Safety and Immunogenicity of a Randomized Phase 1 Prime-Boost Trial With ALVAC-HIV (vCP205) and Oligomeric Glycoprotein 160 From HIV-1 Strains MN and LAI-2 Adjuvanted in Alum or Polyphosphazene.

BACKGROUND: Prime-boost regimens comprising ALVAC-HIV (prime) and human immunodeficiency virus type 1 (HIV) Env (boost) induce HIV-specific neutralizing antibody and cell-mediated immune responses, but the impact of boost schedule and adjuvant requires further definition. METHODS: A phase 1 trial was conducted. In part A (open label), 19 volunteers received oligomeric glycoprotein 160 from HIV strains MN and LAI-2 (ogp160 MN/LAI-2) with dose escalation (25, 50, 100 µg) and either polyphosphazene (pP) or alum adjuvant. In part B, 72 volunteers received either placebo (n=12) or recombinant canarypox virus expressing HIV antigens (ALVAC-HIV [vCP205]) with different doses and schedules of ogp160 MN/LAI-2 in pP or alum (n = 60). RESULTS: The vaccines were safe and well tolerated, with no vaccine-related serious adverse events. Anti-gp70 V1V2 antibody responses were detected in 17 of 19 part A volunteers (89%) and 10%-100% of part B volunteers. Use of a peripheral blood mononuclear cell-based assay revealed that US-1 primary isolate neutralization was induced in 2 of 19 recipients of ogp160 protein alone (10.5%) and 5 of 49 prime-boost volunteers (10.2%). Among ogp160 recipients, those who received pP were more likely than those who received alum to have serum that neutralized tier 2 viruses (12% vs 0%; P = .015). CONCLUSIONS: Administration of ogp160 with pP induces primary isolate tier 2 neutralizing antibody responses in a small percentage of volunteers, demonstrating proof of concept and underscoring the importance of further optimization of prime-boost strategies for HIV infection prevention. CLINICAL TRIALS REGISTRATION: NCT00004579.

Cryptococcus neoformans infection in malignancy.

Cryptococcosis is an opportunistic invasive fungal infection that is well described and easily recognised when it occurs as meningitis in HIV-infected persons. Malignancy and its treatment may also confer a higher risk of infection with Cryptococcus neoformans, but this association has not been as well described. A case of cryptococcosis in a cancer patient is presented, and all cases of coincident C. neoformans infection and malignancy in adults published in the literature in English between 1970 and 2014 are reviewed. Data from these cases were aggregated in order to describe the demographics, type of malignancy, site of infection, clinical manifestations, treatment and outcomes of cryptococcosis in patients with cancer. Haematologic malignancies accounted for 82% of cases, with lymphomas over-represented compared to US population data (66% vs. 53% respectively). Cryptococcosis was reported rarely in patients with solid tumours. Haematologic malignancy patients were more likely to have central nervous system (P < 0.001) or disseminated disease (P < 0.001), receive Amphotericin B as part of initial therapy (P = 0.023), and had higher reported mortality rates than those with solid tumours (P = 0.222). Providers should have heightened awareness of the possibility of cryptococcosis in patients with haematologic malignancy presenting with infection.

Galactomannan antigen detection using bronchial wash and bronchoalveolar lavage in patients with hematologic malignancies.

BACKGROUND: The diagnosis of invasive pulmonary aspergillosis is challenging. It is unclear whether galactomannan (GM) results from bronchial wash (BW) and bronchoalveolar lavage (BAL) samples differ in a clinically meaningful way. RESULTS: Ninety-six paired (BAL and BW) samples from 85 patients were included. The average age was 53 years, 61 % of the patients were male, and 74.1 % had an underlying diagnosis of AML/MDS (ALL 7.1 %, other hematologic malignancy 18.8 %). 57 (67.1 %) patients were neutropenic, and 56 (65.9 %) patients were receiving mold-active drugs at least 48 h prior to bronchoscopy. The overall agreement between GM detection from BW and BAL was 63.5 % (K = 0.152; 95 % CI 0.008-0.311) and 73 % (K = 0.149; 95 % CI 0.048-0.348) at cut off ≥0.5 and ≥1.0, respectively. Among 43 positive samples, using a GM cut-off of 0.5, 39 (90.5 %) were positive in BW samples whereas 12 (29.3 %) were positive in BAL samples. The median level of GM in BW (0.28) samples was significantly higher than in BAL (0.20) samples among 53 samples with negative results (P = 0.001). There was no statistically significant difference in the median GM values between the BW and BAL samples with positive results (P = 0.08). There was no significant difference in GM detection between samples with positive and negative results with regard to antifungal, beta lactam antibacterial treatment or neutropenia (60.5 vs 56.6 %; 53.9 vs 46 %; 65.1 vs 54.7 %, respectively). CONCLUSION: This retrospective study examining two collection techniques suggests that BW may have higher diagnostic yield compared to bronchoalveolar lavage for GM detection.

