Asymptomatic SARS-CoV-2 Infection Is Common Among ART-Treated People With HIV.

BACKGROUND: Limited data are available regarding asymptomatic COVID-19 among people with HIV (PWH). Data on a representative subset of PWH enrolled in Randomized Trial to Prevent Vascular Events in HIV, a global clinical trial, are presented here. METHODS: Randomized Trial to Prevent Vascular Events in HIV is an atherosclerotic cardiovascular disease prevention trial among 7770 PWH on antiretroviral therapy. Beginning April 2020, targeted data on coronavirus disease 2019 (COVID-19) diagnosis and symptoms were collected during routine trial visits. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was defined as either COVID-19 clinical diagnosis or presence of SARS-CoV-2 Immunoglobulin G (IgG) or Immunoglobulin A (IgA) receptor binding domain protein (antispike) antibodies in the absence of prior COVID-19 vaccine. RESULTS: The group (N = 2464) had a median age 53 years, 35% female sex, 47% Black or African American race, median CD4 count 649 c/mm 3 , and 97% with HIV VL <400 cp/m. SARS-CoV-2 infection occurred in 318 persons (13%): 58 with clinical diagnosis and 260 with detectable antibodies. Of these PWH, 304 completed symptom questionnaires: 121 (40%) reported symptoms, but 183 (60%) were asymptomatic. PWH with asymptomatic SARS-CoV-2 infection were more likely to be from low-income or middle-income regions, of Black or African American race, older in age, and with higher atherosclerotic cardiovascular disease risk score. Symptomatic COVID was more common with obesity, metabolic syndrome, and low HDL levels. CD4 counts and HIV viral suppression rates were similar among PWH with symptomatic vs. asymptomatic COVID. CONCLUSIONS: Asymptomatic SARS-CoV-2 infection is common among antiretroviral therapy-treated PWH globally. We determined that 60% of infections in PWH were asymptomatic. HIV clinicians must remain vigilant about COVID-19 testing among PWH to identify asymptomatic cases.

Adapting Education at the Medical College of Georgia at Augusta University in Response to the COVID-19 Pandemic: the Pandemic Medicine Elective.

The Medical College of Georgia (MCG) responded to the COVID-19 pandemic's challenges to medical education with a novel, comprehensive curriculum. The Pandemic Medicine Elective was an effective solution with a safe, virtual alternative to traditional clinical experiences. As the elective evolved to include pre-clinical students and service initiatives across Georgia, students and faculty navigated online platforms to execute critical community-based projects. This curricular development utilized an interdisciplinary approach by faculty across each of MCG's regional campuses. We describe the curriculum of the electives, the student initiatives, and lessons learned while quickly adapting curriculum during the COVID-19 pandemic.

Widely Disseminated Cryptococcosis Manifesting in a Previously Undiagnosed Human Immunodeficiency Virus (HIV)-Positive 18-Year-Old.

BACKGROUND After initial infection with HIV, loss of CD4+ T cells progresses along a predictable timeline. The clinical latency stage lasts an average of 10 years, until the CD4+ T cell count falls below 200 cells/uL or the patient develops an AIDS-defining opportunistic infection/cancer. This report describes an unusual opportunistic infection in a young patient with no prior clinical evidence of HIV infection. CASE REPORT An 18-year-old man presented with fever, abdominal pain, and dyspnea for the previous 2 weeks and was symptomatically treated for gastroenteritis. He presented 2 weeks later with extreme fatigue, and a CT scan revealed diffuse lymphadenopathy. He was transferred to a regional hospital, but upon arrival and prior to detailed investigative work-up, he developed cardiac arrest. Despite maximal resuscitative efforts, he died approximately 8 h after admission. At autopsy, diffuse lymphadenopathy, splenomegaly, and pulmonary congestion were noted. Disseminated cryptococcal infection involving almost every organ system was identified at autopsy. A postmortem HIV-1 antibody test was positive. The cause of death was severe immunodeficiency as a result of advanced HIV infection resulting in disseminated cryptococcal infection, with cerebral edema, herniation, and respiratory failure. CONCLUSIONS This patient's non-specific symptoms in conjunction with his rapid decline made arriving at a correct diagnosis challenging. Only during autopsy was the disseminated fungal infection discovered, leading to suspicion of HIV infection. HIV autopsies are not uncommon, but the clinical history is usually known beforehand. This case report highlights the importance of considering HIV-related conditions in patients presenting with this array of symptoms, as well as to alert healthcare providers and staff to the need for increased biosafety precautions.

Infectious Diseases Physicians: Improving and Protecting the Public's Health: Why Equitable Compensation Is Critical.

