Research Findings - Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV)

Long-Term Cocaine Use and Antiretroviral Therapy Are Associated with Silent Coronary Artery Disease in African Americans with HIV Infection Who Have No Cardiovascular Symptoms

Long-term use of cocaine (>/=15 years) and antiretroviral therapy (ART) have been implicated in cardiovascular complications. Nevertheless, the individual and combined effects of ART and cocaine use on silent coronary artery disease have not been fully investigated. Computed tomography coronary angiography was performed for 165 human immunodeficiency virus (HIV)-infected African American study participants aged 25-54 years in Baltimore, Maryland, with contrast-enhanced 64-slice multidetector computed tomography imaging. Significant (>/=50%) coronary stenosis was detected in 24 (15%) of 165 participants. The prevalence of significant stenosis among those who had used cocaine for >/=15 years and had received ART for >/=6 months was 42%. Exact logistic regression analysis revealed that long-term cocaine use (adjusted odds ratio, 7.75; 95% confidence interval, 2.26-31.2) and exposure to ART for >/=6 months (adjusted odds ratio, 4.35; 95% confidence interval, 1.30-16.4) were independently associated with the presence of significant coronary stenosis. In addition, after controlling for confounding factors, both stavudine use for >/=6 months or combivir use for >/=6 months were independently associated with the presence of significant coronary stenosis. The authors conclude that long-term exposure to ART may be associated with silent coronary artery disease; however, the magnitude of increased risk associated with ART was much lower than the risk associated with cocaine use or traditional risk factors. Cardiovascular monitoring and aggressive modification of cardiovascular risk factors are essential for reducing the risk of coronary artery disease in HIV-infected individuals. Extensive efforts should also be made to develop effective cocaine use cessation programs for HIV-infected cocaine users. Lai, S., Fishman, E.K., Lai, H., Moore, R., Cofrancesco, Jr J., Pannu, H., Tong, W., Du, J., Bartlett, J. Clin. Infect. Dis. January 14, 2008 Epub ahead of print.

Impact of Drug Abuse Treatment Modalities on Adherence to ART/HAART Among a Cohort of HIV Seropositive Women

Methadone maintenance is associated with improved adherence to antiretroviral therapies among HIV-positive illicit drug users; however, little information exists on whether adherence is associated with different drug abuse treatment modalities. Using longitudinal data from the Women's Interagency HIV Study, the authors evaluated the relationship between drug abuse treatment modality and adherence to antiretroviral therapies. In prospective analyses, individuals who reported accessing any drug abuse treatment program were more likely to report adherence to antiretroviral regimens > or = 95% of the time (AOR = 1.39, 95% CI =1.01-1.92). Involvement in either a medication-based or medication-free program was similarly associated with improved adherence. Drug abuse treatment programs, irrespective of modality, are associated with improved adherence to antiretroviral therapies among drug users. Concerted efforts to enroll individuals with drug use histories in treatment programs are warranted to improve HIV disease outcomes. Kapadia, F., Vlahov, D., Wu, Y., Cohen, M.H., Greenblatt, R.M., Howard, A.A., Cook, J.A., Goparaju, L., Golub, E., Richardson, J., and Wilson, T.E. Am. J. Drug Alcohol Abuse. 34(2), pp. 161-170, 2008.

Attribution of Menopause Symptoms in Human Immunodeficiency Virus-Infected or At-Risk Drug-Using Women

The objective of this study was to examine the relationship of human immunodeficiency virus (HIV) and attribution of menopausal symptoms. Peri- and postmenopausal women participating in a prospective study of HIV-infected and at-risk midlife women (the Ms. Study) were interviewed to determine whether they experienced hot flashes and/or vaginal dryness and to what they attributed these symptoms. Of 278 women, 70% were perimenopausal; 54% were HIV-infected; and 52% had used crack, cocaine, heroin, and/or methadone within the past 5 years. Hot flashes were reported by 189 women and vaginal dryness was reported by 101 women. Overall, 69.8% attributed hot flashes to menopause and 28.7% attributed vaginal dryness to menopause. In bivariate analyses, age 45 years and older was associated with attributing hot flashes and vaginal dryness to menopause, and postmenopausal status and at least 12 years of education were associated with attributing vaginal dryness to menopause, but HIV status was not associated with attribution to menopause. In multivariate analysis, significant interactions between age and menopause status were found for both attribution of hot flashes (P = 0.019) and vaginal dryness (P = 0.029). Among perimenopausal women, older age was independently associated with attribution to menopause for hot flashes (adjusted odds ratio = 1.2, 95% CI: 1.1-1.4, P = 0.001) and vaginal dryness (adjusted odds ratio = 1.3, 95% CI: 1.1-1.6, P = 0.011). None of the tested factors were independently associated with attribution to menopause among postmenopausal women. The authors conclude that tailored health education programs may be beneficial in increasing the knowledge about menopause among HIV-infected and drug-using women, particularly those who are perimenopausal. Johnson, T.M., Cohen, H.W., Howard, A.A., Santoro, N., Floris-Moore, M., Arnsten, J.H., Hartel, D.M., and Schoenbaum, E.E. Menopause, January 9, 2008 Epub ahead of print.

Drug Use and Other Risk Factors Related to Lower Body Mass Index Among HIV-Infected Individuals

Malnutrition is associated with morbidity and mortality in HIV-infected individuals. Little research has been conducted to identify the roles that clinical, illicit drug use and socioeconomic characteristics play in the nutritional status of HIV-infected patients. This cross-sectional analysis included 562 HIV-infected participants enrolled in the Nutrition for Healthy Living study conducted in Boston, MA and Providence, RI. The relationship between body mass index (BMI) and several covariates (type of drug use, demographic, and clinical characteristics) were examined using linear regression. Overall, drug users had a lower BMI than non-drug users. The BMI of cocaine users was 1.4kg/m(2) less than that of patients who did not use any drugs, after adjusting for other covariates (p=0.02). The BMI of participants who were over the age of 55 years was 2.0kg/m(2) less than that of patients under the age of 35, and BMI increased by 0.3kg/m(2) with each 100cells/mm(3) increase in CD4 count. HAART use, adherence to HAART, energy intake, AIDS status, hepatitis B and hepatitis C co-infections, cigarette smoking and depression were not associated with BMI in the final model. In conclusion, BMI was lower in drug users than non-drug users, and was lowest in cocaine users. BMI was also directly associated with CD4 count and inversely related to age more than 55 years old. HIV-infected cocaine users may be at higher risk of developing malnutrition, suggesting the need for anticipatory nutritional support. Quach, L.A., Wanke, C.A., Schmid, C.H., Gorbach, S.L., Mkaya Mwamburi, D., Mayer, K.H., Spiegelman, D., and Tang, A.M. Drug Alcohol Depend. 95(1-2), pp. 30-36. Epub February 19, 2008.

