Persistence of Human Immunodeficiency Virus-Associated Cerebral Toxoplasmosis Lesions in Successfully Treated Patients Receiving Combination Antiretroviral Therapy.

Background: Toxoplasmic encephalitis (TE) is a life-threatening complication of people with human immunodeficiency virus (PWH) with severe immunodeficiency, especially those with a CD4+ T-cell count <100 cells/µL. Following a clinical response to anti-Toxoplasma therapy, and immune reconstitution after initiation of combination antiretroviral therapy (ART), anti-Toxoplasma therapy can be discontinued with a low risk of relapse. Methods: To better understand the evolution of magnetic resonance imaging (MRI)-defined TE lesions in PWH receiving ART, we undertook a retrospective study of PWH initially seen at the National Institutes of Health between 2001 and 2012, who had at least 2 serial MRI scans. Lesion size and change over time were calculated and correlated with clinical parameters. Results: Among 24 PWH with TE and serial MRI scans, only 4 had complete clearance of lesions at the last MRI (follow-up, 0.09-5.8 years). Of 10 PWH off all anti-Toxoplasma therapy (median, 3.2 years after TE diagnosis), 6 had persistent MRI enhancement. In contrast, all 5 PWH seen in a pre-ART era study who were followed for >6 months had complete clearance of lesions. TE lesion area at diagnosis was associated with the absolute change in area (P < .0001). Conclusions: Contrast enhancement can persist even when TE has been successfully treated and anti-Toxoplasma therapy has been stopped, highlighting the need to consider diagnostic alternatives in successfully treated patients with immune reconstitution presenting with new neurologic symptoms.

Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study.

BACKGROUND: Worldwide, although predominantly in low-income countries in the Middle East and Africa, up to 13% of hepatitis C virus (HCV) infections are caused by HCV genotype 4. For patients with HCV genotype 1, the combination of ledipasvir and sofosbuvir has been shown to cure high proportions of patients with excellent tolerability, but this regimen has not been assessed for the treatment of HCV genotype 4. We assessed the efficacy, safety, and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir for patients with chronic HCV genotype 4 infections. METHODS: In this single-centre, open-label cohort, phase 2a trial, patients with HCV genotype 4 who were treatment naive or interferon treatment experienced (HIV-negative) were sequentially enrolled at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. We gave patients 12 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) as a single combination tablet once per day. The primary efficacy endpoint was sustained viral response at 12 weeks (SVR12), as measured by the proportion of patients with HCV RNA concentrations less than the lower limit of quantification (COBAS TaqMan HCV test, version 1.0, 43 IU/mL). The primary safety endpoint was the frequency and severity of adverse events. We did our analyses on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS: Between Sept 16, 2013, and Nov 2, 2014, we recruited 21 patients. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR12 (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events and no grade 3 or 4 adverse events occurred that were related to study medications. The most common adverse events were diarrhoea (two patients), fatigue (three patients), nausea (two patients), and upper respiratory infections (two patients). INTERPRETATION: Ledipasvir and sofosbuvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 100% SVR for all patients who received all 12 weeks of study drugs, irrespective of previous treatment status and underlying liver fibrosis. This is the first report of a single-pill, all-oral, interferon-free, ribavirin-free treatment for patients with HCV genotype 4. FUNDING: NIAID, National Cancer Institute and Clinical Center Intramural Program. The study was also supported in part by a Cooperative Research and Development Agreement between NIH and Gilead Sciences.

Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study.

BACKGROUND: Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. METHODS: In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS: Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. INTERPRETATION: In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. FUNDING: National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.

Strategies to eliminate HBV infection.

Chronic HBV infection is a major public health concern affecting over 240 million people worldwide. Although suppression of HBV replication is achieved in the majority of patients with currently available newer antivirals, discontinuation of therapy prior to hepatitis B surface antigen loss or seroconversion is associated with relapse of HBV in the majority of cases. Thus, new therapeutic modalities are needed to achieve eradication of the virus from chronically infected patients in the absence of therapy. The basis of HBV persistence includes viral and host factors. Here, we review novel strategies to achieve sustained cure or elimination of HBV. The novel approaches include targeting the viral and or host factors required for viral persistence, and novel immune-based therapies, including therapeutic vaccines.

CD4+ cell counts and HIV-RNA levels do not predict outcomes of community-acquired pneumonia in hospitalized HIV-infected patients.