Infectious diseases (ID) physicians play a crucial role in public health in a variety of settings. Unfortunately, much of this work is undercompensated despite the proven efficacy of public health interventions such as hospital acquired infection prevention, antimicrobial stewardship, disease surveillance, and outbreak response. The lack of compensation makes it difficult to attract the best and the brightest to the field of ID, threatening the future of the ID workforce. Here, we examine compensation data for ID physicians compared to their value in population and public health settings and suggest policy recommendations to address the pay disparities that exist between cognitive and procedural specialties that prevent more medical students and residents from entering the field. All ID physicians should take an active role in promoting the value of the subspecialty to policymakers and influencers as well as trainees.

Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor-based Regimens for Initial Treatment of HIV Infection: A Systematic Review and Metaanalysis of Randomized Trials.

BACKGROUND: Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS: We searched databases to identify randomized trials that compared NNRTI- vs PI/r-based initial therapy. A metaanalysis calculated risk ratios (RRs) or mean differences (MDs), as appropriate. Primary outcome was death or progression to AIDS. Secondary outcomes were death, progression to AIDS, and treatment discontinuation. We calculated RR of virologic suppression and MD for an increase in CD4 cells at week 48. RESULTS: We included 29 trials with 9047 participants. Death or progression to AIDS occurred in 226 participants in the NNRTI arm and in 221 in the PI/r arm (RR, 1.03; 95% confidence interval, .87-1.22; 12 trials; n = 3825), death in 205 participants in the NNRTI arm vs 198 in the PI/r arm (1.04; 0.86-1.25; 22 trials; n = 8311), and progression to AIDS in 140 participants in the NNRTI arm vs 144 in the PI/r arm (1.00; 0.80-1.25; 13 trials; n = 4740). Overall treatment discontinuation (1.12; 0.93-1.35; 24 trials; n = 8249) and from toxicity (1.21; 0.87-1.68; 21 trials; n = 6195) were comparable, but discontinuation due to virologic failure was more common with NNRTI (1.58; 0.91-2.74; 17 trials; n = 5371). At week 48, there was no difference between NNRTI and PI/r in virologic suppression (RR, 1.03; 0.98-1.09) or CD4(+) recovery (MD, -4.7 cells; -14.2 to 4.8). CONCLUSIONS: We found no difference in clinical and viro-immunologic outcomes between NNRTI- and PI/r-based therapy.

Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options. OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. METHODS: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly. RESULTS: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo. CONCLUSIONS: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.

Crofelemer, a novel agent for treatment of non-infectious diarrhea in HIV-infected persons.

Crofelemer is the first US FDA-approved drug for symptomatic relief in HIV-infected persons on antiretroviral therapy (ART) who have non-infectious diarrhea. With the availability of ART, there is increased survival and decrease in gastrointestinal opportunistic infections. However, diarrhea secondary to ART and HIV enteropathy is common in HIV-infected persons. Crofelemer is manufactured from the red latex sap of the Croton lechleri tree in South America. It has a unique mechanism leading to inhibition of chloride ion secretion by blocking chloride channels in the gastrointestinal lumen. This reduces efflux of sodium and water, which in turn reduces the frequency and consistency of diarrhea. Crofelemer is well tolerated due to minimal systemic absorption and has a good safety profile. The availability of crofelemer will likely have a positive impact on the quality of life in HIV-infected persons and also increase compliance to ART.

Management of noninfectious diarrhea associated with HIV and highly active antiretroviral therapy.

In geographic locations where highly active antiretroviral therapy (HAART) is widely available, the nature of HIV-related diarrhea has shifted from being predominantly a consequence of opportunistic infection to being largely a side effect of HAART agents. With this shift has come a smaller risk for the life-threatening wasting and weight loss, although serious instances of noninfectious diarrhea remain a concern. While estimates vary, in part due to the lack of a standard diarrhea definition, over a quarter of patients receiving HAART experience diarrhea. The negative effect on quality-of-life in patients with HAART-related diarrhea is profound; diarrhea may also increase the risk of poor adherence to treatment, with potentially serious effects on viral suppression and increased risk of drug resistance. Diagnosis of HAART-related diarrhea largely involves ruling out pathogen involvement, which, in addition to laboratory testing, may require endoscopic examination. Treatment was, until recently, mainly supportive in nature. The recent US Food and Drug Administration approval of crofelemer offers the first reliably effective treatment for HAART-related diarrhea.

Etiology and pharmacologic management of noninfectious diarrhea in HIV-infected individuals in the highly active antiretroviral therapy era.