Cancer Knowledge and Opportunities for Education Among HIV-Infected Patients in an Urban Academic Medical Center.

HIV-infected patients frequently present with advanced stage cancer. It is possible that late stage presentation may be related to lack of cancer knowledge and/or barriers to care. Questionnaires were administered to 285 adult HIV-infected patients to evaluate knowledge of cancer risk factors and symptoms and barriers to care between 2011 and 2012. Differences in mean and percent scores by group were assessed using a t test for independent samples and chi-square analysis, respectively. Respondents were predominantly male (64%), African-American (86%), and low income (60% < $10,000/year). Thirty-four (12%) had been diagnosed with cancer, and 169 (59%) had a family history of cancer. The mean knowledge score was 17.5 out of 24 questions (73%). Mean scores were not significantly different by sex, age, race, or income. Respondents with a college education scored significantly higher than those with less than a high school education (p < 0.01). In unadjusted analysis, a higher proportion of patients with a personal/family history of cancer (74%) scored in the highest quartile (>70% correct) compared to those without any personal history of cancer (62%) (p = 0.03). There was a higher level of cancer knowledge in this population compared to studies that have evaluated the HIV-uninfected population. Nevertheless, there were knowledge deficits, suggesting the need for further education about cancer to improve earlier detection rates and, ultimately, outcomes.

Factors associated with treatment failure in vertebral osteomyelitis requiring spinal instrumentation.

Patients with vertebral osteomyelitis may require instrumentation for spinal stabilization. Determining the optimal duration and type of antimicrobial therapy for these patients is challenging. The aim of this study was to examine risk factors for treatment failure, in particular antimicrobial duration, in a cohort of patients requiring spinal instrumentation for vertebral osteomyelitis. We conducted a retrospective cohort study of all patients with vertebral osteomyelitis who had spinal instrumentation between January 2002 and January 2012 at the University of Maryland Medical Center. The primary outcome measure was treatment failure >4 weeks postoperatively. We identified 131 patients with vertebral osteomyelitis requiring spinal instrumentation, 94 of whom had >4 weeks of follow-up and were included in the primary analysis. Treatment failure occurred in 22 of the 94 patients (23%) at a median of 4 months after surgery. Among patients who failed therapy, 20 of 22 failed within 1 year of surgery. Cervical and thoracic infection sites and the presence of negative cultures were associated with fewer treatment failures. Addition of rifampin and the use of chronic suppressive antimicrobials did not affect treatment failure rate. Twenty-three percent of patients with spinal instrumentation for vertebral osteomyelitis experienced treatment failure. Treatment failure almost always occurred within the first year of spinal instrumentation.

Syphilitic hepatitis treated with doxycycline in an HIV-infected patient and review of the literature.

An HIV-infected male patient who had sex with men and with a penicillin allergy presented with liver dysfunction due to secondary syphilis and was successfully treated with doxycycline. This case highlights that syphilitic hepatitis may be overlooked in this particular population, and health care providers should be attuned to this diagnosis. Doxycycline may be an acceptable alternative to penicillin for treatment of this clinical syndrome.

Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin B in critically ill patients at a tertiary care medical center.

Nephrotoxicity was assessed in 173 critically ill patients receiving intravenous colistin or polymyxin B; it occurred in 60.4% and 41.8%, respectively. Further investigation is necessary to elucidate the reason for the difference in nephrotoxicity observed between the groups and to assess the impact of severity of illness and dosing/administration.

Influenza B-induced refractory cardiogenic shock: a case report.