The Challenge of Hepatitis C in the HIV-Infected Person

Hepatitis C virus (HCV) coinfection occurs in an estimated one quarter of HIV-infected persons in Europe, Australia, and the United States. As use of highly active antiretroviral drugs has markedly reduced opportunistic infections, HCV-related liver disease has emerged as a leading cause of death. HIV infection adversely affects both the natural history and the treatment of hepatitis C. Because there are no experimental models of coinfection and because the pathogenesis of each infection is incompletely understood, how HIV infection alters hepatitis C is not clear. This review considers the epidemiology, natural history, treatment, and pathogenesis of hepatitis C in HIV-infected persons. Thomas, D.L. Annual Rev. Med., 59, pp. 473-485, 2008.

Limited Uptake of Hepatitis C Treatment Among Injection Drug Users

The authors characterized hepatitis C virus (HCV) treatment knowledge, experience and barriers in a cohort of community-based injection drug users (IDUs) in Baltimore, MD. In 2005, a questionnaire on HCV treatment knowledge, experience and barriers was administered to HCV-infected IDUs. Self-reported treatment was confirmed from medical records. Of 597 participants, 71% were male, 95% African-American, 31% HIV co-infected and 94% were infected with HCV genotype 1; 70% were aware that treatment was available, but only 22% understood that HCV could be cured. Of 418 who had heard of treatment, 86 (21%) reported an evaluation by a provider that included a discussion of treatment of whom 30 refused treatment, 20 deferred and 36 reported initiating treatment (6% overall). The most common reasons for refusal were related to treatment-related perceptions and a low perceived need of treatment. Compared to those who had discussed treatment with their provider, those who had not were more likely to be injecting drugs, less likely to have health insurance, and less knowledgeable about treatment. Low HCV treatment effectiveness was observed in this IDU population. Comprehensive integrated care strategies that incorporate education, case-management and peer support are needed to improve care and treatment of HCV-infected IDUs. Mehta, S.H., Genberg, B.L., Astemborski, J., Kavasery, R., Kirk, G.D., Vlahov, D., Strathdee, S.A., and Thomas, D.L. J. Community Health. 33(3), pp. 126-133, 2008.

Rapid Fibrosis Progression Among HIV/Hepatitis C Virus-Co-Infected Adults

The objectives of this study were to define the incidence of fibrosis progression among hepatitis C virus (HCV)/HIV-co-infected adults, to assess whether HCV or HIV treatment alters the risk of progression, and to determine the utility of liver biopsy to predict future disease. This prospective cohort evaluated 184 HIV/HCV-co-infected individuals who had at least two liver biopsies (median interval 2.9 years). Biopsies were scored according to the Ishak modified histological activity index scoring system by a single pathologist blind to biopsy sequence. Significant fibrosis progression was defined as an increase of at least two Ishak fibrosis units between the first and second liver biopsy. Logistic regression analysis was used to assess determinants of fibrosis progression. A total of 174 non-cirrhotic patients were eligible; the majority were African-American men undergoing HIV treatment. On initial biopsy, no or minimal fibrosis was identified in 136 patients (77%). Significant fibrosis progression occurred in 41 patients (24%). Measures of HIV disease and its treatment before and after initial biopsy were not significantly different in progressors and non-progressors. Fibrosis progression was not associated with HCV treatment, which was received by 37 patients (21%) but only three sustained HCV-RNA suppression. In adjusted analysis, only an elevated serum aspartate aminotransferase level between biopsies was associated with progression (odd ratio 3.4, 95% confidence interval 1.4-7.9). The authors conclude that over a 3-year interval, significant fibrosis progression can occur in co-infected individuals even if minimal disease was detected on initial biopsy. In this context, factors other than treatment for HIV or HCV modify the risk of fibrosis progression. Sulkowski, M.S., Mehta, S.H., Torbenson, M.S., Higgins, Y., Brinkley, S.C., de Oca, R.M., Moore, R.D., Afdhal, N.H., and Thomas, D.L. AIDS. 21(16), pp. 2209-2216, 2007.

Co-Morbid Medical and Psychiatric Illness and Substance Abuse in HCV-Infected and Uninfected Veterans

Comorbidities may affect the decision to treat chronic hepatitis C virus (HCV) infection. The authors undertook this study to determine the prevalence of these conditions in the HCV-infected persons compared with HCV-uninfected controls. Demographic and comorbidity data were retrieved for HCV-infected and -uninfected subjects from the VA National Patient Care Database using ICD-9 codes. Logistic regression was used to determine the odds of comorbid conditions in the HCV-infected subjects. HCV-uninfected controls were identified matched on age, race/ethnicity and sex. The authors identified 126,926 HCV-infected subjects and 126,926 controls. The HCV-infected subjects had a higher prevalence of diabetes, anemia, hypertension, chronic obstructive pulmonary disease (COPD)/asthma, cirrhosis, hepatitis B and cancer, but had a lower prevalence of coronary artery disease and stroke. The prevalence of all psychiatric comorbidities and substance abuse was higher in the HCV-infected subjects. In the HCV-infected persons, the odds of being diagnosed with congestive heart failure, diabetes, anemia, hypertension, COPD/asthma, cirrhosis, hepatitis B and cancer were higher, but lower for coronary artery disease and stroke. After adjusting for alcohol and drug abuse and dependence, the odds of psychiatric illness were not higher in the HCV-infected persons. The prevalence and patterns of comorbidities in HCV-infected veterans are different from those in HCV-uninfected controls. The association between HCV and psychiatric diagnoses is at least partly attributable to alcohol and drug abuse and dependence. These factors should be taken into account when evaluating patients for treatment and designing new intervention strategies. Butt, A.A., Khan, U.A., McGinnis, K.A., Skanderson, M., and Kent Kwoh, C. J. Viral Hepat. 14(12), pp. 890-896, 2007.

