinear Vpr sequences. To reveal the sequences associated with a specific coreceptor usage genotype, Vpr amino acid sequences were assessed for amino acid diversity and Jensen-Shannon divergence between the two groups. Five amino acid alphabets were used to comprehensively examine the impact of amino acid substitutions involving side chains with similar physiochemical properties. Positions 36, 37, 41, 89, and 96 of Vpr were characterized by statistically significant divergence across multiple alphabets when X4 and R5 sequence groups were compared. In addition, consensus amino acid switches were found at positions 37 and 41 in comparisons of the R5 and X4 sequence populations. These results suggest an evolutionary link between Vpr and gp120 in HIV-1-infected patients.

Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status.

Even in the era of combination antiretroviral therapies used to combat human immunodeficiency virus type 1 (HIV-1) infection, up to 50 % of well-suppressed HIV-1-infected patients are still diagnosed with mild neurological deficits referred to as HIV-associated neurocognitive disorders (HAND). The multifactorial nature of HAND likely involves the HIV-1 accessory protein viral protein R (Vpr) as an agent of neuropathogenesis. To investigate the effect of naturally occurring variations in Vpr on HAND in well-suppressed HIV-1-infected patients, bioinformatic analyses were used to correlate peripheral blood-derived Vpr sequences with patient neurocognitive performance, as measured by comprehensive neuropsychological assessment and the resulting Global Deficit Score (GDS). Our studies revealed unique associations between GDS and the presence of specific amino acid changes in peripheral blood-derived Vpr sequences [neuropsychological impairment Vpr (niVpr) variants]. Amino acids N41 and A55 in the Vpr sequence were associated with more pronounced neurocognitive deficits (higher GDS). In contrast, amino acids I37 and S41 were connected to measurably lower GDS. All niVpr variants were also detected in DNA isolated from HIV-1-infected brain tissues. The implication of these results is that niVpr variants alter the genesis and/or progression of HAND through differences in Vpr-mediated effects in the peripheral blood and/or the brain.

Knowledge, Attitudes, and Acceptability of Pre-Exposure Prophylaxis among Individuals Living with HIV in an Urban HIV Clinic.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) is an effective tool to reduce HIV transmission. The primary objective of this study was to assess awareness of PrEP by individuals living with HIV (HIV+) and acceptance of its use for their HIV negative (HIV-) partners. METHODS: A cross sectional survey was conducted among individuals living with HIV who received care at an urban HIV clinic between January 2013 and June 2013. The survey examined knowledge, attitudes, and acceptability of PrEP, and perception of transmission risk of HIV. Chi-Square test and Fisher's Exact test were used to compare proportions. RESULTS: Among 206 subjects living with HIV, 15.3% (32) had heard of PrEP. Men who have sex with men (MSM) were more likely to be aware of PrEP than all others (p = 0.003). Once educated about PrEP those who believed PrEP would reduce their partner's risk for HIV were more likely to recommend PrEP to their partner (p<0.001). 92% of all respondents said they would be "extremely likely/likely" to discuss PrEP use with their provider. Of 159 subjects whose main partner was HIV-, MSM (p = 0.007), male participants (p = 0.044), and those who were consistently taking meds (p = 0.049) were more likely to be aware of PrEP. Those who perceived they were at risk of transmitting HIV (p<0.001) and those who were consistently taking meds (0.049) were more likely to agree that PrEP could reduce the risk of HIV to their partners. CONCLUSION: This study illustrates a low awareness of PrEP but once educated the willingness of a cohort of individuals living with HIV to recommend PrEP to their partners. Our findings demonstrate the importance of providers informing their patients living with HIV about PrEP, as these persons are an underutilized link to support the uptake of PrEP by their HIV- partners.

Tuberculin skin test conversion rate among short-term health care workers returning from Gaborone, Botswana.