BACKGROUND: An association between influenza A viruses and myocarditis was noted during the 1918 influenza pandemic. Since then, the link between the influenza B virus and fulminant myocarditis or cardiogenic shock has been rarely reported. CASE PRESENTATION: In February 2013, a 50 year-old-woman without known heart disease presented in profound cardiogenic shock with a left ventricular ejection fraction of 10%. Her presentation was preceded by six days of fever, chills, myalgia and fatigue. She had a junctional tachycardia, a troponin I of 12.6 ng/ml and her coronary angiography demonstrated normal coronary arteries. Percutaneous extracorporeal membrane oxygenation was required. An endotracheal aspirate at admission was positive for influenza B. All other respiratory, blood and urine cultures were negative. On day 7, a repeat echocardiography demonstrated significant recovery of left ventricular function with an ejection fraction of 50%. She was later discharged home in good condition. CONCLUSIONS: Influenza B infection can be complicated by fulminant cardiomyopathy leading to cardiogenic shock in adults without preexisting cardiac disease.

HIV in Africa: Challenges and Directions for the Next Decade.

Africa carries a disproportionate burden of the global HIV endemic, accounting for two thirds of the global 33.3 million people living with HIV. While tremendous advances have been made in addressing the HIV epidemic in Africa, considerable challenges remain. Testing for HIV increased by 86% from 2007 to 2009 but more than 75% of people 15-49 years remain unaware of their HIV status. CD4 count at diagnosis tends to be low and linkage to care and treatment is suboptimal. The scale-up of antiretroviral therapy is ongoing but is hampered by the lack of diagnostic capability to monitor response to therapy and a substantial healthcare workforce shortage. Prevention strategies such as male circumcision, pre-exposure prophylaxis, and antiretroviral therapy for prevention have generated great excitement but cost and healthcare infrastructure deficiencies may limit their widespread applicability. Operational research to validate and inform treatment decisions, health care policies, and prevention strategies is sorely needed.

Diagnosis and management of Lyme disease.

Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most common tick-borne illness in the United States. Transmission occurs primarily through the bite of an infected deer tick (Ixodes scapularis). Identification of an erythema migrans rash following a tick bite is the only clinical manifestation sufficient to make the diagnosis of Lyme disease in the absence of laboratory confirmation. The Centers for Disease Control and Prevention recommends a two-tier serologic testing protocol using an enzyme-linked immunosorbent assay initially, followed by the more specific Western blot to confirm the diagnosis when the assay samples are positive or equivocal. The treatment of Lyme disease is determined mainly by the clinical manifestations of the disease. Doxycycline is often the preferred agent for oral treatment because of its activity against other tick-borne illnesses. Preventive measures include avoiding areas with high tick burdens, wearing protective clothing, using tick repellants (e.g., diethyltoluamide [DEET]), performing frequent body checks and bathing following outdoor activities, and instituting environmental landscape modifications (e.g., grass mowing, deer exclusion fencing) to reduce the tick burden. Although there is controversy regarding treatment of post-Lyme disease syndrome and chronic Lyme disease, there is no biologic or clinical trial evidence indicating that prolonged antibiotic therapy is of benefit.

Clinical use of CCR5 inhibitors in HIV and beyond.

Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV-infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick-borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation.

Characterization of Heavily Treatment-Experienced People With HIV and Impact on Health Care Resource Utilization in US Commercial and Medicare Advantage Health Plans.

BACKGROUND: This retrospective administrative claims study aimed to describe clinical characteristics, health care resource utilization (HCRU), and costs of people with HIV (PWH) in US commercial and Medicare Advantage health plans by antiretroviral treatment (ART) experience and CD4+ cell count. METHODS: Data from the national Optum Research Database between January 1, 2014, and March 31, 2018, for adult PWH continuously enrolled 6 months before and ≥12 months after the first ART identified (follow-up) were summarized by treatment (heavily treatment-experienced [HTE] with limited remaining ART options, treatment-experienced but not HTE [non-HTE], or treatment-naive starting a first antiretroviral regimen) and index CD4+ cell count (<200, 200-500, or >500 cells/mm3). RESULTS: Compared with non-HTE (n=7604) and treatment-naive PWH (n=4357), HTE PWH (n=2297) were older (53.5 vs 48.8 and 42.3 years), were more likely to have HIV-related emergency department visits (22.3% vs 12.4% and 18.6%) and inpatient stays (15.8% vs 7.1% and 10.3%), and had a higher mean (SD) daily pill burden (9.7 [7.7] vs 5.1 [5.9] and 3.6 [5.3] pills/d) and a higher mortality rate (5.9% vs 2.9% and 2.3%) during follow-up (all P<.001). More HTE (21.8%) and treatment-naive PWH (27.0%) had <200 CD4+ cells/mm3 vs non-HTE PWH (8.0%; P<.001). All-cause and HIV-related costs were higher among HTE PWH in all CD4+ cell count strata and treatment-naive PWH with CD4+ cell counts <200 cells/mm3 vs non-HTE PWH in all CD4+ cell count strata. CONCLUSIONS: Improved support and clinical monitoring of HTE PWH are needed to prevent worsening outcomes and increased costs.

