Lydia Barakat

Antiretroviral Therapy-Induced Mitochondrial Toxicity: Potential Mechanisms Beyond Polymerase-γ Inhibition

We hypothesized that competition between nucleotide reverse‐transcriptase inhibitor triphosphate and endogenous deoxyribonucleotide triphosphate (dNTP) may lead to depletion of dNTP pools and mitochondrial dysfunction independent of polymerase‐γ (pol‐γ) inhibition. We collected peripheral blood mononuclear cells from 75 adults (25 cases: HIV‐infected patients with mitochondrial toxicity, 25 HIV‐infected positive controls, and 25 HIV‐negative controls). We observed statistically significant individual and group differences in ribonucleotide (RN) and deoxyribonucleotide (dRN) pools. The median values for the RN pools were 10,062 (interquartile range (IQR): 7,090–12,590), 4,360 (IQR: 3,058–6,838), and 2,968 (IQR: 2,538–4,436) pmol/106 cells for negative controls, positive controls, and cases, respectively. Cases had significantly higher absolute mitochondrial DNA copy number as compared with negative controls (P < 0.05). Moreover, cases had significantly higher expression levels of pol‐γ, nucleotide transporters, cellular kinases, and adenosine triphosphate (ATP)–binding cassette (ABC) proteins as compared with controls. Antiretroviral therapy (ART) perturbs RN and dRN pools. Depletion of RN and dRN pools may be associated with ART‐induced mitochondrial toxicity independent of pol‐γ inhibition.

Increased Levels of Macrophage Inflammatory Proteins Result in Resistance to R5-Tropic HIV-1 in a Subset of Elite Controllers

ABSTRACT Elite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4+ T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4+ T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1α (MIP-1α), CCL3 and CCL3L1, were found to be upregulated. The MIP-1α, MIP-1β, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP-1α and/or MIP-1β at the protein level. The supernatant from resistant EC cells contained MIP-1α and MIP-1β and was sufficient to confer R5-tropic resistance to susceptible CD4+ T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry. IMPORTANCE HIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4+ T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV-seropositive individuals.

Trends in hospital deaths among human immunodeficiency virus–infected patients during the antiretroviral therapy era, 1995 to 2011

OBJECTIVE Mortality in hospitalized human immunodeficiency virus (HIV)-infected patients is not well described. We sought to characterize in-hospital deaths among HIV-infected patients in the antiretroviral (ART) era and identify factors associated with mortality. METHODS We reviewed the medical records of hospitalized HIV-infected patients who died from January 1, 1995 to December 31, 2011 at an urban teaching hospital. We evaluated trends in early and late ART use and deaths due to acquired immunodeficiency syndrome (AIDS) and non-AIDS, and identified clinical and demographic correlates of non-AIDS deaths. RESULTS In-hospital deaths declined significantly from 1995 to 2011 (P < 0.0001); those attributable to non-AIDS increased (43% to 70.5%, P < 0.0001). Non-AIDS deaths were most commonly caused by non-AIDS infection (20.3%), cardiovascular (11.3%) and liver disease (8.5%), and non-AIDS malignancy (7.8%). Patients with non-AIDS compared to AIDS-related deaths were older (median age 48 vs 40 years, P < 0.0001), more likely to be on ART (74.1% vs 55.8%, P = 0.0001), less likely to have a CD4 count of <200 cells/mm(3) (47.2% vs 97.1%, P < 0.0001), and more likely to have an HIV viral load of ≤400 copies/mL (38.1% vs 4.1%, P < 0.0001). Non-AIDS deaths were associated with 4.5 and 4.2 times greater likelihood of comorbid underlying liver and cardiovascular disease, respectively. CONCLUSIONS Non-AIDS deaths increased significantly during the ART era and are now the most common cause of in-hospital deaths; non-AIDS infection, cardiovascular and liver disease, and malignancies were major contributors to mortality. Higher CD4 cell count, liver, and cardiovascular comorbidities were most strongly associated with non-AIDS deaths. Interventions targeting non-AIDS-associated conditions are needed to reduce inpatient mortality among HIV-infected patients.

Comparing clinical outcomes in HIV-infected and uninfected older men hospitalized with community-acquired pneumonia

Outcomes of community–acquired pneumonia (CAP) among HIV‐infected older adults are unclear.

Unusual presentation of disseminated Nocardia abscessus infection in a patient with AIDS

A 40-year-old man with AIDS presented with symptoms of a chronic cough, subacute headache, generalised weakness with falls, urinary and faecal incontinence, and acute onset subcutaneous nodules. A chest CT scan showed multiple cavitary and nodular pulmonary infiltrates. MRI of his brain and spinal cord revealed innumerable ring-enhancing lesions. Pathological examination of the purulent material obtained from his subcutaneous lesions, as well as transbronchial tissue specimens obtained by biopsy, revealed beaded and branching Gram-positive rods, subsequently identified by 16S RNA sequencing to be Nocardia abscessus species. We observed an excellent therapeutic response to a combination antimicrobial therapy with resolution of the subcutaneous, pulmonary and central nervous system (CNS) lesions. Infections caused by N. abscessus are rare and typically occur in immunocompromised patients. In this article, we will review the presentation, diagnosis and treatment of N. abscessus infection.