Impact of Hepatitis C Virus Infection and other Comorbidities on Survival in Patients on Dialysis

The impact of hepatitis C virus (HCV) and other comorbid conditions upon survival is not well quantified in patients on dialysis. The authors identified HCV-infected and uninfected persons in the USRDS using claims data in 1997-1998 and followed until September 22, 2002 or death. They used Gray's time-varying coefficients model to examine factors associated with survival. Subjects with a renal transplant were excluded. A total of 5737 HCV-infected and 11 228 HCV-uninfected persons were identified. HCV-infected subjects were younger (mean age 57.8 vs 65.3 years), more likely to be male (57.6%vs 49.6%) and black (54.0%vs 36.4%). They were more likely to have a diagnosis of drug (16.5%vs 4.6%) and alcohol use (14.0%vs 3.1%), and to be human immunodeficiency virus (HIV) co-infected (7.4%vs 1.8%) (all comparisons, P < 0.0005). In an adjusted Gray's time-varying coefficient model, HCV was associated with an increased risk of mortality (P < 0.0005). The hazards were highest at the time of HCV diagnosis and decreased to a stable level 2 years after diagnosis. Other factors associated with increased risk of mortality were (P < 0.0005 unless stated) HIV coinfection; diagnosis of drug use (P = 0.001); coronary artery disease (P = 0.006); stroke; diabetes as the primary cause for renal failure; peripheral vascular disease; depression and presence of anemia. HCV was associated with higher risk of death in patients on dialysis, even after adjusting for concurrent comorbidities. The risk was highest at the time of HCV diagnosis and stabilized over time. Clinical trials of HCV screening and treatment to reduce mortality in this population are warranted. Butt, A.A., Skanderson, M., McGinnis, K.A., Ahuja, T., Bryce, C.L., Barnato, A.E., and Chang, C.C. J. Viral Hepat. 14(10), pp. 688-696, 2007.

Biochemical and Virologic Parameters in Patients Co-Infected with Hepatitis C and HIV Versus Patients with Hepatitis C Mono-Infection

Previous studies of patients with hepatitis C virus (HCV) infection looking at the effect of human immunodeficiency virus (HIV) co-infection on biochemical parameters and HCV RNA level have shown conflicting results. Accurate characterization of the effect of HIV is important for evaluation and treatment of HCV in co-infected persons. The authors studied 315 HCV mono-infected and 75 HCV-HIV co-infected subjects to determine the effect of HIV on biochemical parameters and HCV RNA and to determine the predictors of elevated serum alanine aminotransferase (ALT) levels and HCV RNA levels. Results showed that the co-infected subjects were more likely to be African-American (55% vs 26%, P < 0.0005), have used injection drugs (68% vs 60%, P = 0.02), have detectable HCV RNA (84% vs 70.5%, P = 0.018), have HCV RNA levels >6 log10 IU/mL (60% vs 38%, P = 0.001), and have lower mean serum ALT levels (50.4 IU/mL vs 73.7 IU/mL, P = 0.006). In multivariable analyses, the following factors predicted an ALT level >50 IU/mL: log10 HCV RNA (OR, 1.15; 95% CI, 1.00 to 1.32); HIV co-infection (OR, 0.48; 95% CI, 0.25 to 0.89); and having ever been treated for HCV (OR, 1.92; 95% CI, 1.16 to 3.18). The only significant predictor of HCV RNA level >6 log10 IU/mL was HIV co-infection (OR, 2.75; 95% CI, 1.46 to 5.15). Significant predictors of having a detectable HCV RNA level were female sex (OR, 3.81; 95% CI, 1.18 to 12.25); HIV co-infection (2.45; 95% CI, 1.14 to 5.26); and ever being treated for HCV (OR, 1.96; 95% CI, 1.10 to 3.48). The authors conclude that HCV-HIV co-infected persons have higher HCV RNA levels but lower serum ALT levels than HCV mono-infected patients. Criteria for performing liver biopsy and treating HCV infection in co-infected patients may need to be revisited. Butt, A.A., Tsevat, J., Ahmad, J., Shakil, A.O., Mrus, J.M. Am. J. Med. Sci. 333(5), pp. 271-275, 2007.

Molecular and Bioinformatic Evidence of Hepatitis C Virus Evolution in Brain

Neurocognitive deficits in patients with hepatitis C virus (HCV) infection prompted a search for HCV in brain. HCV was present in the brains of 7 (54%) of 13 patients with viremia, as determined by 5' UTR and E1 (envelope 1) gene analysis. Brain HCV RNA consensus sequences differed from those in plasma and liver in 4 (57%) of 7 patients. The quality of HCV RNA from postmortem brain and liver was assessed and demonstrated to be suitable for sequence analysis. Quasispecies analysis revealed that several mutations present in clones from >1 brain region were absent in clones from liver and plasma. Brain-specific mutations defined several families of related sequences. The patterns of brain-specific mutations in these families were consistent with the evolution of HCV RNA from a common ancestor. Single-nucleotide-polymorphism analysis confirmed that a prominent brain-specific mutation constituted approximately 10% of HCV RNA in cerebellum and medulla but that this mutation was undetectable in the liver and plasma of the same patient. This study introduces novel methods for assessing RNA from postmortem samples. It increases the reported cases of HCV in the brain, provides the first E1 sequences from the brain, and contributes to the growing evidence that HCV replicates and evolves within the brain. Fishman, S.L., Murray, J.M., Eng, F.J., Walewski, J.L., Morgello, S., and Branch, A.D. J. Infect. Dis. 197(4), pp. 597-607, 2008.

Evidence for a Functional RNA Element in the Hepatitis C Virus Core Gene

In the core protein-coding region of hepatitis C virus (HCV), evidence exists for both phylogenetically conserved RNA structures and a +1 alternative reading frame (ARF). To investigate its role in HCV infection, the authors introduced four stop codons into the ARF of a genotype 1a H77 molecular clone. The changes did not alter the core protein sequence, but were predicted to disrupt RNA secondary structures. An attenuated infection was established after inoculation of the mutant HCV RNA into an HCV naive chimpanzee. The acute infection was atypical with low peak viremia, minimal alanine aminotransferase elevation, and early virus control by a diverse adaptive immune response. Sequencing circulating virus revealed progressive reversions at the third and then fourth stop codon. In cell culture, RNA replication of a genome with four stop codons was severely impaired. In contrast, the revertant genome exhibited only a 5-fold reduction in replication. Genomes harboring only the first two stop codons replicated to WT levels. Similarly, reversions at stop codons 3 and 4, which improved replication, were selected with recombinant, infectious HCV in cell culture. The authors conclude that ARF-encoded proteins initiating at the polyprotein AUG are not essential for HCV replication in cell culture or in vivo. Rather, these results provide evidence for a functionally important RNA element in the ARF region. McMullan, L.K., Grakoui, A., Evans, M.J., Mihalik, K., Puig, M., Branch, A.D. Feinstone, S.M., and Rice, C.M. Proc. Natl. Acad. Sci. U S A. 104(8), pp. 2879-2884, 2007. Epub 2007 February 13, 2007.

