Incidence and risk factors for chronic elevation of alanine aminotransferase levels in HIV-infected persons without hepatitis b or c virus co-infection

Chronic liver disease in human immunodeficiency virus (HIV)-infected patients is mostly caused by hepatitis virus co-infection. Other reasons for chronic alanine aminotransferase (ALT) elevation are more difficult to diagnose.

Improved sensitivity of an interferon-gamma release assay (T-SPOT.TB™) in combination with tuberculin skin test for the diagnosis of latent tuberculosis in the presence of HIV co-infection

Background Interferon-gamma release assays (IGRA) are more specific than the tuberculin skin test (TST) for the diagnosis of Mycobacterium tuberculosis infection. Data on sensitivity are controversial in HIV infection. Methods IGRA (T-SPOT.TB) was performed using lymphocytes stored within 6 months before culture-confirmed tuberculosis was diagnosed in HIV-infected individuals in the Swiss HIV Cohort Study. Results 64 individuals (69% males, 45% of non-white ethnicity, median age 35 years (interquartile range [IQR] 31-42), 28% with prior AIDS) were analysed. Median CD4 cell count was 223 cells/μl (IQR 103-339), HIV-RNA was 4.7 log10 copies/mL (IQR 4.3-5.2). T-SPOT.TB resulted positive in 25 patients (39%), negative in 18 (28%) and indeterminate in 21 (33%), corresponding to a sensitivity of 39% (95% CI 27-51%) if all test results were considered, and 58% (95% CI 43-74%) if indeterminate results were excluded. Sensitivity of IGRA was independent of CD4 cell count (p = 0.698). Among 44 individuals with available TST, 22 (50%) had a positive TST. Agreement between TST and IGRA was 57% (kappa = 0.14, p = 0.177), and in 34% (10/29) both tests were positive. Combining TST and IGRA (at least one test positive) resulted in an improved sensitivity of 67% (95% CI 52-81%). In multivariate analysis, older age was associated with negative results of TST and T-SPOT.TB (OR 3.07, 95% CI 1,22-7.74, p = 0.017, per 10 years older). Conclusions T-SPOT.TB and TST have similar sensitivity to detect latent TB in HIV-infected individuals. Combining TST and IGRA may help clinicians to better select HIV-infected individuals with latent tuberculosis who qualify for preventive treatment.

HIV and human herpesvirus 8 co-infection across the globe: Systematic review and meta-analysis.

HIV-infection is an important risk factor for developing Kaposi sarcoma (KS), but it is unclear whether HIV-positive persons are also at increased risk of co-infection with human herpesvirus 8 (HHV-8), the infectious cause of KS. We systematically searched literature up to December 2012 and included studies reporting HHV-8 seroprevalence for HIV-positive and HIV-negative persons. We used random-effects meta-analysis to combine odds ratios (ORs) of the association between HIV and HHV-8 seropositivity and conducted random-effects meta-regression to identify sources of heterogeneity. We included 93 studies with 58,357 participants from 32 countries in sub-Saharan Africa, North and South America, Europe, Asia, and Australia. Overall, HIV-positive persons were more likely to be HHV-8 seropositive than HIV-negative persons (OR 1.99, 95% confidence interval [CI] 1.70-2.34) with considerable heterogeneity among studies (I(2) 84%). The association was strongest in men who have sex with men (MSM, OR 3.95, 95% CI 2.92-5.35), patients with hemophilia (OR 3.11, 95% CI 1.19-8.11), and children (OR 2.45, 95% CI 1.58-3.81), but weaker in heterosexuals who engage in low-risk (OR 1.42, 95% CI 1.16-1.74) or high-risk sexual behavior (OR 1.66, 95% CI 1.27-2.17), persons who inject drugs (OR 1.66, 95% CI 1.28-2.14), and pregnant women (OR 1.68, 95% CI 1.15-2.47), p value for interaction <0.001. In conclusion, HIV-infection was associated with an increased HHV-8 seroprevalence in all population groups examined. A better understanding of HHV-8 transmission in different age and behavioral groups is needed to develop strategies to prevent HHV-8 transmission.

