Viral and host mediators of non-suppressible HIV-1 viremia.

Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as 'producer proviruses', and those that did not as 'non-producer proviruses'. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia.

Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as "producer", and those that did not as "non-producer". Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+ cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+ cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NSV that represent potential targets to disrupt HIV persistence and promote viral silencing.

Intracranial complications of hypercoagulability and superinfection in the setting of COVID-19: illustrative cases.

BACKGROUND: Hypercoagulability with thrombosis and associated inflammation has been well-documented in COVID-19, and catastrophic cerebral venous sinus thromboses (CVSTs) have been described. Another COVID-19-related complication is bacterial superinfection, including sinusitis. Here, the authors reported three cases of COVID-19-associated sinusitis, meningitis, and CVST and summarized the literature about septic intracranial thrombotic events as a cause of headache and fever in COVID-19. OBSERVATIONS: The authors described three adolescent patients with no pertinent past medical history and no prior COVID-19 vaccinations who presented with subacute headaches, photosensitivity, nausea, and vomiting after testing positive for COVID-19. Imaging showed subdural collections, CVST, cerebral edema, and severe sinus disease. Two patients had decline in mental status and progression of neurological symptoms. In all three, emergency cranial and sinonasal washouts uncovered pus that grew polymicrobial cultures. After receiving broad-spectrum antimicrobials and various additional treatments, including two of three patients receiving anticoagulation, all patients eventually became neurologically intact with varying ongoing sequelae. LESSONS: These cases demonstrated similar original presentations among previously healthy adolescents with COVID-19 infections, concurrent sinusitis precipitating CVST, and subdural empyemas. Better recognition and understanding of the multisystem results of severe acute respiratory syndrome coronavirus 2 and the complicated sequelae allows for proper treatment.

Compassionate Use of Remdesivir in Pregnant Women With Severe Coronavirus Disease 2019.

BACKGROUND: Remdesivir is efficacious for severe coronavirus disease 2019 (COVID-19) in adults, but data in pregnant women are limited. We describe outcomes in the first 86 pregnant women with severe COVID-19 who were treated with remdesivir. METHODS: The reported data span 21 March to 16 June 2020 for hospitalized pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection and room air oxygen saturation ≤94% whose clinicians requested remdesivir through the compassionate use program. The intended remdesivir treatment course was 10 days (200 mg on day 1, followed by 100 mg for days 2-10, given intravenously). RESULTS: Nineteen of 86 women delivered before their first dose and were reclassified as immediate "postpartum" (median postpartum day 1 [range, 0-3]). At baseline, 40% of pregnant women (median gestational age, 28 weeks) required invasive ventilation, in contrast to 95% of postpartum women (median gestational age at delivery 30 weeks). By day 28 of follow-up, the level of oxygen requirement decreased in 96% and 89% of pregnant and postpartum women, respectively. Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. Remdesivir was well tolerated, with a low incidence of serious adverse events (AEs) (16%). Most AEs were related to pregnancy and underlying disease; most laboratory abnormalities were grade 1 or 2. There was 1 maternal death attributed to underlying disease and no neonatal deaths. CONCLUSIONS: Among 86 pregnant and postpartum women with severe COVID-19 who received compassionate-use remdesivir, recovery rates were high, with a low rate of serious AEs.

Omadacycline for the Treatment of Mycobacterium abscessus Disease: A Case Series.

BACKGROUND: Omadacycline is an aminomethylcycline antimicrobial approved by the US Food and Drug Administration in 2018 for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It has in vitro activity against nontuberculous mycobacteria, including Mycobacterium abscessus complex, but clinical data for this indication are lacking. METHODS: Omadacycline use was reviewed at an 804-bed academic medical center. Patients were included if they received omadacycline for culture-proven M abscessus disease in 2019. RESULTS: Four patients received omadacycline for the treatment of culture-positive M abscessus disease in 2019. Two patients had cutaneous disease, 1 had pulmonary disease, and 1 had osteomyelitis and bacteremia. The patients received omadacycline for a median duration of 166 days (range, 104-227) along with a combination of other antimicrobial agents. Omadacycline-containing regimens were associated with a clinical cure in 3 of 4 patients, with 1 patient improving on ongoing treatment. Omadacycline's tolerability was acceptable for patients with M abscessus disease, with 1 patient discontinuing therapy in month 6 due to nausea. CONCLUSIONS: Omadacycline is a novel oral option for the treatment of M abscessus disease, for which safe and effective options are needed. Although this case series is promising, further data are required to determine omadacycline's definitive role in the treatment of M abscessus disease.