Clinicopathologic Correlates of Hepatitis C Virus in Brain: A Pilot Study

Hepatitis C virus (HCV) has been detected in the brain tissues of 10 individuals reported to date; it is unclear what clinical factors are associated with this, and with what frequency it occurs. Accordingly, a pilot analysis utilizing reverse transcriptase-polymerase chain reaction (RT- PCR) to detect and sequence HCV in premortem plasma and postmortem brain and liver from 20 human immunodeficiency virus (HIV)-infected and 10 HIV-naive individuals was undertaken. RNA encoding the first 126 amino acids of the HCV E1 envelope protein and the majority of the E1 signal sequence was analyzed in parallel with an 80-base-long segment of the 5' untranslated region (UTR). Liver HCV was detected only in subjects with premortem HCV viremia (10 HIV-infected and 3 HIV-naive). Brain HCV was detected in 6/10 HCV/HIV-coinfected and 1/3 HCV-monoinfected subjects. In the setting of HIV, the magnitude of plasma HCV load did not correlate with the presence of brain HCV. However, coinfected patients with brain HCV were more often off antiretroviral therapy and tended to have higher plasma HIV loads than those with HCV restricted to liver. Furthermore, premortem cerebrospinal fluid (CSF) analysis revealed that HCV/HIV-coinfected patients with brain HCV had detectable CSF HIV, whereas those without brain HCV had undetectable CSF HIV loads (P = .0205). Neuropsychologic tests showed a trend for hierarchical impairment of abstraction/executive functioning in HIV/HCV coinfection, with mean T scores for HIV monoinfected patients 43.2 (7.3), for liver-only HCV 39.5 (9.0), and for those with HCV in brain and liver 33.2 (5.1) (P = .0927). Predominant brain HCV sequences did not match those of the plasma or liver in 4 of the 6 coinfected patients analyzed. The authors conclude that in the setting of HIV/HCV coinfection, brain HCV is a common phenomenon unrelated to the magnitude of HCV viremia, but related to active HIV disease and detectable CSF HIV. Furthermore, there is sequence evidence of brain compartmentalization. Differences in abstraction/executive function of HCV/HIV coinfected patients compared to HIV monoinfected warrant further studies to determine if neuropsychiatric effects are predicated upon brain infection. Murray, J., Fishman, S.L., Ryan, E., Eng, F.J., Walewski, J.L., Branch, A.D., and Morgello, S. J. Neurovirol. 14(1), pp. 17-27, 2008.

The Insulin-like Growth Factor Axis and Risk of Liver Disease in Hepatitis C Virus/HIV-Co-Infected Women

Insulin-like growth factor (IGF) I stimulates the proliferation of hepatic stellate cells (HSC), the primary source of extracellular matrix accumulation in liver fibrosis. In contrast, insulin-like growth factor binding protein (IGFBP) 3, the most abundant IGFBP in circulation, negatively modulates HSC mitogenesis. To investigate the role of the IGF axis in hepatitis C virus (HCV)-related liver disease among high-risk patients, the authors prospectively evaluated HCV-viremic/HIV-positive women. This study comprised a cohort investigation in which total IGF-I and IGFBP-3 were measured in baseline serum specimens obtained from 472 HCV-viremic/HIV-positive subjects enrolled in the Women's Interagency HIV Study, a large multi-institutional cohort. The aspartate aminotransferase to platelet ratio index (APRI), a marker of liver fibrosis, was assessed annually. Normal APRI levels (< 1.0) at baseline were detected in 374 of the 472 HCV-viremic/HIV-positive subjects tested, of whom 302 had complete liver function test data and were studied. IGF-I was positively associated [adjusted odds ratio comparing the highest and lowest quartiles (AORq4-q1), 5.83; 95% confidence interval (CI) 1.17-29.1; Ptrend = 0.03], and IGFBP-3 was inversely associated (AORq4-q1, 0.13; 95% CI 0.02-0.76; Ptrend = 0.04), with subsequent (incident) detection of an elevated APRI level (> 1.5), after adjustment for the CD4 T-cell count, alcohol consumption, and other risk factors. The authors conclude that high IGF-I may be associated with increased risk and high IGFBP-3 with reduced risk of liver disease among HCV-viremic/HIV-positive women. Strickler, H.D., Howard, A.A., Peters, M., Fazzari, M., Yu, H., Augenbraun, M., French, A.L., Young, M., Gange, S., Anastos, K., and Kovacs, A. AIDS. 22(4), pp. 527-531, 2008.

Hepatitis C Infection is Associated with Lower Lipids and High-Sensitivity C-Reactive Protein in HIV-Infected Men

Increased cardiovascular risk has been linked to HIV infection and combination antiretroviral therapy, but the impact of hepatitis C virus (HCV) status on indices of cardiovascular risk has not been routinely assessed in the HIV-infected population. The objective of this study was to analyze associations of HCV, HIV, and combination antiretroviral therapy with lipid levels and C-reactive protein (CRP) among older men. The authors measured fasting total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and high-sensitivity CRP serum levels in a cross-sectional study of 108 HIV-infected and 74 HIV-uninfected at-risk older men. One hundred ten men (60%) had detectable HCV RNA, with no difference by HIV status (p = 0.25). The majority (88%) of men with HCV infection had a history of injection drug use. Among all men, HCV infection was independently associated with lower total cholesterol (p < 0.001), LDL-C (p < 0.001), triglycerides (p = 0.01), and CRP (p = 0.001). Among HIV-infected men, HCV infection was associated with lower total cholesterol (p < 0.001), LDL-C (p < 0.001), and CRP (p = 0.004). HCV infection was associated with lower triglycerides among men on protease inhibitors (PI) (p = 0.02) and non-PI combination antiretroviral therapy (p=0.02), but not among antiretroviral-naive men. These findings demonstrate an association of lower serum lipid and CRP levels with HCV infection and suggest that HCV status should be assessed as an important correlate of cardiovascular risk factors in studies of older men with or at risk for HIV. Floris-Moore, M., Howard, A.A., Lo, Y., Schoenbaum, E.E., Arnsten, J.H., and Klein, R.S. AIDS Patient Care STDS. 21(7), pp. 479-491, 2007.

