Coinfection with HIV-1 and human T-Cell lymphotropic virus type II in intravenous drug users is associated with delayed progression to AIDS

Human T-cell lymphotropic virus (HTLV) type II has spread among intravenous drug users (IDUs), many of whom are coinfected with HIV-1. We have investigated the rate of HTLV-II infection in 3574 Italian IDUs screened for HIV-1, HTLV-I, and HTLV-II from 1986 to the present. HTLV-II proviral load was determined by a real-time polymerase chain reaction specifically designed for tax amplification. The frequency of HTLV-II infection was 6.7% among HIV-1-positive subjects and 1.1% among HIV-1-negative subjects (P < 0.0001). For examination of AIDS progression, a group of 437 HIV-1-monoinfected subjects and another group of 96 HIV-1/HTLV-II-coinfected subjects were monitored. Enrollees were matched at entry by CD4 cell counts and followed for an average of 13 years. HIV-1/HTLV-II coinfection was associated with older age (P < 0.0001) and higher CD4 (P < 0.0001) and CD8 (P < 0.001) cell counts compared with monoinfected IDUs. The number of long-term nonprogressors for AIDS was significantly higher (P < 0.0001) among coinfected patients (13 [13.5%] of 96 patients) than HIV monoinfected patients (5 [1.1%] of 437 patients), showing that HTLV-II exerts a protective role. An increased incidence of liver disease and hepatitis C virus positivity among coinfected IDUs was observed. Five coinfected subjects undergoing antiretroviral therapy showed a significant (P < 0.05) increase in HTLV-II proviral load concomitant to a decrease in HIV-1 viremia, suggesting that the treatment is ineffective against HTLV-II infection.     

Intrahepatic CD4+ cell depletion in hepatitis C virus/HIV-coinfected patients

Coinfection with HIV and hepatitis C virus (HCV)-specific immune responses, increases hepatic inflammation, accelerates hepatic fibrosis, and is associated with deceased treatment responses. We quantified intrahepatic lymphocyte and hepatocyte phenotypes in HCV-infected patients with (n = 38) and without (n = 41) HIV infection. A single pathologist counted positive cells in 5 portal and 5 lobular areas. Coinfected patients had 6.81 +/- 1.9 fewer CD4 cells per portal field (10.58 +/- 1.12 vs. 4.97 +/- 1.09 cells/high-power field [HPF]; P < 0.001) and 0.48 +/- 0.15 more apoptotic lymphocytes per lobular field (0.16 +/- 0.06 vs. 0.64 +/- 0.15 cell/HPF; P = 0.002) than monoinfected patients. The number of portal CD4 cells was not associated with the peripheral CD4 cell number. Portal and lobular CD8 cells did not differ between the 2 groups. Portal proliferative hepatocytes were increased in coinfected patients with HIV RNA levels of >400 copies/mL (1.13 +/- 0.32 cells/HPF; P = 0.01) compared with those with undetectable HIV RNA (0.46 +/- 0.09 cell/HPF) and monoinfected patients (0.45 +/- 0.08 cell/HPF). In conclusion, HIV coinfection is associated with fewer portal CD4 cells and increased lobular lymphocyte apoptosis that may impact on the natural history of HCV infection.     

Laboratory study of HIV-1 and HTLV-I/II coinfection

A Retroviral Coinfection Clinic was established in 1991 at Charity Hospital Medical Center of Louisiana to study patients dually infected with human immunodeficiency virus (HIV) and human T lymphotropic virus (HTLV-I, HTLV-II). Eight patients were evaluated clinically, and by immunological and virological studies. Multiple neuromuscular diseases were observed, including tropical spastic paraparesis, polymyositis, and polyneuropathies. Only one patient developed AIDS. HIV-1 infected patients with HTLV-I, but not HTLV-II, coinfection have maintained stable CD4 counts, despite the fact that quantitative HIV DNA PCR suggests a relatively high copy number. HTLV-I/II antigens were detected in lymphocyte cultures from four patients, and lymphoblastoid cell lines have been established from two. These results support the contention that upregulated HTLV-I/II virus expression and disease manifestations occur during coinfection with HIV, sometimes in association with normal CD4 counts. © 1994 Wiley-Liss, Inc.     