UNLABELLED: Our objective was to determine tuberculin skin test conversion rate of health care workers traveling to Botswana. The rate of tuberculin skin test conversion was 4.2% for the entire group studied or 6.87 per 1000 person weeks (95% CI, 1.87-17.60). BACKGROUND: International travel by health care workers traveling from low incidence countries to areas of the world where tuberculosis is highly endemic places the health care worker at an increased risk of acquiring tuberculosis. OBJECTIVES: To determine the tuberculin skin test conversion rate of health care workers living in the United States with previously negative tuberculin skin test results working for less than 1 year in a hospital in Botswana where tuberculosis is highly endemic. METHODS: We performed a cross-sectional survey among health care workers affiliated with the University of Pennsylvania School of Medicine who participated in patient care in Botswana between July 1st 2004 and June 30th 2009. We recruited health care workers after returning from Botswana who had a documented negative tuberculin skin test in the year prior to travel, who spent at least 2 weeks but not more than 1 year and who had a documented tuberculin skin test 2-3 months post travel. The main study outcome was a positive tuberculin skin test 6-12 weeks after returning from Botswana, defined by an area of at least 10mm induration 48-72h after placement of the tuberculin skin test. RESULTS: 95 Subjects participated in the study and there were 4 tuberculin skin test conversions. The rate of tuberculin skin test conversion in our study population was 4.2% for the entire group studied or 6.87 per 1000 person weeks (95% CI, 1.87-17.60). CONCLUSIONS: The tuberculin skin test conversion rate was higher than the reported conversion rates for those not working in a health care setting.

Use of mobile telemedicine for cervical cancer screening.

Visual inspection of the cervix with application of 4% acetic acid (VIA) is an inexpensive alternative to cytology-based screening in areas where resources are limited, such as in many developing countries. We have examined the diagnostic agreement between off-site (remote) expert diagnosis using photographs of the cervix (photographic inspection with acetic acid, PIA) and in-person VIA. The images for remote evaluation were taken with a mobile phone and transmitted by MMS. The study population consisted of 95 HIV-positive women in Gaborone, Botswana. An expert gynaecologist made a definitive positive or negative reading on the PIA results of 64 out of the 95 women whose PIA images were also read by the nurse midwives. The remaining 31 PIA images were deemed insufficient in quality for a reading by the expert gynaecologist. The positive nurse PIA readings were concordant with the positive expert PIA readings in 82% of cases, and the negative PIA readings between the two groups were fully concordant in 89% of cases. These results suggest that mobile telemedicine may be useful to improve access of women in remote areas to cervical cancer screening utilizing the VIA 'see-and-treat' method.

Vitamin D deficiency is associated with type 2 diabetes mellitus in HIV infection.

BACKGROUND: Metabolic complications, including type 2 diabetes mellitus and metabolic syndrome, are increasingly recognized among HIV-infected individuals. Low vitamin D levels increase the risk of type 2 diabetes mellitus, and vitamin D supplementation has been shown to decrease the risk of type 2 diabetes mellitus in patients without HIV infection. OBJECTIVES: The primary objective was to determine whether vitamin D deficiency (serum 25-hyrdoxyvitamin D <20 ng/ml) was associated with type 2 diabetes mellitus among HIV-infected patients. Our secondary objective was to determine whether vitamin D deficiency was associated with metabolic syndrome in HIV. METHODS: We conducted a cross-sectional study among participants enrolled in the prospective Modena (Italy) HIV Metabolic Clinic Cohort. Clinical and laboratory data, including history of type 2 diabetes mellitus, fasting blood glucose, components of metabolic syndrome, and 25-hydroxyvitamin D levels, were obtained for all participants. RESULTS: After adjusting for vitamin D supplementation, sex, age, body mass index, and hepatitis C virus co-infection, vitamin D deficiency was associated with type 2 diabetes mellitus [adjusted odds ratio (OR) 1.85; 95% confidence interval (CI) 1.03-3.32; P = 0.038]. The association between vitamin D deficiency and metabolic syndrome was not significant after adjusting for vitamin D supplementation, sex, age and body mass index (adjusted OR 1.32; 95% CI 1.00-1.75; P = 0.053). CONCLUSIONS: Our study demonstrates an association between vitamin D deficiency and type 2 diabetes mellitus. Clinical trials are needed to better characterize the association between vitamin D deficiency and type 2 diabetes mellitus in HIV infection and to evaluate whether vitamin D is able to prevent or delay the onset of type 2 diabetes mellitus.