Immune Status at Presentation to Care Did not Improve among Antiretroviral-Naive Persons from 1990 to 2006

Human immunodeficiency virus (HIV) prevention initiatives to improve access to HIV services have increased over time. Despite this, >250,000 cases of HIV infection in the US are undiagnosed, and many infected persons do not present for care until their HIV infection is advanced. Late presentation may increase the risk of HIV transmission and make HIV infection more difficult to treat effectively. With more effective HIV therapy, it has been the hope that patients might present earlier in their disease course. To assess immune status and time of HIV diagnosis in patients who newly presented for care, researchers analyzed data for the period 1990-2006 from patients who were antiretroviral naive at presentation to the Johns Hopkins HIV Clinic in Baltimore, Maryland. They compared CD4 (+) cell count and time from HIV diagnosis at presentation by demographic characteristics at enrollment. The median presenting CD4(+) cell count decreased from 371 cells/mm(3) during 1990-1994 to 276 cells/mm(3) during 2003-2006 (P<.01) overall and decreased within individual demographic groups. There was also a decrease in the median time from HIV diagnosis to presentation for care (271 days in 1990-1994 to 196 days in 2003-2006; P<.01). Multivariate analysis revealed that, in addition to CD4(+) cell count at presentation, male sex was associated with lower CD4(+) cell counts (-93 cells/mm(3)), as was black race (-71 cells/mm(3)) and older age (-20 cells/mm(3) per 10 years). These findings show that there has been a decrease in time from diagnosis of HIV infection to presentation for care, coupled with an increase in the severity of immunodeficiency at time of presentation, over the past 16 years in Maryland. The findings highlight the urgent need to develop effective strategies for providing earlier HIV testing and referral into care. Keruly, J., and Moore, R. Immune Status at Presentation to Care Did not Improve among Antiretroviral-Naive Persons from 1990 to 2006. Clin. Infect. Dis., 45(10), pp. 1369-1374, 2007.

Herpes Simplex Virus-2 and HIV among Noninjecting Drug Users in New York City

This study sought to examine the relationship between herpes simplex virus 2 (HSV-2) seroprevalence and HIV seroprevalence among noninjecting heroin and cocaine users in New York City. Four hundred sixty-two noninjecting cocaine and heroin users were recruited from a drug detoxification program in New York City. Smoking crack cocaine, intranasal use of heroin, and intranasal use of cocaine were the most common types of drug use. A structured interview was administered and a serum sample was collected for HIV and HSV testing. HIV prevalence was 19% (95% CI 15%-22%) and HSV-2 seroprevalence was 60% (95% CI 55%-64%). The adjusted risk ratio for the association between HSV-2 and HIV was 1.9 (95% CI 1.21%-2.98%). The relationship between HSV-2 and HIV was particularly strong among females, among whom 86% were HSV-2 seropositive, 23% were HIV seropositive, and all HIV seropositives were also HSV-2 seropositive. The findings suggest that HSV-2 is an important factor in sexual transmission of HIV among noninjecting cocaine and heroin users in New York City, especially among females. The estimated population attributable risk for HIV infection attributable to HSV-2 infection in this sample was 38%, underscoring the importance of programs to manage HSV-2 infection as part of comprehensive HIV prevention for noninjecting drug users. Des Jarlais, D., Hagan, H., Arasteh, K., McKnight, C., Perlman, D., and Friedman, S. Herpes Simplex Virus-2 and HIV among Non Injecting Drug Users in New York City. Sex Transm. Dis., 34(11), pp. 923-927, 2007.

Factors Associated with the Prevalence and Incidence of Trichomonas Vaginalis Infection among African American Women in New York City Who Use Drugs

Trichomoniasis vaginalis, the most prevalent nonviral sexually transmitted infection, is associated with negative reproductive outcomes and increased HIV transmission and may be overrepresented among African Americans. A total of 135 African American women who used drugs were screened for Trichomonas vaginalis on >/=2 occasions between March 2003 and August 2005. Women were administered a structured questionnaire in a community-based research center, underwent serological testing for HIV and HSV-2, and were screened for Neisseria gonorrhoeae and Chlamydia trachomatis. Fifty-one women (38%) screened positive for T. vaginalis at baseline. Twenty-nine (31%) of 95 women with negative results of baseline tests became infected, for an incidence of 35.1 cases per 100 person-years at risk (95% confidence interval [CI], 23.5-49.0). Prevalent infection was associated with drug use in the past 30 days, and incident infection was associated with sexual behavior in the past 30 days, namely having >1 male sex partner. Women who reported having >1 partner were 4 times as likely as women with fewer partners to acquire T. vaginalis (hazard ratio, 4.3; 95% CI, 2.0-9.4). These findings suggest that T. vaginalis may be endemic in this community of African American women. A control strategy that includes T. vaginalis screening in nonclinical settings and rapid point-of-care testing could contribute to the disruption of transmission of this pathogen. Miller, M., Liao, Y., Gomez, A. M., Gaydes, C., and D'Mellow, D. Factors Associated with the Prevalence and Incidence of Trichomonas Vaginalis Infection Among African American Women in New York City Who Use Drugs. J. Infect. Dis., 197(4), pp. 503-509, 2008.

Risk Factors for Methadone Outside Treatment Programs: Implications for HIV Treatment among Injection Drug Users

Diversion of methadone outside treatment programs occurs, yet reasons for use of ''street methadone '' are characterized poorly. Self-medication for withdrawal symptoms is one plausible hypothesis. Among HIV-infected drug users, some antiretroviral medications can reduce potency of methadone, yet any association between such effects and the use of supplemental methadone sources remains undetermined. This study sought to estimate the frequency and risk factors for use of street methadone. Injection drug users (IDUs) recruited through extensive community outreach in 1988-89 and 1994 were followed semi-annually with questionnaires about health history, use of licit and illicit drugs including methadone and HIV-related assays. Analyses were performed using generalized estimating equation logistic regression. Of 2811 IDUs enrolled and eligible for analysis, 493 people reported use of street methadone over 12,316 person-years of follow-up (4.0/100 person-years). In multivariate analyses, street methadone use was more common among women, whites, those 40-59 years old, those who reported withdrawal symptoms, past methadone program attendance (6-12 months before visit), recent heroin injection with or without cocaine (but not cocaine alone), smoking or sniffing heroin and reported trading sex. Street methadone was not associated with HIV infection or treatment. The results suggest that older IDUs still using heroin may be using street methadone to treat signs of withdrawal. The absence of a higher rate of street methadone use in HIV seropositive IDUs reveals that antiretroviral/methadone interactions are not a primary determinant of use outside of treatment settings. Vlahov, D., O 'Driscoll, P., Mehta, S., Ompad, D., Gern, R., Galai, N., and Kirk, G. Risk Factors for Methadone Outside Treatment Programs: Implications for HIV Treatment among Injection Drug Users. Addiction, 102(5), pp. 771-777, 2007.

