Neuronal modulation of hepatic lipid accumulation induced by bingelike drinking.

Excessive alcohol consumption, including binge drinking, is a common cause of fatty liver disease. Binge drinking rapidly induces hepatic steatosis, an early step in the pathogenesis of chronic liver injury. Despite its prevalence, the process by which excessive alcohol consumption promotes hepatic lipid accumulation remains unclear. Alcohol exerts potent effects on the brain, including hypothalamic neurons crucial for metabolic regulation. However, whether or not the brain plays a role in alcohol-induced hepatic steatosis is unknown. In the brain, alcohol increases extracellular levels of adenosine, a potent neuromodulator, and previous work implicates adenosine signaling as being important for the development of alcoholic fatty liver disease. Acute alcohol exposure also increases both the activity of agouti-related protein (AgRP)-expressing neurons and AgRP immunoreactivity. Here, we show that adenosine receptor A2B signaling in the brain modulates the extent of alcohol-induced fatty liver in mice and that both the AgRP neuropeptide and the sympathetic nervous system are indispensable for hepatic steatosis induced by bingelike alcohol consumption. Together, these results indicate that the brain plays an integral role in alcohol-induced hepatic lipid accumulation and that central adenosine signaling, hypothalamic AgRP, and the sympathetic nervous system are crucial mediators of this process.

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.

The impact of nelfinavir exposure on cancer development among a large cohort of HIV-infected patients.

BACKGROUND: Preclinical studies suggest that the antiretroviral agent, nelfinavir mesylate (NFV), may have antineoplastic properties. The relationship between NFV and cancer incidence among HIV-infected patients is unknown. METHODS: We evaluated the impact of NFV on cancer development in a large cohort of HIV-infected persons with 108 cancer events during 13,421 person-years of follow-up. Using multivariate time-updated Cox proportional hazard models, the risk of cancer among those receiving NFV were compared to those on non-NFV antiretroviral regimens. RESULTS: The risk of cancer among those receiving NFV was similar to those on non-NFV antiretroviral regimens (hazard ratio 1.0, 95% confidence interval 0.5, 1.7, P = 0.90). We also examined AIDS-defining and non-AIDS-defining cancers separately and found no significant associations between NFV use and cancer risk. Antiretroviral use, with or without a protease inhibitor (PI) component, was associated with a reduced risk of AIDS-defining cancers compared with no antiretroviral therapy; however, the risk of cancer was the same among those using PI or PI-sparing regimens. DISCUSSION: Despite reports that NFV may have tumoricidal activity, we found no significant relationship between NFV or PI use compared with other antiretrovirals and the risk of developing cancer among a large cohort of HIV-infected persons.

Is HIV becoming more virulent? Initial CD4 cell counts among HIV seroconverters during the course of the HIV epidemic: 1985-2007.

BACKGROUND: Whether human immunodeficiency virus (HIV) seroconverters have been presenting with progressively lower CD4 cell counts over the course of the HIV epidemic is controversial. Additional data on whether HIV might have become more virulent on a population level (measured by post-seroconversion CD4 cell counts) may provide important insights regarding HIV pathogenesis. METHODS: To determine whether post-seroconversion CD4 cell counts have changed over time, we evaluated 2174 HIV seroconverters as part of a large cohort study during the period 1985-2007. Participants were documented antiretroviral-naive HIV seroconverters who had a CD4 cell count measured within 6 months after receiving a diagnosis of HIV infection. Multiple linear regression models were used to assess trends in initial CD4 cell counts. RESULTS: The mean initial CD4 cell count decreased during the study period from 632 cells/mm(3) in 1985-1990 to 553 cells/mm(3) in 1991-1995, 493 cells/mm(3) in 1996-2001, and 514 cells/mm(3) in 2002-2007. During those periods, the percentages of seroconverters with an initial CD4 cell count <350 cells/mm(3) were 12%, 21%, 26%, and 25%, respectively. In the multiple linear model, the mean decrease in CD4 cell count from 1985-1990 was 65 cells/mm(3) in 1991-1995 (P < .001)), 107 cells/mm(3) in 1996-2001 (P < .001), and 102 cells/mm(3) in 2002-2007 (P < .001). Similar trends occurred with regard to CD4 cell percentage and total lymphocyte count. Similar decreases in initial CD4 cell counts were observed among African American and white persons during the epidemic. DISCUSSION: A significant decrease in initial CD4 cell counts among HIV seroconverters in the United States has occurred during the HIV epidemic. These data provide an important clinical correlate to suggestions that HIV may have adapted to the host, resulting in a more virulent infection.

Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study.

OBJECTIVE: To describe trends in incidence rates of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) during the HIV epidemic and to evaluate predictors, including the impact of antiretroviral therapy, of cancer development. DESIGN: Retrospective analysis of a multicenter, prospective natural history study including 4498 HIV-infected US military beneficiaries with 33 486 person-years of follow-up. METHODS: Predictors evaluated included demographics, clinical data, time-updated CD4 cell counts, HIV viral loads, and antiretroviral history. Time periods were classified as early pre (1984-1990), late pre (1991-1995), early post (1996-2000), and late post (2001-2006) HAART eras. Cox proportional hazard models were used to evaluate the association of specific factors with cancer. RESULTS: Ten percent of HIV-infected persons developed cancer. ADC rates increased between the early and late pre-HAART eras (7.6 and 14.2 cases per 1000 person-years) and have since declined from 5.4 to 2.7 in the early and late HAART eras, respectively (P < 0.001). Rates of NADCs have risen over the four periods (2.9, 2.8, 4.2, 6.7, P = 0.0004). During the late HAART era, 71% of cancers were NADCs. Predictors for ADCs included low CD4 cell count, noncancer AIDS diagnosis, and lack of HAART. NADCs were predicted by increasing age and white race (due to skin cancers). CONCLUSION: Although the rate of ADCs continues to fall, the rate of NADCs is rising and now accounts for the majority of cancers in HIV-infected persons. The development of NADCs is associated with increasing age among HIV patients. HAART use is protective for ADCs, but did not significantly impact NADCs.

Effect of HAART on incident cancer and noncancer AIDS events among male HIV seroconverters.

OBJECTIVE: To explore the impact of highly active antiretroviral therapy (HAART) on the prevention of AIDS-defining cancers relative to other AIDS-defining events. DESIGN: Prospective cohort study using 2,121 HIV+ male seroconverters (median age: 28 years, 51% white/non-Hispanic) in the Tri-Service AIDS Clinical Consortium (n = 1694) and the Multicenter AIDS Cohort Study (n = 427). METHODS: Poisson regression models, with calendar periods to represent antiretroviral therapy, were extended to analyze first incident AIDS-defining cancers and other first AIDS-defining events as competing risks. RESULTS: Eighty-one AIDS-defining cancers (64 Kaposi sarcomas; 17 non-Hodgkin lymphomas) and 343 other AIDS events occurred during 14,483 person-years in 1990-2006. The rate ratio of AIDS-defining cancers during the HAART calendar period was 0.26 (95% confidence limits: 0.15, 0.46) and of other AIDS-defining events was 0.28 (95% confidence limits: 0.21, 0.36) compared with the monotherapy/combination therapy calendar period, adjusting for age, infection duration, race, and cohort. The association of HAART with decreased AIDS incidence seemed to be equal (interaction ratio = 0.95 (95% confidence limits: 0.51, 1.74) for AIDS-defining cancers and other AIDS-defining events. CONCLUSIONS: In human immunodeficiency virus-infected men, HAART seems equally protective against first AIDS-defining cancers and other first AIDS-defining events.

Comparisons of causes of death and mortality rates among HIV-infected persons: analysis of the pre-, early, and late HAART (highly active antiretroviral therapy) eras.

METHODS: Comparisons of death-related variables during the 3 eras were performed. RESULTS: The number of deaths declined over the study period, with 987 deaths in the pre-HAART era, 159 deaths in the early HAART era (1997-1999), and 78 deaths in the late HAART era (2000-2003) (P < 0.01). The annual death rate peaked in 1995 (10.3 per 100 patients) and then declined to <2 deaths per 100 persons in the late HAART era (P < 0.01). The proportion of deaths attributable to infection decreased, but infection remained the leading cause of death in our cohort, followed by cancer. Of those who died, there was an increasing proportion of non-HIV-related deaths (32% vs. 9%; P < 0.01), including cardiac disease (22% vs. 8%; P < 0.01) and trauma (8% vs. 2%; P = 0.01) in the post-HAART versus pre-HAART era. Despite the absence of intravenous drug use and the low prevalence of hepatitis C coinfection in our cohort, an increasing proportion of deaths in the HAART era were attributable to liver disease, although the numbers are small. CONCLUSIONS: Despite increasing concerns regarding antiretroviral resistance, the death rate among HIV-infected persons in our cohort continues to decline. Our data show a lower death rate than that reported among many other US HIV-infected populations; this may be the result of open access to health care. A shift in the causes of death toward non-HIV-related causes suggests that a more comprehensive health care approach may be needed for optimal life expectancy; this may include enhanced screening for malignancy and heart disease as well as preventive measures for liver disease and accidents.