Progression of Liver Fibrosis in HIV/HCV Co-Infection: A Comparison between Non-Invasive Assessment Methods and Liver Biopsy.

OBJECTIVES To evaluate the diagnostic performance of seven non-invasive tests (NITs) of liver fibrosis and to assess fibrosis progression over time in HIV/HCV co-infected patients. METHODS Transient elastography (TE) and six blood tests were compared to histopathological fibrosis stage (METAVIR). Participants were followed over three years with NITs at yearly intervals. RESULTS Area under the receiver operating characteristic curve (AUROC) for significant fibrosis (> = F2) in 105 participants was highest for TE (0.85), followed by FIB-4 (0.77), ELF-Test (0.77), APRI (0.76), Fibrotest (0.75), hyaluronic acid (0.70), and Hepascore (0.68). AUROC for cirrhosis (F4) was 0.97 for TE followed by FIB-4 (0.91), APRI (0.89), Fibrotest (0.84), Hepascore (0.82), ELF-Test (0.82), and hyaluronic acid (0.79). A three year follow-up was completed by 87 participants, all on antiretroviral therapy and in 20 patients who completed HCV treatment (9 with sustained virologic response). TE, APRI and Fibrotest did not significantly change during follow-up. There was weak evidence for an increase of FIB-4 (mean increase: 0.22, p = 0.07). 42 participants had a second liver biopsy: Among 38 participants with F0-F3 at baseline, 10 were progessors (1-stage increase in fibrosis, 8 participants; 2-stage, 1; 3-stage, 1). Among progressors, mean increase in TE was 3.35 kPa, in APRI 0.36, and in FIB-4 0.75. Fibrotest results did not change over 3 years. CONCLUSION TE was the best NIT for liver fibrosis staging in HIV/HCV co-infected patients. APRI-Score, FIB-4 Index, Fibrotest, and ELF-Test were less reliable. Routinely available APRI and FIB-4 performed as good as more expensive tests. NITs did not change significantly during a follow-up of three years, suggesting slow liver disease progression in a majority of HIV/HCV co-infected persons on antiretroviral therapy.

High prevalence of herpes simplex virus (HSV)- type 2 co-infection among HIV-positive women in Ukraine, but no increased HIV mother-to-child transmission risk.

BACKGROUND Over 3500 HIV-positive women give birth annually in Ukraine, a setting with high prevalence of sexually transmitted infections. Herpes simplex virus Type 2 (HSV-2) co-infection may increase HIV mother-to-child transmission (MTCT) risk. We explored factors associated with HSV-2 seropositivity among HIV-positive women in Ukraine, and its impact on HIV MTCT. METHODS Data on 1513 HIV-positive women enrolled in the Ukraine European Collaborative Study from 2007 to 2012 were analysed. Poisson and logistic regression models respectively were fit to investigate factors associated with HSV-2 seropositivity and HIV MTCT. RESULTS Median maternal age was 27 years (IQR 24-31), 53% (796/1513) had been diagnosed with HIV during their most recent pregnancy and 20% had a history of injecting drugs. Median antenatal CD4 count was 430 cells/mm(3) (IQR 290-580). Ninety-six percent had received antiretroviral therapy antenatally. HSV-2 seroprevalence was 68% (1026/1513). In adjusted analyses, factors associated with HSV-2 antibodies were history of pregnancy termination (APR 1.30 (95% CI 1.18-1.43) for ≥ 2 vs. 0), having an HIV-positive partner (APR 1.15 (95% CI 1.05-1.26) vs partner's HIV status unknown) and HCV seropositivity (APR 1.23 (95 % CI 1.13-1.35)). The overall HIV MTCT rate was 2.80% (95% CI 1.98-3.84); no increased HIV MTCT risk was detected among HSV-2 seropositive women after adjusting for known risk factors (AOR 1.43 (95% CI 0.54-3.77). CONCLUSION No increased risk of HIV MTCT was detected among the 68% of HIV-positive women with antibodies to HSV-2, in this population with an overall HIV MTCT rate of 2.8%. Markers of ongoing sexual risk among HIV-positive HSV-2 seronegative women indicate the importance of interventions to prevent primary HSV-2 infection during pregnancy in this high-risk group.