Characteristics of Treatment-naïve HBV-Infected Individuals with HIV-1 Coinfection: A Cross-sectional Study from South India

Purpose: Human immunodeficiency virus-1 (HIV-1) and hepatitis B virus (HBV) coinfection has become a major health problem across the globe. The increased life expectancy of HIV-1 patients due to antiretroviral therapy has led to the emergence of liver disease as a major mortality factor among them. The purpose of the study was to examine the baseline characteristics of HBV in treatment-naïve HBV/HIV coinfection from southern India compared to monoinfected individuals. Materials and Methods: The study was cross sectional in design, and samples were examined from 80 HIV-1, 70 HBV and 35 HBV/HIV-coinfected individuals using chemiluminescent microparticle immunoassay, real-time polymerase chain reaction and flow cytometry assays. Results: There was a significant increase in HBV DNA (P = 0.0001), higher hepatitis B e antigen percentage difference (P = 0.027) and lower CD4 counts (P = 0.01) among the HBV/HIV-coinfected individuals, but no difference in the HIV-1 viral load compared to HIV-1-monoinfected individuals. Also, the aspartate aminotransferase levels, prothrombin time and the international normalised ratio were significantly high among coinfected individuals. Conclusion: These findings conclude that HIV-1 coinfection can have serious implications on the outcome of HBV-related liver disease. To the contrary, HBV infection had no consequence on the progression of HIV-1 disease but distinctly lowered CD4+ T-cells.     

Expression of chemokine receptors CCR5 and CXCR4 on CD4+ T cells and plasma chemokine levels during treatment of active tuberculosis in HIV-1-coinfected patients

The pathogenesis of persistently elevated plasma HIV viremia in patients coinfected with tuberculosis (TB) during anti-TB treatment in Africans remains unknown. We examined the expression of chemokine receptors CCR5 and CXCR4 on CD4+ T cells and plasma chemokine levels of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, regulated on activation normal T expressed and secreted (RANTES), and stromal cell-derived factor (SDF)-1alpha among TB patients with HIV coinfection during the first 2 months of anti-TB treatment. During treatment of TB, the plasma HIV-1 load and CD4+ T-cell count remained unchanged. Levels of CCR5 and CXCR4 expression on CD4+ T cells as well as plasma levels of chemokines remained persistently elevated during anti-TB treatment. Persistently elevated plasma HIV viremia also paralleled persistently elevated expressions of activated CCR5+ or CXCR4+ CD4+ T cells. These results suggest that increased expression of CCR5 and CXCR4 on an activated CD4+ T-cell population coupled with persistently elevated chemokines may provide a suitable condition for continuous replication of HIV associated with TB coinfection. This, in turn, may contribute, at least in part, to the observed persistently elevated plasma HIV viremia in coinfected patients despite anti-TB treatment.     

Baseline CD4+ T-Cell Counts Predict HBV Viral Kinetics to Adefovir Treatment in Lamivudine-Resistant HBV-Infected Patients with or without HIV Infection

Abstract

Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. Methods: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. Results: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. Conclusion: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV.     

Molecular and cellular interactions of HIV-1/HTLV coinfection and impact on AIDS progression