Immune-profiling of ZIKV-infected patients identifies a distinct function of plasmacytoid dendritic cells for immune cross-regulation.

Zika virus (ZIKV) is a mosquito-borne pathogen with increasing public health significance. To characterize immune responses to ZIKV, here we examine transcriptional signatures of CD4 T, CD8 T, B, and NK cells, monocytes, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs) from three individuals with ZIKV infection. While gene expression patterns from most cell subsets display signs of impaired antiviral immune activity, pDCs from infected host have distinct transcriptional response associated with activation of innate immune recognition and type I interferon signaling pathways, but downregulation of key host factors known to support ZIKV replication steps; meanwhile, pDCs exhibit a unique expression pattern of gene modules that are correlated with alternative cell populations, suggesting collaborative interactions between pDCs and other immune cells, particularly B cells. Together, these results point towards a discrete but integrative function of pDCs in the human immune responses to ZIKV infection.

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication.

Although dendritic cells are among the human cell population best equipped for cell-intrinsic antiviral immune defense, they seem highly susceptible to infection with the Zika virus (ZIKV). Using highly purified myeloid dendritic cells isolated from individuals with naturally acquired acute infection, we here show that ZIKV induces profound perturbations of transcriptional signatures relative to healthy donors. Interestingly, we noted a remarkable downregulation of antiviral interferon-stimulated genes and innate immune sensors, suggesting that ZIKV can actively suppress interferon-dependent immune responses. In contrast, several host factors known to support ZIKV infection were strongly upregulated during natural ZIKV infection; these transcripts included AXL, the main entry receptor for ZIKV; SOCS3, a negative regulator of ISG expression; and IDO-1, a recognized inducer of regulatory T cell responses. Thus, during in vivo infection, ZIKV can transform the transcriptome of dendritic cells in favor of the virus to render these cells highly conducive to ZIKV infection.

Emerging Causes of Arbovirus Encephalitis in North America: Powassan, Chikungunya, and Zika Viruses.

Arboviruses are arthropod-borne viruses transmitted by the bite of mosquitoes, ticks, or other arthropods. Arboviruses are a common and an increasing cause of human illness in North America. Powassan virus, Chikungunya virus, and Zika virus are arboviruses that have all recently emerged as increasing causes of neurologic illness. Powassan virus almost exclusively causes encephalitis, but cases are rare, sporadic, and restricted to portions of North America and Russia. Chikungunya virus has spread widely across the world, causing millions of infections. Encephalitis is a rare manifestation of illness but is more common and severe in neonates and older adults. Zika virus has recently spread through much of the Americas and has been associated mostly with microcephaly and other congenital neurologic complications. Encephalitis occurring in infected adults has also been recently reported. This review will discuss the neuropathogenesis of these viruses, their transmission and geographic distribution, the spectrum of their neurologic manifestations, and the appropriate method of diagnosis.

Rapid-Growing Mycobacteria Infections in Medical Tourists: Our Experience and Literature Review.

BACKGROUND: "Medical tourism" has gained popularity over the past few decades. This is particularly common with patients seeking elective cosmetic surgery in the developing world. However, the risk of severe and unusual infectious complications appears to be higher than for patients undergoing similar procedures in the United States. OBJECTIVES: The authors describe their experience with atypical mycobacterial infections in cosmetic surgical patients returning to the United States postoperatively. METHODS: A review of patient medical records presenting with infectious complications after cosmetic surgery between January 2010 and July 2015 was performed. Patients presenting with mycobacterial infections following cosmetic surgery were reviewed in detail. An extensive literature review was performed for rapid-growing mycobacteria (RGM) related to cosmetic procedures. RESULTS: Between January 2010 and July 2015, three patients presented to our institution with culture-proven Mycobacterium abscessus at the sites of recent cosmetic surgery. All had surgery performed in the developing world. The mean age of these patients was 36 years (range, 29-44 years). There was a delay of up to 16 weeks between the initial presentation and correct diagnosis. All patients were treated with surgical drainage and combination antibiotics with complete resolution. CONCLUSIONS: We present series of patients with mycobacterial infections after cosmetic surgery in the developing world. This may be related to the endemic nature of these bacteria and/or inadequate sterilization or sterile technique. Due to low domestic incidence of these infections, diagnosis may be difficult and/or delayed. Consulting physicians should have a low threshold to consider atypical etiologies in such scenarios. LEVEL OF EVIDENCE: 5 Therapeutic.

Integrase inhibitors in late pregnancy and rapid HIV viral load reduction.