Early Immunologic and Virologic Responses to Highly Active Antiretroviral Therapy and Subsequent Disease Progression among HIV-Infected Injection Drug Users

Researchers examined the prevalence and prognostic value of early responses to highly active antiretroviral therapy (HAART) among community-based injection drug users (IDUs) in Baltimore. Virologic (HIV RNA <1000 copies/ml) and immunologic (CD4 >500 cells/ul or increase of 50 cells/ul from the pre-HAART level) responses were examined in the 1st year of HAART initiation. Cox regression was used to examine the effect of early response on progression to new AIDS diagnosis or AIDS-related death. Among 258 HAART initiators, 75(29%) had no response, 53(21%) had a virologic response only, 38(15%) had an immunologic response only and 92(36%) had a combined immunologic and virologic response in the first year of therapy. Poorer responses were observed in those who were older, had been recently incarcerated, reported injecting drugs, had not had a recent outpatient visit and had some treatment interruption within the 1st year of HAART. In multiple Cox regression analysis, the risk of progression was lower in those with combined virologic and immunologic response than in non-responders, (relative hazard [RH], 0.32; 95% confidence interval [CI], 0.17-0.60). Those with discordant responses had reduced risk of progression compared to non-responders but experienced faster progression than those with a combined response, although none of these differences was statistically significant. Early discordant and non response to HAART was common, often occurred in the setting of injection drug use and treatment interruption and was associated with poorer survival. Interventions to reduce treatment interruptions and to provide continuity of HIV care during incarceration among IDUs are needed to improve responses and subsequent survival. Mehta, S., Lucas, G., Astemborski, J., Kirk, G., Vlahov, D., and Galai, N. Early Immunologic and Virologic Responses to Highly Active Antiretroviral Therapy and Subsequent Disease Progression among HIV-Infected Injection Drug Users. AIDS Care, 19(5), pp. 637-645, 2007.

A Ten-Year Analysis of the Incidence and Risk Factors for Acute Pancreatitis Requiring Hospitalization in an Urban HIV Clinical Cohort

To assess the incidence of and risk factors for acute pancreatitis in HIV-infected patients in the contemporary highly active antiretroviral therapy (HAART) era, researchers evaluated all cases of acute pancreatitis requiring hospitalization between 1996 and 2006 in a cohort receiving care from Johns Hopkins Hospital's HIV clinic. A nested, case-control analysis was employed for initial episodes of acute pancreatitis, and conditional logistic regression was used to assess risk factors. Of 5970 patients followed for 23,460 person-years (PYs), there were 85 episodes of acute pancreatitis (incidence: 3.6 events/1000 PYs). The incidence of pancreatitis from 1996 to 2000 was 2.6 events/1000 PYs; the incidence from 2001 to 2006 was 5.1 events/1000 PYs (p = 0.0014, comparing rates in two time periods). In multivariate regression, factors associated with pancreatitis included female gender (adjusted odds ratio [AOR] 2.96 [1.69, 5.19]; p < 0.001); stavudine [an antiretroviral therapy} use (AOR 2.19 [1.16, 4.15]; p = 0.016); aerosolized pentamidine use (OR 6.27; [1.42, 27.63]; p = 0.015); and a CD4 count <50 cells/mm(3) (AOR 10.47 [3.33, 32.90]; p < 0.001). Race/ethnicity, primary HIV risk factor, HIV-1 RNA, and newer HAART regimens were not associated with an increased risk of pancreatitis after adjustment for the above factors. Pancreatitis remains a significant cause of morbidity in the HIV population in the HAART era. Acute pancreatitis is associated with female gender, severe immunosuppression, and stavudine and aerosolized pentamidine usage. Of note, newer antiretrovirals were not associated with an increased risk of pancreatitis. Riedel, D., Gebo, K., Moore, R., and Lucas, G. A Ten-Year Analysis of the Incidence and Risk Factors for Acute Pancreatitis Requiring Hospitalization in an Urban HIV Clinical Cohort. AIDS Patient Care STDS, 22(2), pp. 113-121, 2008.

End-Stage Renal Disease and Chronic Kidney Disease in a Cohort of African-American HIV-Infected and At-Risk HIV-Seronegative Participants Followed between 1988 and 2004

HIV-infected African-Americans are at increased risk of end-stage renal disease requiring renal replacement therapy (RRT). This study sought to compare the incidence of RRT in a cohort of 4509 HIV-infected and 1746 HIV-seronegative African-Americans and describe temporal trends in RRT and chronic kidney disease (CKD) in HIV infection. Incident RRT was defined by matching participant identifiers with the US Renal Data System; CKD was defined as an estimated glomerular filtration rate < 60 ml/min per 1.73m for >/= 3 months. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated by indirect adjustment. Risk factors for RRT were assessed by person-time methods and Poisson regression. RRT was initiated in 24 HIV-seronegative subjects over 13415 person-years of follow-up (SIR, 2.3; 95% CI, 1.5-3.4), in 51 HIV-infected participants without AIDS over 10780 person-years (SIR, 6.9; 95% CI, 5.1-9.0), and in 125 participants with AIDS over 9833 person-years. SIR, 16.1; 95% CI, 13.4-19.2). In HIV-infected African-Americans, RRT incidences were 5.8 and 9.7/1000 person-years in the pre-HAART and HAART eras, respectively (adjusted rate ratio 1.2; 95% CI, 0.8-1.9). In supplementary analyses, CKD incidence declined significantly in the HAART era compared with pre-HAART, but the CKD period prevalence increased. Nearly 1% of HIV-infected African-Americans initiated RRT annually, a rate that was similar in the HAART and pre-HAART eras. However, while new cases of CKD decreased, the prevalence of CKD increased in the HAART era. This increase reflects improvements in survival among individuals with HIV-associated CKD. Lucas, G., Mehta, S., Atta, M., Kirk, G., Galai, N., Vlahov, D., and Moore, R. End-Stage Renal Disease and Chronic Kidney Disease in a Cohort of African-American HIV-Infected and At-Risk HIV-Seronegative Participants Followed between 1988 and 2004. AIDS, 21(18), pp. 2435-2443, 2007.

