Braden R. Hale

Clinical Outcomes of Elite Controllers, Viremic Controllers, and Long-Term Nonprogressors in the US Department of Defense HIV Natural History Study

Durable control of human immunodeficiency virus (HIV) replication and lack of disease progression in the absence of antiretroviral therapy were studied in a military cohort of 4586 subjects. We examined groups of elite controllers (ie, subjects with plasma HIV RNA levels of <50 copies/mL; prevalence, 0.55% [95% confidence interval {CI}, 0.35%-0.80%]), viremic controllers (ie, subjects with plasma HIV RNA levels of 50-2000 copies/mL; prevalence, 3.34% [95% CI, 2.83%-3.91%]), and subjects with a lack of disease progression (ie, long-term nonprogressors [LTNPs]) through 7 years of follow-up (LTNP7s; prevalence, 3.32% [95% CI, 2.70%-4.01%]) or 10 years of follow-up (LTNP10s; prevalence, 2.04% [95% CI, 1.52%-2.68%]). For elite and viremic controllers, spontaneous virologic control was established early and was typically observed when the initial viral load measurement was obtained within 1 year of estimated seroconversion. Elite controllers had favorable time to development of AIDS (P=.048), a CD4 cell count of 350 cells/microL (P= .009), and more-stable CD4 cell trends, compared with viremic controllers. LTNPs defined by 10-year versus 7-year criteria had a longer survival time (P=.001), even after adjustment for differing periods of invulnerability (P= .042). Definitions of controllers and LTNPs describe distinct populations whose differing clinical outcomes improve with the stringency of criteria, underscoring the need for comparability between study populations.

Nonalcoholic fatty liver disease among HIV-infected persons.

Objective:To describe the prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) among HIV-infected persons not infected with hepatitis C virus (HCV). Design:A cross-sectional study among HIV-infected patients in a large HIV clinic. Methods:NAFLD was defined as steatosis among patients without viral hepatitis (B or C) coinfection or excessive alcohol use. The prevalence of NAFLD was identified by ultrasound examination evaluated by 2 radiologists blinded to the clinic information; liver biopsies were performed on a subset of the study population. Factors associated with NAFLD were evaluated by proportional odds logistic regression models. Results:Sixty-seven of 216 patients (31%) had NAFLD based on ultrasound evaluation. Among those with NAFLD, steatosis was graded as mild in 60%, moderate in 28%, and severe/marked in 12%. Factors associated with the degree of steatosis on ultrasound examination in the multivariate model included increased waist circumference [odds ratio (OR) 2.1 per 10 cm, P < 0.001], elevated triglyceride levels (OR 1.2 per 100 mg/dL, P = 0.03), and lower high-density lipoprotein levels (OR 0.7, per 10 mg/dL, P = 0.03). African Americans were less likely to have NAFLD compared with whites (14% vs. 35%), although this did not reach statistical significance (OR 0.4, P = 0.08). Similar associations were noted for the subset of patients diagnosed by liver biopsy. CD4 cell count, HIV viral load, duration of HIV infection, and antiretroviral medications were not independent risk factors associated with NAFLD after adjustment for dyslipidemia or waist circumference. Conclusions:NAFLD was common among this cohort of HIV-infected HCV-seronegative patients. NAFLD was associated with a greater waist circumference, low high-density lipoprotein, and high triglyceride levels. Antiretroviral medications were not associated with NAFLD; prospective studies are needed to confirm this finding.

Clinical and epidemiologic characteristics of an outbreak of novel H1N1 (swine origin) influenza A virus among United States military beneficiaries.

BACKGROUND A novel swine-origin influenza A (H1N1) virus was identified in March 2009 and subsequently caused worldwide outbreaks. The San Diego region was an early focal point of the emerging pandemic. We describe the clinical and epidemiologic characteristics of this novel strain in a military population to assist in future outbreak prevention and control efforts. METHODS We performed an epidemiologic evaluation of novel H1N1 virus infections diagnosed in San Diego County among 96,258 local US military beneficiaries. The structured military medical system afforded the ability to obtain precise epidemiologic information on the impact on H1N1 virus infection in a population. The novel H1N1 virus was confirmed using real-time reverse transcriptase polymerase chain reaction (rRT-PCR). RESULTS From 21 April through 8 May 2009, 761 patients presented with influenza-like illness and underwent rRT-PCR testing. Of these patients, 97 had confirmed novel H1N1 virus infection, with an incidence rate of 101 cases per 100,000 persons. The median age of H1N1 patients with H1N1 virus infection was 21 years (interquartile range, 15-25 years). Fever was a universal symptom in patients with H1N1 virus infection; other symptoms included cough (present in 96% of patients), myalgia or arthralgia (57%), and sore throat (51%). Sixty-eight (70%) of our patients had an identifiable epidemiologic link to another confirmed patient. The largest cluster of cases of H1N1 virus infection occurred on a Navy ship and involved 32 (8%) of 402 crew members; the secondary attack rate was 6%-14%. The rapid influenza testing that was used during this outbreak had a sensitivity of 51% and specificity of 98%, compared with rRT-PCR. Only 1 patient was hospitalized, and there were no deaths. CONCLUSIONS A novel H1N1 influenza A virus caused a significant outbreak among military beneficiaries in San Diego County, including a significant cluster of cases onboard a Navy ship. The outbreak described here primarily affected adolescents and young adults and resulted in a febrile illness without sequelae.