BACKGROUND: Minimizing time to HIV viral suppression is critical in pregnancy. Integrase strand transfer inhibitors (INSTIs), like raltegravir, are known to rapidly suppress plasma HIV RNA in nonpregnant adults. There are limited data in pregnant women. OBJECTIVE: We describe time to clinically relevant reduction in HIV RNA in pregnant women using INSTI-containing and non-INSTI-containing antiretroviral therapy (ART) options. STUDY DESIGN: We conducted a retrospective cohort study of pregnant HIV-infected women in the United States from 2009 through 2015. We included women who initiated ART, intensified their regimen, or switched to a new regimen due to detectable viremia (HIV RNA >40 copies/mL) at ≥20 weeks gestation. Among women with a baseline HIV RNA permitting 1-log reduction, we estimated time to 1-log RNA reduction using the Kaplan-Meier estimator comparing women starting/adding an INSTI in their regimen vs other ART. To compare groups with similar follow-up time, we also conducted a subgroup analysis limited to women with ≤14 days between baseline and follow-up RNA data. RESULTS: This study describes 101 HIV-infected pregnant women from 11 US clinics. In all, 75% (76/101) of women were not taking ART at baseline; 24 were taking non-INSTI containing ART, and 1 received zidovudine monotherapy. In all, 39% (39/101) of women started an INSTI-containing regimen or added an INSTI to their ART regimen. Among 90 women with a baseline HIV RNA permitting 1-log reduction, the median time to 1-log RNA reduction was 8 days (interquartile range [IQR], 7-14) in the INSTI group vs 35 days (IQR, 20-53) in the non-INSTI ART group (P < .01). In a subgroup of 39 women with first and last RNA measurements ≤14 days apart, median time to 1-log reduction was 7 days (IQR, 6-10) in the INSTI group vs 11 days (IQR, 10-14) in the non-INSTI group (P < .01). CONCLUSION: ART that includes INSTIs appears to induce more rapid viral suppression than other ART regimens in pregnancy. Inclusion of an INSTI may play a role in optimal reduction of HIV RNA for HIV-infected pregnant women presenting late to care or failing initial therapy. Larger studies are urgently needed to assess the safety and effectiveness of this approach.

Current practice of HIV postexposure prophylaxis treatment for sexual assault patients in an emergency department.

BACKGROUND: Comprehensive data that address current HIV nonoccupational postexposure prophylaxis (nPEP) practices in the emergency care of sexual assault patients are limited. The U.S. Centers for Disease Control and Prevention released HIV nPEP guidelines in 2005 and updated guidelines for Sexually Transmitted Disease Treatment in 2006 and 2010, each of which support providing nPEP to sexual assault patients. This study examined the offer, acceptance, and adherence rates of nPEP among sexual assault patients treated at an emergency department (ED). METHODS: We conducted a retrospective review between January 1, 2008, and December 31, 2011, of women, aged 16 years and older, treated for sexual assault in an academic ED that participates in the sexual assault nurse examiner program. FINDINGS: One hundred seventy-one female patients were treated in the ED for 179 sexual assault events. nPEP was not indicated in 19 cases and was offered to all 138 of patients for whom nPEP was appropriate. Five patient cases that exceeded the 72-hour exposure window were offered nPEP. Of the 143 patient cases offered nPEP, 124 (86.7%) initiated nPEP. Of the 124 who accepted PEP, 34 (27.4%) had documented completion of the 28-day course. CONCLUSIONS: nPEP was offered in all 138 cases where patients were eligible for treatment. Of patients who accepted nPEP, a minority are documented to have completed a course of treatment. Systems to improve postassault follow-up care should be considered.

Patient attrition between the emergency department and clinic among individuals presenting for HIV nonoccupational postexposure prophylaxis.

BACKGROUND: Nonoccupational postexposure prophylaxis (nPEP) is recommended after a sexual or parenteral exposure to human immunodeficiency virus (HIV). Patients frequently seek care in an emergency department (ED) after an exposure and are usually referred to an HIV clinic for further management. There have been few data on determinants of attrition after presentation to EDs for nPEP. METHODS: From July 2010 to June 2011, we prospectively recorded all referrals to nPEP programs from 2 large EDs at 2 academic medical centers in Boston, Massachusetts. Data were recorded on patient demographics, nature of potential HIV exposures, referrals to and attendance at HIV clinics, and reported completion of 28 days of antiretroviral therapy (ART). Multivariable logistic regression was used to evaluate risk factors for (1) patient attrition between the ED and HIV clinic follow-up and (2) documented completion of ART. RESULTS: Of 180 individuals who were referred to clinic follow-up for nPEP care from the ED, 98 (54.4%) attended a first nPEP clinic visit and 43 (23.9%) had documented completion of a 28-day course of ART. Multivariable analysis revealed older age (adjusted odds ratio [aOR], 0.96; 95% confidence interval [CI], .93-.99) and self-payment (aOR, 0.32; 95% CI, .11-.97) were significant predictors for failing to attend an initial HIV clinic appointment. Women were less likely than men to complete a 28-day ART regimen (aOR, 0.34; 95% CI, .15-.79). CONCLUSIONS: Commonly used nPEP delivery models may not be effective for all patients who present with nonoccupational exposures to HIV. Interventions are needed to improve rates of follow-up and completion of nPEP to reduce the risk of preventable HIV infections.