Incidence and Outcomes of Malignancy in the HAART Era in an Urban Cohort of HIV-infected Individuals

This study sought to investigate trends, patient characteristics, and survival associated with AIDS-defining cancer (ADC) and non-AIDS defining cancer (NADC) in the HAART era. Retrospective analysis was conducted of all incident malignancies occurring in 1996-2005 among 2566 patients in an urban HIV clinic. Clinical profiles of NADC were compared with ADC and the general cohort. Incidence was examined by Poisson analysis. Standardized incidence ratios (SIR) compared cancer risk with that in the general population. Survival was analyzed by Kaplan-Meier and Cox proportional hazards models. Between 1996 and 2005, 138 ADC and 115 NADC were diagnosed. ADC rates decreased from 12.5 to 3.5 cases/1000 person-years (P < 0.001 for trend) while NADC rates increased from 3.9 to 7.1 cases/1000 person-years (P = 0.13 for trend). Incidence of the most common NADC was higher than expected, including cancers of the lung [n = 29; SIR, 5.5; 95% confidence interval (CI), 3.7-8.0], liver (n = 13, SIR, 16.5; 95% CI, 8.8-28.2), anus (n = 10; SIR, 39.0; 95% CI, 18.7-71.7), head and neck (n = 14; SIR, 5.1; 95% CI, 2.8-8.6), and Hodgkin's lymphoma (n = 8; SIR, 9.8; 95% CI, 4.2-19.2). Survival after cancer diagnosis did not differ between ADC and NADC. Advanced age was associated with NADC (P < 0.01 for trend) and increased mortality in ADC (age > or = 50 years adjusted hazard ratio, 2.21; 95% CI, 1.00-4.89). These findings show that rates of ADC decreased while NADC increased within this cohort. Several NADC occurred at rates significantly higher than expected, indicating that screening and suspicion for NADC should increase in care for HIV-infected patients. Long, J., Engels, E., Moore, R., and Gebo, K. Incidence and Outcomes of Malignancy in the HAART Era in an Urban Cohort of HIV-Infected Individuals. AIDS, 22(4), pp. 489-496, 2008.

Burden of HIV Infection among Aboriginal Injection Drug Users in Vancouver, British Columbia

Researchers sought to examine whether there were differential rates of HIV incidence among Aboriginal and non-Aboriginal IDU in a Canadian setting. Data were derived from 2 prospective cohort studies of IDU in Vancouver, British Columbia. Using the Kaplan-Meier method and Cox proportional hazards regression, the HIV incidence was compared among Aboriginal and non-Aboriginal participants. Overall, 2496 individuals were recruited between May 1996 and December 2005. Compared with that of non-Aboriginal persons, the baseline HIV prevalence was higher among Aboriginal persons (16.0% vs 25.1%; P<.001). Among participants who were HIV negative at baseline, the cumulative HIV incidence at 48 months was higher among Aboriginal persons (18.5% vs 9.5%; P<.001). In multivariate analyses, Aboriginal ethnicity was independently associated with elevated HIV incidence (relative hazard=1.59; 95% confidence interval=1.12, 2.26; P=.009). Aboriginal persons in Vancouver had a significantly elevated burden of HIV infection, which highlights the need for a culturally sensitive and evidence-based response that is proactive with HIV-prevention programs. Wood, E., Montaner, J., Li, K., Zhang, R., Barney, L., Strathdee, S., Tyndall, M., and Kerr, T. Burden of HIV Infection among Aboriginal Injection Drug Users in Vancouver, British Columbia. Am. J. Public Health, 98(3), pp. 515-519, 2008.

HIV Rates and Risk Behaviors are Low in the General Population of Men in Southern India but High in Alcohol Venues: Results from Two Probability Surveys

As the HIV epidemic continues to expand in India, empirical data are needed to determine the course of the epidemic for high-risk populations and the general population. Two probability surveys were conducted in Chennai slums among a household sample of men and alcohol venue patrons ("wine shops") to compare HIV and other sexually transmitted disease (STD) prevalence and to identify STD behavioral risk factors. The wine shop sample (n = 654) had higher rates of HIV and prevalent STDs (HIV, herpes simplex virus 2 [HSV-2], syphilis, gonorrhea, or Chlamydia) compared with the household sample (n = 685) (3.4% vs. 1.2%, P = 0.007 and 21.6% vs. 11.8%, P < 0.0001, respectively). High-risk behaviors in the household sample were rare (<4%), but 69.6% of wine shop patrons had >2 partners, 58.4% had unprotected sex with a casual partner, and 54.1% had exchanged sex for money in the past 3 months. A multivariate model found that older age, ever being married, ever being tested for HIV, and having unprotected sex in the past 3 months were associated with STD prevalence in wine shop patrons. Prevalent HIV and STDs, and sexual risk behaviors are relatively low among the general population of men; however, men who frequent alcohol venues practice high-risk behaviors and have high rates of STDs, including HIV, and are likely to have an important role in expanding the Indian epidemic. Go, V., Solomon, S., Srikrishnan, A., Sivaram, S., Johnson, S., Sripaipan, T., Murugavel, K., Latkin, C., Mayer, K., and Celentano, D. HIV Rates and Risk Behaviors are Low in the General Population of Men in Southern India but High in Alcohol Venues: Results from Two Probability Surveys. J. Acquir. Immune Defic. Syndr., 46(4), pp. 491-497, 2007.