Increasing rates of community-acquired methicillin-resistant Staphylococcus aureus infections among HIV-infected persons.

Community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) rates have rapidly increased in the general population; however, little data on recent incidence rates and risk factors of CA-MRSA infections among HIV patients appear in the literature. A retrospective study was conducted from 1993 through 2005 among patients at a large HIV clinic. Trends in CA-MRSA infection incidence rates, clinical characteristics and risk factors for CA-MRSA were evaluated. Seven percent of our cohort developed a CA-MRSA infection during the study period. The rate of CA-MRSA infections among HIV-infected population significantly increased since 2003, with an incidence of 40.3 cases/1000 person-years in 2005, which was 18-fold higher than the general population served at our facility. In all, 90% of infections were skin/soft tissue infections with a predilection for buttock or scrotal abscess formation; 21% of patients experienced a recurrent infection. Risk factors included a low CD4 count at the time of infection (odds ratio [OR] per 100 CD4 cells 0.84, P = 0.03), high maximum log10 HIV viral load (OR 4.54, P<0.001), recent use of β-lactam antibiotics (OR 6.0 for receipt of two prescriptions, P<0.001) and a history of syphilis (OR 4.55, P = 0.01). No patient receiving trimethoprim-sulfamethoxazole prophylaxis developed a CA-MRSA infection. Over the study period, CA-MRSA accounted for an increasing percentage of positive wound cultures and Staphylococcus aureus isolates, 37% and 65%, respectively, during 2005. In conclusion, CA-MRSA infections have rapidly increased among HIV-infected patients, a group which has a higher rate of these infections than the general population. Risk factors for CA-MRSA among HIV-infected patients include low current CD4 cell count, recent β-lactam antibiotic use and potentially high-risk sexual activity as demonstrated by a history of syphilis infection.

Methylene blue competes with paraquat for reduction by flavo-enzymes resulting in decreased superoxide production in the presence of heme proteins

Methylene blue competes 100 to 600 times more effectively than paraquat for reduction by three different flavo-containing enzymes; xanthine oxidase, NADH cytochrome c reductase, and NADPH cytochrome c reductase. Paraquat and methylene blue both interact with deflavo xanthine oxidase, indicating that neither electron acceptor reacted at the FAD site of the enzyme where molecular oxygen is reduced to superoxide. As the paraquat radical also directly reduced acetylated cytochrome c the hemeprotein could not be utilized for measuring superoxide production in the presence of the herbicide. In the presence of cytochrome c the methylene blue caused a sharp decrease in both paraquat-induced superoxide and hydroxyl radical production.

A randomized clinical trial comparing revaccination with pneumococcal conjugate vaccine to polysaccharide vaccine among HIV-infected adults

BACKGROUND The risk of pneumococcal disease persists, and antibody responses to revaccination with the 23-valent polysaccharide vaccine (PPV) are low among human immunodeficiency virus (HIV)-infected adults. We determined whether revaccination with the 7-valent pneumococcal conjugate vaccine (PCV) would enhance these responses. METHODS In a randomized clinical trial, we compared the immunogenicity of revaccination with PCV ( n = 131) or PPV (n = 73) among HIV-infected adults (median CD4 cell count, 533 cells/mm(3)) who had been vaccinated with PPV 3-8 years earlier. HIV-uninfected adults (n = 25) without prior pneumococcal vaccination received 1 dose of PCV. A positive response was defined as a >or=2-fold increase (from baseline to day 60) in capsule-specific immunoglobulin G, with a postvaccination level >or=1000 ng/mL for at least 2 of the 4 serotypes. RESULTS HIV-infected persons demonstrated a higher frequency of positive antibody responses to PCV than to PPV (57% vs 36%) (P = .004) and greater mean changes in the immunoglobulin G concentration from baseline to day 60 for serotypes 4, 9V, and 19F (P < .05, for all), but not for serotype 14. However, by day 180, both outcomes were similar. Responses to PCV were greater in frequency and magnitude for all serotypes in HIV-uninfected adults, compared with those in HIV-infected adults. CONCLUSIONS Among persons with HIV infection, revaccination with PCV was only transiently more immunogenic than PPV, and responses were inferior to those in HIV-uninfected subjects with primary vaccination. Pneumococcal vaccines with more robust and sustained immunogenicity are needed for HIV-infected adults. Clinical trial registration. ClinicalTrials.gov identifier NCT00622843.