Management of HIV in the pregnant woman.

The treatment of human immunodeficiency virus (HIV)-infected pregnant women is one of the most effective HIV-prevention interventions known. With prenatal testing, antiviral therapy, scheduled cesarean section when indicated, and formula feeding when feasible, rates of neonatal and perinatal HIV infection can diminish significantly. Although significant prevention is achievable, new cases of HIV in neonates continue to occur both worldwide and locally due to limited resources, delayed diagnosis, lack of linkage to care, and lack of timely effective therapy. Where those resources are available, the management of HIV infection in the pregnant woman requires a multidisciplinary expert approach to achieve optimal outcomes for both mother and child.

Impact of age, gender, and pregnancy on syphilis screening using the Captia Syphilis-G assay.

BACKGROUND: Discordant results have been reported between treponemal-specific enzyme immunoassays (EIA) screening and confirmatory tests such as the Treponemal pallidum particle agglutination (TPPA) assay. The performance of IgG EIA screening in specific populations, such as pregnant women, is not well defined. We reviewed laboratory results of 34,251 samples from individuals who underwent IgG EIA screening at a large Boston academic medical center, so as to calculate positive concordance of these screening tests with a confirmatory TPPA or subsequent rapid plasma reagin (RPR) test by age, gender, pregnancy, and obstetric or gynecologic (Ob/Gyn) service. METHODS: We conducted a retrospective, cross-sectional study of the Captia Syph-G EIA serum samples between 2004 and 2007. Binary regression modeling was used to identify independent associations between demographic variables and positive concordance of EIA screening with RPR and confirmatory TPPA tests. RESULTS: Of 34,251 samples, 631 (1.8%) had a positive IgG EIA screen. In all, 79% of samples with a positive EIA had a reactive TPPA, and 48% had a positive RPR. Patients less than 40 years of age, females, and women on an Ob/Gyn clinical service had significantly lower rates of positive concordance between EIA screening and TPPA reactivity when covariate adjusted in regression modeling, whereas women on Ob/Gyn service were significantly associated with lower positive concordance with RPR testing. CONCLUSIONS: The relatively low positive concordances between EIA screening and confirmatory studies were more pronounced in low-risk patients, and it is important to define test performance in diverse patient populations.

Gordonia bronchialis bacteremia and pleural infection: case report and review of the literature.

Gordonia species are aerobic actinomycetes recently recognized as causing human disease, often in the setting of intravascular catheter-related infections. We describe a case of Gordonia bronchialis bacteremia and pleural space infection in the absence of an indwelling intravascular catheter and review the breadth of reported infections with this emerging pathogen.

Ocular syphilis among HIV-infected individuals.

We describe a human immunodeficiency virus (HIV)-infected individual with ocular manifestations of secondary syphilis. Twelve other cases of HIV-associated ocular syphilis are also presented. Six of 12 individuals had normal cerebrospinal fluid study results, and 3 patients required retreatment within 1.5 years. In patients with HIV infection, clinicians should be vigilant for ocular syphilis despite normal cerebrospinal fluid measures and for syphilis reinfection.

Maternal neutralizing antibody and transmission of hepatitis C virus to infants.

To determine whether lower levels of hepatitis C virus (HCV)-specific neutralizing antibodies (nAb) are associated with an increased risk of mother-to-child transmission (MTCT) of HCV, HCV nAb titers were assessed in 63 mothers coinfected with HCV and human immunodeficiency virus (HIV) type 1. Of the mothers, 16 transmitted HCV to their infant, but no difference was detected between the ability of maternal plasma from transmitters and nontransmitters to neutralize heterologous HCV pseudoparticles (median nAb titer, 1:125 vs. 1:100; P = .23). In the setting of HIV/HCV coinfection, we found no evidence that HCV nAbs are associated with the prevention of MTCT of HCV.