Acute trichinellosis increases susceptibility to Giardia lamblia infection in the mouse model

The intestinal protozoan parasite Giardia lamblia causes diarrhoea in humans and animals. In the present study, we used the C57BL/6 inbred mouse model to assess the impact of a nematode (Trichinella spiralis) infection on the course of a G. lamblia (clone GS/M-83-H7) infection. Acute trichinellosis coincided with transient intestinal inflammation and generated an intestinal environment that strongly promoted growth of G. lamblia trophozoites although the local anti-Giardia immunoglobulin (Ig) A production was not affected. This increased G. lamblia infection intensity correlated with intestinal mast cell infiltration, mast cell degranulation, and total IgE production. Furthermore, a G. lamblia single-infection investigated in parallel also resulted in intestinal mast cell accumulation but severe infiltration was triggered in the absence of IgE. Recently, intestinal mast cells emerging during a G. lamblia infection were reported to be involved in those immunological mechanisms that control intestinal proliferation of the parasite in mice. This anti-giardial activity was assumed to be related to the capacity of mast cells to produce IL-6. However, this previous assumption was questioned by our present immunohistological findings indicating that murine intestinal mast cells, activated during a G. lamblia infection were IL-6-negative. In the present co-infection experiments, mast cells induced during acute trichinellosis were not able to control a concurrent G. lamblia infection. This observation makes it feasible that the T. spiralis infection created an immunological and physiological environment that superimposed the anti-giardial effect of mast cells and thus favoured intestinal growth of G. lamblia trophozoites in double-infected mice. Furthermore, our findings raise the possibility that intestinal inflammation e.g. as a consequence of a 'pre-existing' nematode infection is a factor which contributes to increased susceptibility of a host to a G. lamblia infection. The phenomenon of a 'pre-existing' nematode infection prior to a G. lamblia infection is a frequent constellation in endemic areas of giardiasis and may therefore have a direct impact on the epidemiological situation of the disease.

Influence of inhibitory killer immunoglobulin-like receptors and their HLA-C ligands on resolving hepatitis C virus infection

An estimated 2%-3% of the world's population is chronically infected with hepatitis C virus (HCV) and this is a major cause of liver disease worldwide. Following acute infection, outcome is variable with acute HCV successfully resolved in some individuals (20%-30%), but in the majority of cases the virus is able to persist. Co-infection with human immunodeficiency virus has been associated with a negative impact on the course of HCV infection. The host's immune response is an important correlate of HCV infection outcome and disease progression. Natural killer (NK) cells provide a major component of the antiviral immune response by recognising and killing virally infected cells. NK cells modulate their activity through a combination of inhibitory and activatory receptors such as the killer immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen (HLA) Class I molecules. In this workshop component, we addressed the influence of KIR genotypes and their HLA ligands on resolving HCV infection and we discuss the implications of the results of the study of Lopez-Vazquez et al. on KIR and HCV disease progression.

Higher plant diversity promotes higher diversity of fungal pathogens, while it decreases pathogen infection per plant