Safety and immunogenicity of an HIV-1 gp120-CD4 chimeric subunit vaccine in a phase 1a randomized controlled trial.

A major challenge for HIV vaccine development is to raise anti-envelope antibodies capable of recognizing and neutralizing diverse strains of HIV-1. Accordingly, a full length single chain (FLSC) of gp120-CD4 chimeric vaccine construct was designed to present a highly conserved CD4-induced (CD4i) HIV-1 envelope structure that elicits cross-reactive anti-envelope humoral responses and protective immunity in animal models of HIV infection. IHV01 is the FLSC formulated in aluminum phosphate adjuvant. We enrolled 65 healthy adult volunteers in this first-in-human phase 1a randomized, double-blind, placebo-controlled study with three dose-escalating cohorts (75 µg, 150 µg, and 300 µg doses). Intramuscular injections were given on weeks 0, 4, 8, and 24. Participants were followed for an additional 24 weeks after the last immunization. The overall incidence of adverse events (AEs) was not significantly different between vaccinees and controls. The majority (89%) of vaccine-related AE were mild. The most common vaccine-related adverse event was injection site pain. There were no vaccine-related serious AE, discontinuation due to AE, intercurrent HIV infection, or significant decreases in CD4 count. By the final vaccination, all vaccine recipients developed antibodies against IHV01 and demonstrated anti-CD4i epitope antibodies. The elicited antibodies reacted with CD4 non-liganded Env antigens from diverse HIV-1 strains. Antibody-dependent cell-mediated cytotoxicity against heterologous infected cells or gp120 bound to CD4+ cells was evident in all cohorts as were anti-gp120 T-cell responses. IHV01 vaccine was safe, well tolerated, and immunogenic at all doses tested. The vaccine raised broadly reactive humoral responses against conserved CD4i epitopes on gp120 that mediates antiviral functions.

Viral load decay in antiretroviral-naïve patients receiving once-daily tenofovir and emtricitabine plus twice-daily nevirapine.

PURPOSE: The once-daily nucleoside reverse transcriptase inhibitor backbone of tenofovir and emtricitabine has been proven effective in combination with efavirenz and protease inhibitors in large clinical trials. This study evaluated tenofovir and emtricitabine in combination with nevirapine. METHODS: Viral load was assessed at baseline, Day 3, and Day 7 in addition to Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, and 84 in 10 antiretroviral-naïve patients participating in an open-label clinical trial of tenofovir and emtricitabine once daily in combination with nevirapine twice daily. RESULTS: All patients achieved viral decay with this combination. Two patients discontinued prior to virologic suppression, one with a viral load of 55 copies/mL. Virologic suppression (<50 copies/mL) was achieved by Week 24 in the remaining 8 patients. An undetectable viral load was maintained during > or =60 weeks follow-up. CONCLUSION: In this study of treatment-naïve patients, the combination of tenofovir and emtricitabine plus twice-daily nevirapine produced sustained viral load decay in patients including those with a high baseline viral load.

Lack of fluoroquinolone resistance in non-typhoidal salmonella bacteremia in HIV-infected patients in an urban US setting.

Non-typhoidal salmonella (NTS) bacteremia is a significant cause of morbidity and mortality in HIV-infected individuals worldwide. Recent reports have noted increasing resistance of NTS isolates to fluoroquinolones, the recommended first-line therapy for NTS bacteremia. The outcomes and risk factors for NTS bacteremia in HIV-infected patients in an urban US setting were evaluated. From January 2002 to December 2006, 26 episodes of NTS bacteremia were identified in 16 patients. The risk factors for NTS bacteremia were low CD4 count, high viral load, and lack of antiretroviral therapy (ART). Recurrences appeared related to lack of immune reconstitution in patients not on ART. Unlike reports from Asia, no fluoroquinolone resistance was identified in any of the Salmonella strains isolated in this setting. Optimal treatment of NTS in the HIV-infected patient in the United States should include therapy with fluoroquinolones as well as attaining complete viral suppression and immune reconstitution with ART.