Hepatitis C in Puerto Rico: A Time for Public Health Action

Studies investigating the seroprevalence of HCV infection have been carried out in diverse populations, showing an estimated worldwide prevalence of 3%. A seroprevalence survey conducted among randomly selected non-institutionalized adults aged 21-64 years in San Juan, Puerto Rico in 2001-2002 revealed that 6.3% were positive for HCV antibodies. These data suggest that Puerto Ricans are burdened with a significantly greater prevalence of HCV infection compared to the general United States population aged 20-69 years (0.9%-4.3%). This article reviews data from multiple studies and sources that, taken together, establish the need to address HCV infection in Puerto Rico with prompt and decisive public health actions. Some of these actions include (1) establish hepatitis C prevention as a priority for state and municipal public health authorities, (2) raise awareness and educate target populations about HCV transmission and prevention, (3) increase clinician awareness of the HCV reporting system and the epidemiology and management of hepatitis C, (4) increase availability of diagnosis and treatment facilities, (5) increase access to effective drug treatment services, and (6) develop appropriate control measures to help reduce continued transmission in correctional settings. Perez, C., Albizu, C., Pena, M., Torres, E., Reyes, J., Colon, H., Ortiz, A., and Suarez, E. Hepatitis C in Puerto Rico: A Time for Public Health Action. P. R. Health Sci. J., 26(4), pp. 395-400, 2007.

HIV Risks Among Gay- and Non-Gay-Identified Migrant Money Boys in Shanghai, China

Men having sex with men (MSM) now account for 7% of all HIV/AIDS cases in China and there is growing awareness that internal rural-to-urban migration might shift the HIV epidemic within China by broadening social and sexual mixing. About 70% of HIV/AIDS infections are among rural residents, of whom 80% are males and 60% aged 16-29. This young, male, rural-to-urban migrant population has been identified as the tipping point for the AIDS epidemic in China. A subgroup of these migrants is the ''money boy'' population, i.e. those who engage in same-sex transactional sex for economic survival. However, the literature addressing money boys is very limited. This study examined factors for preventing substance abuse and HIV among two types of money boys ''gay-identified'' and ''non-gay-identified'' living in the Shanghai metropolitan area. Results reveal gay and non-gay money boys were not significantly different in terms of age, income, marriage status and education. Both groups shared similar patterns of substance use. Both groups had high self-reported depressive symptoms and low HIV knowledge. However, sexual orientation differentially predicted HIV testing, with gay money boys more likely to be tested for HIV. Non-gay money boys showed fewer sexual risks. Additional HIV prevention strategies are needed which target MSM (including money boys) within rapidly changing China. Wong, F., Huang, Z., He, N., Smith, B., Ding, Y., Fu, C., and Young, D. HIV Risks among Gay- and Non-Gay-Identified Migrant Money Boys in Shanghai, China. AIDS Care, 20(2), pp. 170-180, 2008.

Substance Use and HIV Risks Among Male Heterosexual and 'Money Boy' Migrants in Shanghai, China

There is a growing awareness that internal migration in China might shift the HIV epidemic by broadening the social and sexual mixing of its population. However, little is known about how drug use/abuse might contribute to the spread of HIV. This qualitative study examined factors for preventing substance abuse and HIV among two types of male migrants living in the Shanghai metropolitan area; the general migrant population and so-called "money boys" (those who engaged in same-sex activities for money). Compared to most male migrants, the ''money boys'' had a slightly better economic situation; rarely visited their hometowns; used alcohol less but drugs more; had more knowledge about HIV and sexually transmitted diseases; higher HIV/ STD testing rates and fewer HIV risk behaviors. The general male migrants had more misconceptions about HIV (e.g. the need to pay for HIV testing) than the ''money boys". However, it was noted that ''money boys'' who were new to the enterprise and men who have sex with men but did not engage in commercial sex often lacked HIV knowledge and protective skills. Given the needs of various sub-types of ''migrants'', differential approaches to HIV prevention are needed. He, N., Wong, F., Huang, Z., Thompson, E., and Fu, C. Substance Use and HIV Risks Among Male Heterosexual and 'Money Boy ' Migrants in Shanghai, China. AIDS Care, 19(1), pp. 109-115, 2007.

HIV Risks Among Two Types of Male Migrants in Shanghai, China: Money Boys vs. General Male Migrants

This study examined HIV/AIDS-related knowledge, attitudes and behaviours among ''money boys'' (men who engage in same-sex transactional sex) and general male migrants in Shanghai, China. A quantitative cross-sectional design with self-administered paper-and-pencil instruments was used. A total of 239 money boys were enrolled using community popular opinion leader and respondent-driven sampling methods, and 100 general male migrants were enrolled through venue-based sampling. Compared to general male migrants, money boys were significantly younger, better educated, more likely to be single, earned a higher income, suffered greater stress, and were less satisfied with life in Shanghai. Both groups had substantial misconceptions about HIV/AIDS, although general male migrants were less well informed. Furthermore, both groups reported low rates of condom use, regardless of who their sexual partners were. Money boys were more likely to use alcohol, had more sexual partners and more casual sex partners, and were more likely to engage in other sexual risks. Moreover, they were likely to be the victims of sexual violence at the hands of their clients. More than half of the money boys had been tested for HIV and 3% self-reported to be HIV-positive, whereas only 1% of the general male migrants had ever been tested and all self-reported to be HIV-negative. Infection with other sexually transmitted diseases was also reported by money boys. This study suggests an urgent need to implement HIV/AIDS prevention and intervention programs targeting male migrants, especially money boys and their clients. He, N., Wong, F., Huang, Z., Ding, Y., Fu, C., Smith, B., Young, D., and Jiang, Q. HIV Risks Among Two Types of Male Migrants in Shanghai, China: Money Boys vs. General Male Migrants. AIDS, 21 Suppl 8, pp. S73-S79, 2007.

Oral Direct Renin Inhibition: Premise, Promise, and Potential Limitations of a New Antihypertensive Drug

The first oral direct renin inhibitor, aliskiren, recently received approval for the treatment of hypertension. This article addresses the premise, promise, and potential limitations of this new class of renin-angiotensin system inhibitor. Although aliskiren adds to a list of more than 100 drugs approved for the treatment of hypertension, its introduction into clinical medicine is of particular interest because of the novel mechanism of action: inhibition of renin's catalytic activity, the most proximal and rate-limiting step in renin-angiotensin system activation. By producing more complete renin-angiotensin system inhibition than with existing agents, direct renin inhibitors may afford greater protection from hypertensive complications. Other potential advantages include additional blood pressure reduction when used in combination therapy, a placebo-like side-effect profile, avid renal concentration, and long duration of action. Potential limitations include modest levels of blood pressure reduction that are equivalent to but not greater than angiotensin receptor blockers, reduced gastrointestinal absorption with a high-fat meal, and large reactive increases in renin secretion--the functional importance of which is under intense investigation. The results of outcomes trials are eagerly awaited. Shafiq, M.M., Menon, D.V., and Victor, R.G. Am. J. Med. 121(4), pp. 265-271, 2008.