In the last 10 years HIV-1/human T-cell leukemia virus (HIV-1/HTLV) coinfection has emerged as a worldwide health problem. The numbers of HIV-1/HTLV-1 coinfections in South America and Africa are increasing, as well as HIV-1/HTLV-2 coinfections in the USA and Europe. Coinfections by either HTLV-1 or HTLV-2 and HIV-1 frequently occur in persons with a history of injection drug use. Since HTLV-1 preferentially infects CD4+ T-cells and HTLV-2 has a tropism for CD8+ T-cells, the influence of coinfection on HIV-1 disease progression may be different. The effect of HIV-1/HTLV-1 coinfection on HIV-I pathogenesis is controversial as soluble factors produced by HTLV-1 infected cells can either enhance or suppress HIV-1 infection. In HTLV-1/HIV-1 coinfected patients, upregulation of HIV-1 expression was attributed to strong activation of cytokines that promoted HIV infection. The introduction of HAART has dramatically reduced HIV-1 morbidity and mortality, but has given rise to an increased number of inflammatory syndromes. While HAART is successful for controlling HIV disease, it has little impact on HTLV-1/2 genome expression. The consequence of coinfection, even with HAART, may well be the reported increase in neurologic disease. Several epidemiologic and in vitro studies of the influence of HTLV infection on HIV-1 related AIDS progression suggest that HTLV-1 infection can promote HIV-1 replication and accelerate the clinical progression to AIDS. However, other studies have not confirmed these observations. The differences in study outcomes could be related to the occurrence of different HIV-1 phenotypes in clinical disease. In contrast, evidence points to a confirmed protective role of HTLV-2 that is manifested as improved survival and delayed progression to AIDS. The protective effect may be the result of maintaining normal-range levels of CD4 and CD8 counts, lowering HIV replication, and immune activation. As a corollary, the number of long-term nonprogressors for AIDS in the HIV-1/HTLV-2 coinfected group was found to be significantly higher than in HIV-1 monoinfected cases. Investigations of the natural factors induced by HTLV-2 that influence HIV-1 replication show that CCL3L1 (an isoform of CCL3) is preferentially induced in HTLV-2 exposed seronegative HIV individuals and in long-term nonprogressor HTLV-2/HIV-1 coinfected persons. The CCL3L 1 inhibits HIV replication and thus acts as a potent effector against both HIV infection and disease progression. As a complement to upregulation of CCL3L1, other chemokines and cytokines induced by HTLV-2 may contribute to induction of the Th1 response against invading pathogens, in contrast to the dominant Th2 response that appears to favor HIV infection. The number of individuals with either single HIV-1 or HTLV-2 infection, in a cohort of Italian intravenous drug users monitored for 20 years, decreased significantly over time. However, the magnitude of HTLV-2 decrease was significantly less than that of HIV-1, pointing to the need for increased attention to, and control of, HTLV infection. In conclusion, the long-term effects of HIV and HTLV coinfections are poorly understood and the mechanisms of dysregulation of cellular biosynthesis by HTLV that impact HIV disease progression remain elusive.     

Effect of coinfection with GB virus C on survival among patients with HIV infection

BACKGROUND: Previous studies have suggested that people with human immunodeficiency virus (HIV) infection who are coinfected with GB virus C (GBV-C, or hepatitis G virus) have delayed progression of HIV disease. GBV-C is related to hepatitis C virus but does not appear to cause liver disease. METHODS: We examined the effect of coinfection with GBV-C on the survival of patients with HIV infection. We also evaluated cultures of peripheral-blood mononuclear cells infected with both viruses to determine whether GBV-C infection alters replication in vitro. RESULTS: Of 362 HIV-infected patients, 144 (39.8 percent) had GBV-C viremia in two tests. Forty-one of the patients with GBV-C viremia (28.5 percent) died during the follow-up period, as compared with 123 of the 218 patients who tested negative for GBV-C RNA (56.4 percent; P<0.001). The mean duration of follow-up for the entire cohort was 4.1 years. In a Cox regression analysis adjusted for HIV treatment, baseline CD4+ T-cell count, age, sex, race, and mode of transmission of HIV, the mortality rate among the 218 HIV-infected patients without GBV-C coinfection was significantly higher than that among the 144 patients with GBV-C coinfection (relative risk, 3.7; 95 percent confidence interval, 2.5 to 5.4). HIV replication, as measured by the detection of p24 antigen in culture supernatants, was reproducibly inhibited in cultures of peripheral-blood mononuclear cells by GBV-C coinfection. Coinfection did not alter the surface expression of HIV cellular receptors on peripheral-blood mononuclear cells, as determined by flow cytometry. CONCLUSIONS: GBV-C infection is common in people with HIV infection and is associated with significantly improved survival.     