BACKGROUND: Outcomes of community-acquired pneumonia (CAP) in relation to CD4+ cell counts have not been established. We examined the correlation of CD4+ cell count and HIV-RNA level with the clinical outcomes of CAP in hospitalized HIV-infected patients. METHODS: This was a retrospective study of 127 adult hospitalized patients with HIV infection enrolled with the CAP Organization (CAPO), examining the time to clinical stability (TCS), length of hospital stay (LOS), and all-cause mortality. RESULTS: Mortality data were available for 117 HIV-infected patients with CAP. Death within 28 days was reported in 28 patients. The risk of mortality at 28 days was not significant when adjusted for CD4+ cell count (p=0.123), HIV-RNA <400-1000 copies/ml (p=0.093), HIV-RNA ≥ 1000-10,000 copies/ml (p=0.543), and HIV-RNA ≥ 10,000-100,000 copies/ml (p=0.383). The propensity-adjusted Cox proportional hazards regression models did not show any statistically significant differences in LOS or TCS for CD4+ cell counts (p=0.590 and p=0.420, respectively) or HIV-RNA levels (p=0.470 and p=0.080, respectively). Multivariable Cox proportional hazards models did not reveal any statistically significant relationships between CD4+ cell counts or HIV-RNA levels with LOS or TCS. CONCLUSIONS: Our study shows that clinical outcomes of HIV-infected patients with CAP are not predicted by CD4+ cell counts or HIV-RNA levels after adjusting for confounders. The management of CAP in patients with HIV infection should not be based on CD4+ cell counts or HIV-RNA levels of the HIV infection.

Methicillin-resistant Staphylococcus aureus resistance to non-beta-lactam antimicrobials in the United States from 1996 to 2008.

We report the resistance rates of Staphylococcus aureus to non-beta-lactam antimicrobials from The Surveillance Network Database-USA (Eurofins-Medinet, Chantilly, VA). Specimens studied were from lower respiratory tract, wounds, and blood. Patients were stratified by age group and patient setting. There were 2,053,219 isolates of S. aureus and 973,116 of methicillin-resistant S. aureus (MRSA). The MRSA rate increased until 2004 and then leveled off. MRSA showed decreasing resistance to tetracycline and trimethoprim-sulfamethoxazole (TMP-SMX). By age group, the greatest MRSA rate increase was for individuals 17 years and younger. Non-beta-lactam antimicrobials and particularly TMP-SMX should be considered therapeutic options for staphylococcal infections.

Clinical outcomes of HIV-infected patients hospitalized with bacterial community-acquired pneumonia.

BACKGROUND: There are limited and conflicting data on clinical outcomes of community-acquired pneumonia (CAP) among HIV-infected patients. METHODS: Secondary analyses of clinical outcomes of CAP were performed for 118 patients with HIV infection and 2790 patients without HIV infection enrolled in the Community-Acquired Pneumonia Organization (CAPO) international study. After adjustment for significant confounders, the effect of HIV infection on length of stay (LOS) and time to clinical stability (TCS) were examined by survival analyses and overall mortality and CAP-related mortality by logistic regression methods. RESULTS: After adjusting for significant confounders, hospitalized HIV-infected patients with CAP did not have longer times to reach clinical stability (HR 1.126; 95% CI 0.917-1.391; p=0.251) or longer stays in the hospital (HR 1.191, 95% CI 0.979-1.449; p=0.080). In addition, HIV infection did not significantly influence overall mortality rates (OR 1.205, 95% CI 0.686-2.116; p=0.517) or CAP-related mortality rates (OR 1.338; 95% CI 0.623-3.725; p=0.355). CONCLUSION: The presence of HIV infection did not influence the clinical outcomes of CAP among patients assessed at CAPO centers. It is not intended that our results be extrapolated to populations receiving limited healthcare for advanced HIV disease, malnourishment and parasitic diseases.

Focus on the liver: alcohol use, highly active antiretroviral therapy, and liver disease in HIV-infected patients.

Since the introduction of highly active antiretroviral therapy (HAART) in the 1990 s, liver disease is emerging as a major cause of morbidity and mortality among HIV-infected patients. This is attributed to a variety of factors, including HAART hepatotoxicity, coinfection with hepatitis B and C virus (HBV and HCV, respectively), and alcohol abuse. Several studies have examined the effects of HAART and HCV/HBV coinfection on liver toxicity. However, the impact of alcohol consumption as a cofactor for hepatotoxicity in HIV patients is only beginning to be understood. Similar to the general population, alcohol use is common in the HIV population but is often overlooked by health care providers. Approximately 25 percent of recently diagnosed HIV patients are alcohol dependent; moreover, alcohol dependence has been associated with HIV treatment failure. Alcohol/HAART interactions appear crucial for the development of liver disease in HIV patients. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly, alcoholic- and HAART-induced liver disease share many potential mechanisms of injury, including altered metabolism of certain signaling molecules (i.e., cytokines) and dysfunction of some cell components (i.e., proteasomes and mitochondria).