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Tafenoquine for Weekly Prophylaxis against Plasmodium falciparum

Tafenoquine is a promising new 8-aminoquinoline drug that may be useful for malaria prophylaxis in nonpregnant persons with normal glucose-6-phosphate dehydrogenase (G6PD) function. A randomized, double-blind, placebo-controlled chemoprophylaxis trial was conducted with adult residents of northern Ghana to determine the minimum effective weekly dose of tafenoquine for the prevention of infection by Plasmodium falciparum. The primary end point was a positive malaria blood smear result during the 13 weeks of study drug coverage. Relative to the placebo, all 4 tafenoquine dosages demonstrated significant protection against P. falciparum infection: for 25 mg/week, protective efficacy was 32% (95% confidence interval [CI], 20%-43%); for 50 mg/week, 84% (95% CI, 75%-91%); for 100 mg/week, 87% (95% CI, 78%-93%); and for 200 mg/week, 86% (95% CI, 76%-92%). The mefloquine dosage of 250 mg/week also demonstrated significant protection against P. falciparum infection (protective efficacy, 86%; 95% CI, 72%-93%). There was little difference between study groups in the adverse events reported, and there was no evidence of a relationship between tafenoquine dosage and reports of physical complaints or the occurrence of abnormal laboratory parameters. Tafenoquine dosages of 50, 100, and 200 mg/week were safe, well tolerated, and effective against P. falciparum infection in this study population.

Endemic Infectious Diseases of Afghanistan

The current crisis in Afghanistan has resulted in an influx of Western military personnel, peacekeepers, humanitarian workers, and journalists. At the same time, unprecedented numbers of internally displaced persons and refugees have overwhelmed much of the already fragile infrastructure, setting the stage for outbreaks of infectious diseases among both foreigners and local populations. This review surveys the literature concerning the infectious diseases of Afghanistan and south-central Asia, with particular emphasis on diseases not typically seen in the Western world.

Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons

Objective: To describe the prevalence of neurocognitive impairment (NCI) among early diagnosed and managed HIV-infected persons (HIV+) compared to HIV-negative controls. Methods: We performed a cross-sectional study among 200 HIV+ and 50 matched HIV-uninfected (HIV−) military beneficiaries. HIV+ patients were categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200 cells/mm3) or later stage patients (n = 100 in each group); both groups were diagnosed early and had access to care. NCI was diagnosed using a comprehensive battery of standardized neuropsychological tests. Results: HIV+ patients had a median age of 36 years, 91% were seroconverters (median window of 1.2 years), had a median duration of HIV of 5 years, had a CD4 nadir of 319, had current CD4 of 546 cells/mm3, and 64% were on highly active antiretroviral therapy (initiated 1.3 years after diagnosis at a median CD4 of 333 cells/mm3). NCI was diagnosed among 38 (19%, 95% confidence interval 14%–25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV− patients. Conclusions: HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment.

Prevalence and factors associated with liver test abnormalities among human immunodeficiency virus-infected persons.

BACKGROUND & AIMS Liver disease is a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. We evaluated the prevalence, etiology, and factors associated with liver dysfunction in patients during the highly active antiretroviral therapy era. METHODS We performed liver tests (baseline and after a 6-month follow-up period) in HIV-infected patients treated at a large clinic. Comprehensive laboratory and ultrasound analyses were performed. Factors associated with liver test abnormalities were assessed using multivariate logistic regression models. RESULTS Eighty of 299 HIV-positive patients (27%) had abnormal liver test results during the 6-month study period. The majority of abnormalities were grade 1. Of those with liver test abnormalities, the most common diagnosis was nonalcoholic fatty liver disease (30%), followed by excessive alcohol use (13%), chronic hepatitis B (9%), chronic active hepatitis C (5%), and other (hemochromatosis and autoimmune hepatitis, 2%); 8 participants (10%) had more than 1 diagnosis. In total, 39 HIV patients with abnormal liver test results (49%) had a defined underlying liver disease. Despite laboratory tests and ultrasound examination, 41 abnormal liver test results (51%) were unexplained. Multivariate analyses of this group found that increased total cholesterol levels (odds ratio, 1.6 per 40-mg/dL increase; P = .01) were associated with liver abnormalities. CONCLUSIONS Liver test abnormalities are common among HIV patients during the highly active antiretroviral therapy era. The most common diagnosis was nonalcoholic fatty liver disease. Despite laboratory and radiologic investigations into the cause of liver dysfunction, 51% were unexplained, but might be related to unrecognized fatty liver disease.