CD4 T-cell count and HIV-1 infection in adults with uncomplicated malaria

BACKGROUND: HIV-1-negative children with malaria have reversible lymphocyte and CD4 count decreases. We assessed the impact of malaria parasitemia on the absolute CD4 count in both HIV-1-infected and non-HIV-infected adults. METHODS: In Ndola, Zambia, at the health-center level, we treated 327 nonpregnant adults for confirmed, uncomplicated, clinical malaria. We assessed HIV-1 status, CD4 count, and HIV-1 viral load (if HIV-1-infected) at enrollment and at 28 and 45 days after treatment. RESULTS: After successful antimalarial treatment, the median CD4 count at day 28 of follow-up increased from 468 to 811 cells/microL in HIV-1-negative and from 297 to 447 cells/microL in HIV-1-positive patients (paired t test, P < 0.001 for both). CD4 count increment was inversely correlated with CD4 count at day 0 in both HIV-1-negative (P < 0.001) and HIV-1-positive patients (P = 0.03). After successful treatment, the proportion of patients with CD4 count <200/microL at day 45 decreased from 9.6% to 0% in HIV-1-negative and from 28.7% to 13.2% in HIV-1-positive malaria patients (P < 0.001 for both). In patients with detectable but mostly asymptomatic parasitemia, CD4 count and, if HIV-1-infected, viral load at day 45 of follow-up were similar to those observed at enrollment. CONCLUSION: Interpretation of absolute CD4 count might be biased during or just after a clinical malaria episode. Therefore, in malaria-endemic areas, before taking any decision on the management of HIV-1-positive individuals, their malaria status should be assessed.     

Prevalence of cryoglobulinemia in hepatitis C virus (HCV) positive patients with and without human immunodeficiency virus (HIV) coinfection.

BACKGROUND: Coinfection with human immunodeficiency virus (HIV) has been shown to influence the natural history of hepatitis C infection. OBJECTIVE: Our interest was to determine if HIV coinfection influences the prevalence of cryoglobulinemia in hepatitis C virus (HCV) infected persons. STUDY DESIGN: A total of 384 HCV RNA positive (234 HIV-infected and 150 HIV-uninfected) participants were tested at two visits, 18 months apart, for HCV and HIV RNA, CD4, and liver enzyme levels. Serum cryoglobulin levels were measured at a subsequent visit for a subset of the sample. RESULTS: HIV-infected participants had significantly higher HCV RNA levels (P < 0.0001) and aspartate transaminase (AST) levels (P < 0.0001), but not alanine transaminase (ALT) levels (P > 0.05) as compared with HIV-uninfected participants. These findings were consistent at both visits and no significant changes were observed between visits. Fifty (19%) of the 264 participants tested had detectable cryoglobulins. No difference was observed in HIV seropositivity among participants with or without cryoglobulinemia (68% versus 61%; odds ratio = 1.34, P = 0.37). However, among HIV coinfected participants, elevated AST levels (P = 0.04) and lower CD4 levels (P = 0.02) were associated with cryoglobulinemia. CONCLUSIONS: While previously reported associations were found between HIV and coinfection with HCV in this study, we did not find an association between HIV infection and cryoglobulinemia.     

Association of HIV infection and HIV/HCV coinfection with C-reactive protein levels: the fat redistribution and metabolic change in HIV infection (FRAM) study

OBJECTIVE: Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)-infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy. DESIGN: Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression. RESULTS: Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV-infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively. CONCLUSIONS: In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.     

Coinfection with Schistosoma mansoni reactivates viremia in rhesus macaques with chronic simian-human immunodeficiency virus clade C infection

We tested the hypothesis that helminth parasite coinfection would intensify viremia and accelerate disease progression in monkeys chronically infected with an R5 simian-human immunodeficiency virus (SHIV) encoding a human immunodeficiency virus type 1 (HIV-1) clade C envelope. Fifteen rhesus monkeys with stable SHIV-1157ip infection were enrolled into a prospective, randomized trial. These seropositive animals had undetectable viral RNA and no signs of immunodeficiency. Seven animals served as virus-only controls; eight animals were exposed to Schistosoma mansoni cercariae. From week 5 after parasite exposure onward, coinfected animals shed eggs in their feces, developed eosinophilia, and had significantly higher mRNA expression of the T-helper type 2 cytokine interleukin-4 (P = 0.001) than animals without schistosomiasis. Compared to virus-only controls, viral replication was significantly increased in coinfected monkeys (P = 0.012), and the percentage of their CD4(+) CD29(+) memory cells decreased over time (P = 0.05). Thus, S. mansoni coinfection significantly increased viral replication and induced T-cell subset alterations in monkeys with chronic SHIV clade C infection.     