Infectious Mimicry Complicates Diagnosis in Hemophagocytic Syndrome Caused by Anaplastic Large-Cell Lymphoma

Hemophagocytic syndrome (HPS) arises secondary to genetic, rheumatologic, neoplastic, and infectious causes. We discuss a patient whose presentation was consistent with systemic infection but was discovered to have HPS of unknown etiology. The presenting symptoms, as well as unremarkable malignancy and rheumatologic workups, led to the pursuit of an infectious cause, but the patient was ultimately discovered to have an occult anaplastic large-cell lymphoma (ALCL). This case demonstrates the diagnostic challenges that result from infectious mimicry in the context of HPS—first, in distinguishing noninfectious HPS from the systemic inflammation that can result from a widespread infectious process, second, in the identification of the precipitating cause of HPS. While evidence of these challenges has been suggested by the limited literature on HPS and ALCL, our case illustrates the diagnostic dilemma that arises when tissue biopsy does not quickly reveal an etiology. It is important that all physicians be aware that HPS can mimic infection and be prepared to redirect the workup when an infectious etiology for HPS cannot be identified.

Steroid-exacerbated HIV-associated cutaneous Kaposi's sarcoma immune reconstitution inflammatory syndrome: 'Where a good intention turns bad'.

A 51-year-old man with head and neck skin lesions was diagnosed with Kaposi’s sarcoma (KS) as his initial presentation of acquired immunodeficiency syndrome. Following initiation of antiretroviral therapy and subsequent full virologic suppression, his facial lesions worsened, consistent with immune reconstitution inflammatory syndrome (IRIS). He was started on glucocorticoids in an attempt to ameliorate the KS-IRIS but experienced paradoxical worsening of the KS lesions. Steroids were subsequently discontinued and he required chemotherapy for severe and cosmetically disfiguring skin lesions. This article describes the potential for worsening of KS lesions in individuals started on glucocorticoids for KS-IRIS as this has been reported rarely in published literature. The mechanisms underlying this phenomenon remain poorly understood but potential explanations are offered in the case discussion. This article aims to raise clinician awareness on the harms of steroid use in patients with KS-IRIS.

Training the next generation of HIV providers: impact of trainees on patient satisfaction in an urban HIV clinic

ABSTRACT For persons living with HIV and AIDS (PLWHA), care by an HIV-specialist improves outcomes and satisfaction with ones HIV primary care provider (PCP) promotes engagement with care. In the United States, we are facing a workforce shortage of HIV providers. As we aim to train a new generation of HIV providers, it is unclear how PLWHA perceive their experience when cared for by trainees compared to experienced providers. Therefore we assessed patient satisfaction with HIV providers, both trainees in an HIV Primary Care residency program and HIV-specialists. A secondary objective was to evaluate providers’ performance in adhering to standard management guidelines for HIV-associated and non-HIV-associated conditions. We surveyed 75 PLWHA, including 51 (68%) assigned to an HIV-specialist PCP and 24 (32%) to a trainee PCP. Overall patient satisfaction on a 10-point scale was similar (mean 9.6 HIV-specialist vs 9.7 trainee, p = 0.71) and remained similar in multivariate logistic regression analysis when controlling for patient age, gender, race, and recently establishing care (Odds Ratio 1.1, 95% Confidence Interval 0.3–5.0). Participants in the trainee group were more likely to feel their provider “always” spent enough time with them (100% vs 81%, p = 0.03). Adherence to HIV guidelines was similar, though trainees were more likely to document counseling on risk reduction (83% vs 47%, p = 0.005) and adherence to antiretroviral therapy (100% vs 66%, p = 0.001). In conclusion, in a structured HIV-training program, residents can provide subspecialty level care in an HIV continuity clinic with levels of performance and patient satisfaction equivalent to those of experienced specialists.

Characterizing Patients with Very-Low-Level HIV Viremia: A Community-Based Study.

Objective: Very-low-level viremia (VLLV) is a relatively new concept in the realm of human immunodeficiency virus (HIV) care. Newer generation assays are now able to detect plasma HIV RNA Viral Load (VL) levels as low as 20 copies/mL. The authors characterized patients with VLLV (VL between 20 and 50 copies/mL) in order to identify possible risk factors associated with virologic failure and poor clinical outcomes. Methods: The authors reviewed 119 consecutive charts of patients with VLLV. Sociodemographic data were extracted and viral load and CD4 counts were trended over a 12 month period (February 2013-February 2014). Regression analysis was used to assess the role of different factors on virologic failure at 1 year. Results: Of the study participants with evaluable data (n = 100), the median age was 53 years (interquartile range: 43-57.5), 67% were nonwhite, 34% were women, 58% were smokers, 47% were alcoholics, 58% had a history of intravenous drug use, and 40% were coinfected with hepatitis C virus. More than half of the participants had 3 or more comorbidities and their HIV pill burden was high (more than 2 pills daily). After 12 months, 65 participants achieved undetectable viral load levels, whereas 15 experienced virologic failure (2 consecutive viral loads > 50 copies/mL) and the remaining 20 had persistent VLLV. In the virologic failure group, there was a predominance of white males (66%) with a significant number of comorbidities and pill burden. Univariate logistic regression suggested that there was a difference between the failure versus nonfailure groups in terms of race, ethnicity, and alcohol use. Multivariate regression with virological failure as the outcome suggested a trend only in terms of participant’s alcohol use. Conclusion: Most patients with initial VLLV (70%) achieved virologic suppression at 1 year with no antiretroviral therapy changes. Thus, VLLV does not necessarily predict virologic failure and should not prompt more frequent clinic visits or antiretroviral regimen changes. Further research is needed in order to determine the predictors of virologic failure in this subset of patients and the clinicians’ attitude toward VLLV.