Diarrhea remains a common problem for patients with human immunodeficiency virus (HIV) infection despite highly active antiretroviral therapies (HAART) and can negatively affect patient quality of life and lead to discontinuation or switching of HAART regimens. In the era of HAART, diarrhea from opportunistic infections is uncommon, and HIV-associated diarrhea often has noninfectious causes, including HAART-related adverse events and HIV enteropathy. Diarrhea associated with HAART is typically caused by protease inhibitors (eg, ritonavir), which may damage the intestinal epithelial barrier (leaky-flux diarrhea) and/or alter chloride ion secretion (secretory diarrhea). HIV enteropathy may result from direct effects of HIV on gastrointestinal tract cells and on the gastrointestinal immune system and gut-associated lymphoid tissue, which may be active sites of HIV infection and ongoing inflammation and mucosal damage. New therapies targeting the pathogenic mechanisms of noninfectious diarrheas are needed.

Ethnicity and gender differences in lipodystrophy of HIV-positive individuals taking antiretroviral therapy in Ontario, Canada.

PURPOSE: This study assessed ethnicity and gender differences in prevalence, type, and severity of antiretroviral-associated lipodystrophy in HIV-positive individuals in Ontario. METHODS: This was a cross-sectional analysis of the Ontario Cohort Study (OCS), a prospective study of HIV-positive patients in Ontario. Lipodystrophy was defined as at least 1 major or 2 minor self-reported changes of peripheral lipoatrophy and/or central lipohypertrophy. Prevalence, type, and severity were compared by ethnicity (Black, White, or Other) and gender. Univariate and multivariate logistic regression analyses identified predictors of lipodystrophy. RESULTS: Data were available for 778 participants (659 men, 119 women). There were 517 Whites, 121 Blacks, and 140 patients of Other ethnicities. In univariate analyses, Whites reported more peripheral lipoatrophy (P = .004) and abdominal lipohypertrophy (P = .04); these ethnic differences were observed in males (P = .05 and P = .03, respectively) but not females. Males reported more peripheral lipoatrophy (P = .01), whereas females had more central lipohypertrophy (P < .0001) and mixed fat redistribution (P < .0001). Multivariable regression analyses revealed Black women to be most vulnerable to lipodystrophy (P = .02), particularly lipohypertrophy (P < .0001). CONCLUSIONS: Ethnicity and gender are important factors influencing lipodystrophy. Combining lipoatrophy and lipohypertrophy into a single entity is not appropriate. Black women were most vulnerable to lipohypertrophy, which has important implications for antiretroviral therapy roll-out in Africa.

Disparities in outcomes for African American and Latino subjects in the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial.

To benefit maximally from antiretroviral therapy, patients with HIV infection must enter care before their disease is advanced and adhere to care. We sought to determine if and where on this continuum of care racial/ethnic disparities were evident. Data from the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial, which evaluated three strategies for initial HIV therapy, were compared for White, African American, and Latino subjects. Outcomes included progression of disease and death, HIV viral suppression, and change in CD4(+) cell count. Multivariate Cox proportional hazard models adjusted for known predictors of survival. There were 1357 subjects, including 368 non-Latino white, 751 non-Latino African American, and 238 Latino subjects. At baseline, the two latter groups were more likely to have had AIDS and had lower CD4(+) cell counts than white subjects. In follow-up, African American subjects had lower self-reported adherence to therapy, lower CD4(+) cell count increases, and lower odds of viral suppression. African American and Latino subjects had unadjusted hazard ratios of progression of disease or death of 1.57 (1.17, 2.10; p = 0.0025) and 1.57 (1.09, 2.26; p = 0.02), respectively. Adjusting for baseline differences and differences in adherence, CD4(+) cell count change, and viral suppression accounted for the disparities in outcomes. Opportunities to reduce disparities in outcomes for African American and Latino patients exist along the continuum of HIV care. Efforts to promote access to HIV testing and care and to improve adherence have the potential to reduce racial/ethnic disparities in outcomes of patients with HIV infection.

Abacavir/lamivudine combination in the treatment of HIV: a review.

Abacavir has been at the center of research and clinical interest in the last two years. The frequency of the associated abacavir hypersensitivity syndrome has decreased substantially since the introduction of routine testing for the HLA-B*5701 allele; the activity of the drug in HIV-infected persons with HIV RNA values more than 100,000 copies/mL has been questioned; the possible increased risk of myocardial infarction after recent exposure to abacavir has been debated; and the drug has been moved from the "recommended" category to the "alternative" category in several guidelines. Still, the drug remains a useful agent in combination with other drugs, including lamivudine, for the treatment of HIV infection. This review will focus on the pharmacokinetics, activity, side effects, and resistance profile of both abacavir and lamivudine, including a thorough review of all of the recent studies relevant to both drugs.

Profile of etravirine for the treatment of HIV infection.

Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with the advantages of in vitro potency against many strains of virus resistant to efavirenz and nevirapine, as well as a higher genetic barrier to resistance. Etravirine is indicated for use in treatment-experienced patients, and the approved dose in adults is 200 mg twice daily. Etravirine should be administered after a meal as bioavailability is significantly reduced when taken in the fasting state. Etravirine is a substrate of CYP3A4, CYP2C9, CYP2C19, and uridine diphosphate glucuronyltransferase, and induces CYP3A4, weakly inhibits CYP2C9 and moderately inhibits CYP2C19. Etravirine may be coadministered with nucleoside/tide reverse transcriptase inhibitors, raltegravir and boosted darunavir, lopinavir, and saquinavir without dosage adjustment. Etravirine should not be given with other NNRTIs, unboosted protease inhibitors, and atazanavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir due to unfavorable drug interactions. In randomized, controlled trials, twice daily etravirine combined with darunavir/ritonavir plus optimized background therapy demonstrated better efficacy compared to darunavir/ritonavir plus optimized background therapy alone in treatment-experienced populations out to 96 weeks follow-up. The main etravirine-associated toxicity is mild to moderate self-limiting rash, although severe and sometimes fatal hypersensitivity reactions have been reported. Etravirine offers a potent sequencing option after the development of resistance to first-line NNRTIs, and is a welcome addition to this established drug class.

Antiretroviral medication adherence and class- specific resistance in a large prospective clinical trial.

OBJECTIVE: To assess the association between adherence to antiretroviral therapy and the presence of class-specific antiretroviral medication resistance. DESIGN: Secondary analysis of prospective clinical trial data. METHODS: Participants randomized to the protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) strategies of the Community Programs for Clinical Research on AIDS (CPCRA) Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study were included. Adherence was measured by 7-day self-report. Virological failure was defined as an HIV-RNA more than 1000 at or after 4 months. The association between cumulative adherence and the development of class-specific genotypic resistance was assessed by Cox regression analysis. RESULTS: Included were 457 and 446 antiretroviral-naive participants on the protease inhibitor and NNRTI strategies, respectively. The median time to initial virological failure in the protease inhibitor strategy was 1.2 years; 135 (30%) individuals failed with resistance. The median time to initial virological failure in the NNRTI strategy was 3.0 years; 127 (28%) failed with resistance. No association was found between cumulative adherence and protease inhibitor resistance [hazard ratio 1.1, 95% confidence interval (CI) 0.9-1.4 per 10% lower adherence]. However, lower cumulative adherence was associated with an increased risk of NNRTI resistance at initial virological failure (hazard ratio 1.2, 95% CI 1.1-1.3 per 10% lower adherence). In both strategies, lower cumulative adherence was associated with an increased risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance at initial virological failure. CONCLUSION: Adherence-resistance relationships are class-specific. For NRTIs and NNRTIs, initial virological failure with resistance is more likely at lower levels of cumulative adherence.

Understanding HIV phenotypic resistance testing: usefulness in managing treatment-experienced patients.

This review discusses how "virtual" and conventional phenotypic assays establish clinical cutoffs predictive of response in HIV isolates from antiretroviral-experienced patients. Sophisticated phenotypic assays that incorporate linear regression modeling and conventional phenotypic assays have been used to define and validate clinical cutoffs (i.e. the correlation between viral susceptibility and treatment response) for most antiretrovirals, including the newer protease inhibitors. Using these clinical cutoff values, clinical data show that the newer protease inhibitors retain activity against the majority of isolates from treatment-experienced patients and from those with baseline resistance to multiple protease inhibitors. The utility of phenotypic resistance testing methods have therefore been validated in the clinical setting. In summary, HIV drug resistance testing is currently the recommended standard of care for the selection of antiretroviral regimens for HIV-infected patients in multiple clinical settings. An understanding of the basic principles of phenotypic resistance testing is crucial for providing optimal care, particularly for antiretroviral-experienced patients.

New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir.

BACKGROUND: The introduction and approval of new antiretroviral agents in the US and Canada bring new opportunities and new challenges. Arguably, for the first time ever, clinicians have the drugs necessary to achieve the goal of suppressing HIV RNA to levels less than 50 copies/mL in even the most treatment-experienced patients and in those with extensive drug-limiting resistance mutations. However, the use of these new agents is complicated by many drug-drug interactions and--to some extent--pre-existing mutations. To derive maximum durability from the use of these newer drugs, a thorough understanding of their indications and limitations is critical. OBJECTIVE: To thoroughly review the six most recently approved or soon-to-be-approved antiretroviral drugs in the US and Canada: tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir. METHODS: Discussion of the indications for, and pharmacokinetics, resistance profile, activity, toxicity, and clinical trials results of, the six new agents. RESULTS/CONCLUSIONS: These six new agents have resulted in marked progress towards the goal of being able to provide HIV-infected individuals with the drugs necessary to achieve decades of durable suppression of HIV without substantial toxicity.

Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes.

BACKGROUND: Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. OBJECTIVES: To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). METHODS: The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. RESULTS: Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). CONCLUSIONS: Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.