Characterization of membrane-bound IL-22+ T cell subsets in HIV-1 patients coinfected with Mycobacterium tuberculosis

BackgroundPreviously, we have found that IL-22 could be not only secreted outside of cells, but also highly expressed on the T cells membrane in HIV-1 negative patients with tuberculosis (TB). However, the study on membrane-bound IL-22+ cells of HIV-1 infected patients is rare. Therefore, we investigated antigen-specific membrane-bound IL-22+ T cell subsets in Mycobacterium tuberculosis (M.tb) coinfection of HIV-1 infected individuals.MethodsA case–control study that enrolled 74 HIV-1 infected participants was carried out, including HIV-1 monoinfection (HIV+TB?, n = 43), HIV-1 infected patients with latent TB (HIV+LTB, n = 18) and HIV-1 coinfected patients with active TB (HIV+TB+, n = 13). We made use of an IFN-γ release assay (IGRA) to screen LTB individuals. Purified protein derivative (PPD) and phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) were used as specific-stimulators to detect the levels of peripheral blood membrane-bound IL-22+ T cell subsets via cell surface staining and flow cytometry among three groups.ResultsAn approximate rate of 24.3% (n = 18 out of 74) of latent M.tb infection among HIV-1 positive population in Eastern China. Interestingly, HMBPP-specific CD3+Vγ2+ T cells were impaired in HIV+TB+patients compared with HIV+LTB patients (P < 0.05). Furthermore, increases of PPD-specific and HMBPP-specific membrane-bound IL-22+ T cell subsets including CD3+, CD3+CD4+ and CD3+Vγ2+ T cells were observed in HIV+TB+group rather than HIV+LTB groups (all P < 0.05).ConclusionAntigen-specific membrane-bound IL-22+ T cells were highly expressed in M.tb coinfection of HIV-1 infected individuals, and may play an important role in anti-TB immune response during coinfection with HIV-1.     

Comparison of hepatitis C viral loads in patients with or without human immunodeficiency virus.

A better understanding of how human immunodeficiency virus (HIV) coinfection affects the course of hepatitis C virus (HCV) infection is required to select patients with HIV who would benefit from current HCV therapy. Between June 1996 and March 2000, HCV RNA levels were quantified for 1,279 patients at the Louisiana State University Health Sciences Center; 28 of these patients were coinfected with HIV. HCV loads were quantified by the Bayer branched-DNA assay with a lower limit of detection of 0.2 Meq/ml. We compared the median HCV RNA levels of for patients coinfected with HIV and HCV and patients infected only with HCV who were in the same age range (23 to 55 years). The median HCV load for the 28 patients coinfected with HCV and HIV (17.8 Meq/ml) was significantly greater (P < 0.05) than that for similarly aged patients infected only with HCV (6.1 Meq/ml). The HCV load did not correlate with age or sex for either group of patients. A significant (R = -0.4; P < 0.05) negative correlation was observed between HCV load and CD4 count in the coinfected group, for whom the CD4 counts at the time of HCV load analysis ranged from 6 to 1,773/mm(3). The increased HCV load in patients coinfected with HCV and HIV compared to that in patients infected only with HCV and the inverse relationship of the HCV load to the CD4 count indicate that immunosuppression results in decreased control of HCV replication. In addition, we report significantly higher HCV loads among coinfected African Americans than Caucasians.     

Diagnosis and management of cirrhosis in coinfected patients

HIV coinfection is associated with faster progression of liver disease resulting from hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Thus, liver complications have become a major cause of illness and death in coinfected patients. Controlling HIV through highly active antiretroviral therapy may slow disease progression to nearly the rate of HIV-negative persons. Several antiretroviral regimens have been associated with drug-induced liver injury, however, which is more common in patients coinfected with hepatitis B or C. After development of cirrhosis and decompensation, survival is shorter in coinfected patients. Diagnosis and management of cirrhosis should be the same for coinfected and monoinfected HBV/HCV patients. The main complications of cirrhosis are ascites, spontaneous bacterial peritonitis, bleeding esophageal varices, hepatic encephalopathy, the hepatorenal syndrome, and hepatocellular carcinoma. Liver transplantation is feasible in patients with HIV infection, and early evaluation for this option is crucial because of the accelerated course of complications in HIV coinfection.     