Fungal plant pathogens are common in natural communities where they affect plant physiology, plant survival, and biomass production. Conversely, pathogen transmission and infection may be regulated by plant community characteristics such as plant species diversity and functional composition that favor pathogen diversity through increases in host diversity while simultaneously reducing pathogen infection via increased variability in host density and spatial heterogeneity. Therefore, a comprehensive understanding of multi-host multi-pathogen interactions is of high significance in the context of biodiversity-ecosystem functioning. We investigated the relationship between plant diversity and aboveground obligate parasitic fungal pathogen (''pathogens'' hereafter) diversity and infection in grasslands of a long-term, large-scale, biodiversity experiment with varying plant species (1-60 species) and plant functional group diversity (1-4 groups). To estimate pathogen infection of the plant communities, we visually assessed pathogen-group presence (i.e., rusts, powdery mildews, downy mildews, smuts, and leaf-spot diseases) and overall infection levels (combining incidence and severity of each pathogen group) in 82 experimental plots on all aboveground organs of all plant species per plot during four surveys in 2006. Pathogen diversity, assessed as the cumulative number of pathogen groups on all plant species per plot, increased log-linearly with plant species diversity. However, pathogen incidence and severity, and hence overall infection, decreased with increasing plant species diversity. In addition, co-infection of plant individuals by two or more pathogen groups was less likely with increasing plant community diversity. We conclude that plant community diversity promotes pathogen-community diversity while at the same time reducing pathogen infection levels of plant individuals.

Major challenges in clinical management of TB/HIV co-infected patients in Eastern Europe compared with Western Europe and Latin America.

INTRODUCTION Rates of both TB/HIV co-infection and multi-drug-resistant (MDR) TB are increasing in Eastern Europe (EE). Data on the clinical management of TB/HIV co-infected patients are scarce. Our aim was to study the clinical characteristics of TB/HIV patients in Europe and Latin America (LA) at TB diagnosis, identify factors associated with MDR-TB and assess the activity of initial TB treatment regimens given the results of drug-susceptibility tests (DST). MATERIAL AND METHODS We enrolled 1413 TB/HIV patients from 62 clinics in 19 countries in EE, Western Europe (WE), Southern Europe (SE) and LA from January 2011 to December 2013. Among patients who completed DST within the first month of TB therapy, we linked initial TB treatment regimens to the DST results and calculated the distribution of patients receiving 0, 1, 2, 3 and ≥4 active drugs in each region. Risk factors for MDR-TB were identified in logistic regression models. RESULTS Significant differences were observed between EE (n=844), WE (n=152), SE (n=164) and LA (n=253) for use of combination antiretroviral therapy (cART) at TB diagnosis (17%, 40%, 44% and 35%, p<0.0001), a definite TB diagnosis (culture and/or PCR positive for Mycobacterium tuberculosis; 47%, 71%, 72% and 40%, p<0.0001) and MDR-TB prevalence (34%, 3%, 3% and 11%, p <0.0001 among those with DST results). The history of injecting drug use [adjusted OR (aOR) = 2.03, (95% CI 1.00-4.09)], prior TB treatment (aOR = 3.42, 95% CI 1.88-6.22) and living in EE (aOR = 7.19, 95% CI 3.28-15.78) were associated with MDR-TB. For 569 patients with available DST, the initial TB treatment contained ≥3 active drugs in 64% of patients in EE compared with 90-94% of patients in other regions (Figure 1a). Had the patients received initial therapy with standard therapy [Rifampicin, Isoniazid, Pyrazinamide, Ethambutol (RHZE)], the corresponding proportions would have been 64% vs. 86-97%, respectively (Figure 1b). CONCLUSIONS In EE, TB/HIV patients had poorer exposure to cART, less often a definitive TB diagnosis and more often MDR-TB compared to other parts of Europe and LA. Initial TB therapy in EE was sub-optimal, with less than two-thirds of patients receiving at least three active drugs, and improved compliance with standard RHZE treatment does not seem to be the solution. Improved management of TB/HIV patients requires routine use of DST, initial TB therapy according to prevailing resistance patterns and more widespread use of cART.

Babesia spp. in European wild ruminant species: parasite diversity and risk factors for infection.