Dalbavancin Use in Vulnerable Patients Receiving Outpatient Parenteral Antibiotic Therapy for Invasive Gram-Positive Infections.

INTRODUCTION: Dalbavancin is approved for acute bacterial skin and skin structure infections (ABSSSIs) but offers a potential treatment option for complicated invasive gram-positive infections. Importantly, dalbavancin's real benefits may be in treating complicated infections in vulnerable patient populations, such as persons who inject drugs (PWID). METHODS: A multicenter retrospective analysis was performed from March 2014 to April 2017 to assess 30- and 90-day clinical cure and adverse drug events (ADEs) in adult patients who received ≥ 1 dose of dalbavancin for a non-ABSSSI indication. RESULTS: During the study period, 45 patients received dalbavancin, 28 for a non-ABSSSI indication. The predominant infections treated included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). Half of the patients had positive Staphylococcus aureus in cultures, 29% methicillin resistant and 21% methicillin susceptible. Most patients were prescribed dalbavancin as sequential treatment with a median of 13.5 days of prior antibiotic therapy. The most common reason for choosing dalbavancin over standard therapy use was PWID (54%). Seven patients were lost to follow-up at day 30. Of the remaining evaluable patients, 30-day clinical cure was achieved in 15/21 (71%) patients. The most common reason for failure was lack of source control (4/6, 67%). At day 90, relapse occurred in two patients. Three patients had a potential dalbavancin-associated ADE: two patients with renal dysfunction and one patient with pruritus. CONCLUSIONS: This study demonstrates a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections in select vulnerable OPAT patients.

HIV Viral Dynamics of Lopinavir/Ritonavir Monotherapy as Second-Line Treatment: A Prospective, Single-Arm Trial.

BACKGROUND: Characterizing viral response to lopinavir/ritonavir (LPV/r) monotherapy as second-line treatment may guide recommendations for resource-limited settings (RLS). METHODS: We conducted a 48-week prospective, single-arm study of LPV/r monotherapy in patients failing first-line therapy in Nigeria. The primary outcome was sustained HIV-1 viral load (VL) <400 copies/mL at 48 weeks. RESULTS: Of 30 enrolled patients, 28 (93%) achieved viral suppression on LPV/r, while 29 (96%) experienced low-level viremia. At 48 weeks, 9 (30%) met the primary outcome of sustained viral suppression; 14 (47%) patients were suppressed on LPV/r in a snapshot analysis. Detectable VLs at 12 and 24 weeks were strongly associated with treatment failure at 48 weeks. New resistance mutations were not detected. The trial was stopped early due to treatment failure. CONCLUSION: In this study, the rate of virologic failure among patients on a second-line lopinavir monotherapy regimen was relatively high and predicted by early detectable viremia. However, no LPV/r-associated resistance mutations were detected despite fluctuating low-level viremia, demonstrating the high genetic barrier to resistance of the protease inhibitor class which could be useful in RLS.

Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection.

Plasmablastic lymphoma of the oral cavity is a form of non-Hodgkin lymphoma (NHL) and was first described in 1997. We describe a case of plasmablastic lymphoma in an HIV-infected patient who presented with an expanding oral lesion and symptoms of a toothache. We review all cases of plasmablastic lymphoma that have been reported in the literature. Plasmablastic lymphoma is strongly associated with immunodeficiency, and most particularly, with HIV infection. The pathophysiological origin of plasmablastic lymphoma has not been fully characterised, but the presence of Epstein-Barr virus (EBV) has often been documented in biopsy specimens, supporting a role for EBV in the pathogenesis of this lymphoma. The differential diagnosis for an expanding oral lesion includes both infectious and malignant processes. Biopsy is essential for making a correct and prompt diagnosis. Treatment usually involves chemotherapy, but antiretroviral therapy may also have an important role. Infectious disease clinicians should be aware of this newly described and increasingly encountered lymphoma, since it is prominently associated with immunosuppression and may be mistaken for other entities.