Incidence and risk factors for the occurrence of non-AIDS-defining cancers among human immunodeficiency virus-infected individuals.

BACKGROUND: The objective of this study was to determine the rates and predictors of non-AIDS-defining cancers (NADCs) among a cohort of human immunodeficiency virus (HIV)-infected individuals. METHODS: The authors conducted a retrospective study of 4144 HIV-infected individuals who had 26,916 person-years of follow-up and who had open access to medical care at 1 of the United States military HIV clinics during the years 1988-2003. Cancer incidence rates were race specific and were adjusted for age; these were compared with national rates using logistic regression to assess predictors of NADC development. RESULTS: One hundred thirty-three NADCs were diagnosed with a rate of 980 diagnoses per 100,000 person-years. The most frequent NADCs were skin carcinomas (basal cell and squamous cell), Hodgkin disease, and anal carcinoma. The results showed that there were higher rates of melanoma, basal and squamous cell skin carcinomas, anal carcinoma, prostate carcinoma, and Hodgkin disease among the HIV-infected cohort compared with age-adjusted rates for the general United States population. Predictors of NADCs included age older than 40 years (odds ratio [OR], 12.2; P < 0.001), Caucasian/non-Hispanic race (OR, 2.1; P < 0.001), longer duration of HIV infection (OR, 1.2; P < 0.001), and a history of opportunistic infection (OR, 2.5; P < 0.001). The use of highly active antiretroviral therapy (HAART) was associated with lower rates of NADCs (OR, 0.21; P < 0.001). A low CD4 nadir or CD4 count at diagnosis (< 200 cells/mL) was not predictive of NADCs. CONCLUSIONS: The most frequent NADCs were primary skin malignancies. Melanoma, basal and squamous cell skin carcinomas, anal carcinoma, prostate carcinoma, and Hodgkin disease occurred at higher rates among HIV-infected individuals. The implementation of screening programs for these malignancies should be considered. Most risk factors for the development of NADCs are nonmodifiable; however, the use of HAART appeared to be beneficial in protecting against the development of malignant disease.

Correlates of human herpesvirus-8 seropositivity among U.S. military members recently infected with human immunodeficiency virus.

BACKGROUND: Human herpesvirus 8 (HHV-8), the cause of Kaposi's sarcoma, is common among HIV-infected persons. The exact route of transmission of HHV-8 in various populations is still debated. GOAL: The goal was to define the correlates of HHV-8 infection among men recently infected with human immunodeficiency virus. STUDY DESIGN: Three hundred forty-two HIV-infected U.S. military men were evaluated using a questionnaire regarding potential risk factors and laboratory data, including HHV-8, herpes simplex virus 2 (HSV-2), syphilis, hepatitis B, and hepatitis C serologies. RESULTS: The seroprevalence of HHV-8 was 32%. HHV-8 was significantly associated with hepatitis B seropositivity (odds ratio [OR], 2.44; 95% confidence interval [CI], 1.5-4.1), and black ethnicity was negatively associated with HHV-8 (OR, 0.6; 95% CI, 0.3-0.9) in the multivariate analysis. HHV-8 was not associated with drug use or hepatitis C seropositivity. Among men who have sex with men (MSM), HHV-8 infection correlated with hepatitis B seropositivity (OR, 2.2; 95% CI, 1.1-4.3) and HSV-2 (OR, 2.6; 95% CI, 1.4-4.9). Among heterosexuals, the correlates of HHV-8 were different; blacks as compared with whites (OR, 0.3; 95% CI, 0.1-0.8) and married versus single status (OR, 0.4; 95% CI, 0.2-0.9) were associated with a lower rate of HHV-8 infection. Among heterosexuals, hepatitis B, HSV-2, and sexual behaviors were not associated with HHV-8. CONCLUSION: This study suggests that the seroprevalence of HHV-8 is increased in both MSM and heterosexual men with HIV infection, and that the route(s) of HHV-8 acquisition might be different between MSM and heterosexuals.