A systematic review of the associations between HIV/HCV coinfection and biomarkers of cardiovascular disease

The incidence of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection has been increasing with over 10 million people affected globally. The role biomarkers play as predictors of cardiovascular disease (CVD) risk among coinfected individuals is not well defined. We aimed to systematically review current evidence describing CVD biomarkers among individuals with HIV/HCV coinfection. We searched EMBASE, CINAHL, Google Scholar, PubMed, and Web of Science from inception to June 2017. MeSH terms and keywords were used to identify studies with information on HIV/HCV coinfection and CVD biomarkers (structural, functional, and serological) such as carotid intima‐media thickness (CIMT), endothelial markers, C‐reactive protein (CRP), homocysteine, and lipids. Among 332 articles screened, 28 were included (39,498 participants). Study designs varied: 18 cross‐sectional, 9 cohort, and 1 clinical trial. Compared with healthy controls and people with HIV or HCV monoinfection, individuals with HIV/HCV coinfection had statistically significant lower levels of lipids and CRP and higher levels of endothelial markers (sICAM‐1 and sVCAM‐1), CIMT, homocysteine, and IL‐6. One study found the odds of carotid plaque in coinfected individuals was 1.64 (0.91–2.94) compared with healthy controls, and another study showed the prevalence of vascular plaques (carotid and femoral) in coinfected individuals was higher compared with HIV monoinfected individuals (44% vs 14%, P = 0.04). Biomarkers of CVD have different patterns of association with HIV/HCV coinfection compared with monoinfection and healthy controls. Prospective studies are needed to confirm the predictive value of these biomarkers for clinical CVD risk among coinfected individuals.     

HIV/hepatitis C virus-coinfected patients with normal alanine aminotransferase levels

BACKGROUND AND AIMS: The significance of normal alanine aminotransferase (ALT) levels in patients with HIV/hepatitis C virus (HCV) coinfection is not well understood. METHODS: We performed a cross-sectional retrospective analysis on consecutive HIV/HCV-coinfected patients (n = 89) who underwent a liver biopsy during a 2-year period. Similar data were also collected on HCV-monoinfected patients (n = 117). RESULTS: Mean ALT levels and the percentage of patients with normal ALT (< or =40 U/L) levels were similar in HIV/HCV-coinfected (mean +/- SD, 81.7 +/- 56.1 U/L; 21%) and HCV-monoinfected patients (97.3 +/- 100.7 U/L; 18%; P = 0.19 and 0.54, respectively). Coinfected patients, however, had significantly advanced necroinflammation (P= 0.001) and fibrosis (P = 0.02) compared with monoinfected patients. The percentage of patients with advanced necroinflammation (grades 3 or 4) was lower in HCV-monoinfected patients with normal ALT levels compared with those with elevated ALT (5% vs 20%, respectively). In contrast, the percentage of coinfected patients with advanced necroinflammation was similar whether the patient had normal or elevated ALT levels (32% vs 37%, respectively). CONCLUSIONS: In coinfected patients, normal ALT levels are not an indicator of mild necroinflammation and may not portend a more benign disease course.     

GBV-C coinfection is negatively correlated to Fas expression and Fas-mediated apoptosis in HIV-1 infected patients

Persistent coinfection with the apathogenic GB virus C (GBV-C) is associated with slower disease progression of human immunodeficiency virus (HIV)-1 infection. Aim of this study was to investigate whether Fas plays a role in this beneficial effect. Fas expression and susceptibility to Fas-mediated apoptosis (FMA) was analyzed in peripheral blood mononuclear cells (PBMCs) of HIV-1 patients coinfected and non-coinfected with GBV-C. Fas expression and function was evaluated in 42 GBV-C coinfected and 101 non-coinfected HIV-1 patients. Thirteen healthy and 11 Hepatitis C virus (HCV)-monoinfected individuals were analyzed as controls. Cell surface Fas expression was determined by flow cytometric analysis. Apoptosis was evaluated by staining with Annexin V and Viaprobe followed by multiparameter flow cytometry analysis. In untreated HIV-1 patients GBV-C coinfection was associated with significantly lower percentage of Fas expressing cells as compared to GBV-C non-coinfected individuals. Expression of Fas was directly correlated with sensitivity to Fas-mediated apoptosis. Sensitivity to FMA was unchanged in GBV-C coinfected patients. PBMCs of patients receiving highly active antiretroviral therapy (HAART) did not show such a difference. Untreated HIV-1 patients with GBV-C coinfection have reduced cell surface Fas expression. Lower FMA of T-cells might contribute to prolonged survival of GBV-C coinfected HIV-1 patients.     

Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection

Antiretroviral therapy (ART) has a significant impact on HIV-1 RNA levels, the CD4 cell count, and immune activation. We examined whether these changes are associated with a change in the rate of tryptophan degradation (expressed as the kynurenine to tryptophan ratio, kyn/trp) as an estimate for the activity of interferon-gamma inducible enzyme indoleamine (, )-dioxygenase (IDO). Plasma levels of tryptophan, kynurenine, and neopterin were measured pretherapy and 6 months postinitiation of therapy in 45 patients with HIV-1 RNA levels of less than 1000 copies/ml 6 months after initiation of ART. Before ART, the patients had decreased tryptophan and increased kynurenine concentrations compared to healthy controls. During ART, average tryptophan levels increased; in the same time kynurenine and kyn/trp decreased (P < 0.001), although not to normal levels. Since pretherapy tryptophan concentrations correlated inversely with neopterin, and kynurenine correlated with viral load and neopterin but not with CD4 cell count, the data support the view that HIV production may induce immune activation and consequently tryptophan is degraded at a higher rate. In agreement, kyn/trp positively correlated with neopterin (r(s) = 0.60, P < 0.001), with virus load (r(s) = 0.37, P = 0.013), and very weakly with CD4(+) cells counts (r(s) = 0.30, P = 0.049). The change in the kyn/trp ratio during ART correlated more strongly with the change in neopterin levels (r(s) = 0.49, P = 0.001) than with the change in HIV RNA levels and weakly with the CD4 cell count. The data underscore the fact that both neopterin production and tryptophan degradation are triggered by immune activation. Tryptophan degradation is increased in HIV infection and partially reversed under ART. The data agree with the concept that immune activation is the common background of IDO activation which may be an important factor underlying T-cell hyporesponsiveness.     

Relationship between hepatitis C virus (HCV) and insulin resistance, endothelial perturbation, and platelet activation in HIV–HCV–coinfected patients under highly active antiretroviral treatment

Insulin resistance is associated with highly active antiretroviral therapy in HIV-infected patients, and the risk of developing insulin resistance is increased in hepatitis C virus (HCV)-infected patients. The aim of the present study was to determine whether hepatitis C virus infection constitutes an additional risk factor for insulin resistance or other prothrombotic conditions in HIV–HCV coinfected patients under highly active antiretroviral therapy. One hundred eighteen HIV-infected patients were studied: 50 who had no history of anti-HIV treatment and 68 who were receiving therapy with highly active antiretroviral treatment. The treatment-naive group consisted of 35 HCV-negative subjects and 15 HCV-positive ones. Within the treated group, 50 patients were HCV negative and 18 were HCV positive. For each patient, the lipid profile was determined and the following values measured: glucose, soluble P-selectin (as a marker of platelet activation), soluble thrombomodulin, von Willebrand factor and soluble vascular cell adhesion molecule-1 (as endothelial markers), and insulin resistance. No significant difference (p>0.05) for any variable was found among subjects with or without HCV coinfection in the treatment-naïve group. Among patients under highly active antiretroviral therapy, however, those with HCV coinfection showed higher values (p<0.05) for insulin resistance (homeostasis model assessment value: 2.65 vs. 1.79), glucose (93 vs. 86 mg/dl), endothelial markers (von Willebrand factor, 204 vs. 123%; soluble vascular cell adhesion molecule-1, 650 vs. 482 ng/ml), and platelet activation marker (soluble P-selectin, 78 vs. 51 ng/ml) in parallel with lower CD4+ cells counts (289 vs. 402 cells/mm³) and higher HIV-1 viral loads (305 vs. 50 copies/ml) compared to patients without HCV coinfection. Glucose, soluble P-selectin, and von Willebrand factor were independently related to HCV infection. The presence of HCV coinfection during HIV treatment was closely related to higher values of insulin resistance, to activated platelets, and to endothelial perturbation in parallel with lower CD4+ cell counts and higher HIV-1 viral loads compared to patients without HCV coinfection. On the basis of these results, it may be preferable to treat HCV infection prior to initiating treatment for HIV infection in HIV–HCV–coinfected patients.