Babesia are tick-borne parasites that are increasingly considered as a threat to animal and public health. We aimed to assess the role of European free-ranging wild ruminants as maintenance mammalian hosts for Babesia species and to determine risk factors for infection. EDTA blood was collected from 222 roe deer (Capreolus c. capreolus), 231 red deer (Cervus e. elaphus), 267 Alpine chamois (Rupicapra r. rupicapra) and 264 Alpine ibex (Capra i. ibex) from all over Switzerland and analysed by PCR with pan-Babesia primers targeting the 18S rRNA gene, primers specific for B. capreoli and Babesia sp. EU1, and by sequencing. Babesia species, including B. divergens, B. capreoli, Babesia sp. EU1, Babesia sp. CH1 and B. motasi, were detected in 10.7% of all samples. Five individuals were co-infected with two Babesia species. Infection with specific Babesia varied widely between host species. Cervidae were significantly more infected with Babesia spp. than Caprinae. Babesia capreoli and Babesia sp. EU1 were mostly found in roe deer (prevalences 17.1% and 7.7%, respectively) and B. divergens and Babesia sp. CH1 only in red deer. Factors significantly associated with infection were low altitude and young age. Identification of Babesia sp. CH1 in red deer, co-infection with multiple Babesia species and infection of wild Caprinae with B. motasi and Babesia sp. EU1 are novel findings. We propose wild Caprinae as spillover or accidental hosts for Babesia species but wild Cervidae as mammalian reservoir hosts for B. capreoli, possibly Babesia sp. EU1 and Babesia sp. CH1, whereas their role regarding B. divergens is more elusive.

Trends in incidences and risk factors for hepatocellular carcinoma and other liver events in HIV and hepatitis C virus co-infected individuals from 2001 to 2014: a multi-cohort study.

BACKGROUND  While liver-related deaths in HIV and hepatitis C virus (HCV) co-infected individuals have declined over the last decade, hepatocellular carcinoma (HCC) may have increased. We described the epidemiology of HCC and other liver events in a multi-cohort collaboration of HIV/HCV co-infected individuals. METHODS  We studied all HCV antibody-positive adults with HIV in the EuroSIDA Study, the Southern Alberta Clinic Cohort, the Canadian Co-infection Cohort, and the Swiss HIV Cohort Study from 2001 to 2014. We calculated the incidence of HCC and other liver events (defined as liver-related deaths or decompensations, excluding HCC) and used Poisson regression to estimate incidence rate ratios. RESULTS  Our study comprised 7,229 HIV/HCV co-infected individuals (68% male, 90% white). During follow-up, 72 cases of HCC and 375 other liver events occurred, yielding incidence rates of 1.6 (95% confidence interval (CI): 1.3, 2.0) and 8.6 (95% CI: 7.8, 9.5) cases per 1,000 person-years of follow-up, respectively. The rate of HCC increased 11% per calendar year (95% CI: 4%, 19%) and decreased 4% for other liver events (95% CI: 2%, 7%), but only the latter remained statistically significant after adjustment for potential confounders. High age, cirrhosis, and low current CD4 cell count were associated with a higher incidence of both HCC and other liver events. CONCLUSIONS  In HIV/HCV co-infected individuals, the crude incidence of HCC increased from 2001 to 2014, while other liver events declined. Individuals with cirrhosis or low current CD4 cell count are at highest risk of developing HCC or other liver events.

Prevalence and predictors of kaposi sarcoma herpes virus seropositivity: a cross-sectional analysis of HIV-infected adults initiating ART in Johannesburg, South Africa

Background Kaposi sarcoma (KS) is the most common AIDS-defining tumour in HIV-infected individuals in Africa. Kaposi sarcoma herpes virus (KSHV) infection precedes development of KS. KSHV co-infection may be associated with worse outcomes in HIV disease and elevated KSHV viral load may be an early marker for advanced HIV disease among untreated patients. We examined the prevalence of KSHV among adults initiating antiretroviral therapy (ART) and compared immunological, demographic and clinical factors between patients seropositive and seronegative for KSHV. Results We analyzed cross-sectional data collected from 404 HIV-infected treatment-naïve adults initiating ART at the Themba Lethu Clinic, Johannesburg, South Africa between November 2008 and March 2009. Subjects were screened at ART initiation for antibodies to KSHV lytic K8.1 and latent Orf73 antigens. Seropositivity to KSHV was defined as positive to either lytic KSHV K8.1 or latent KSHV Orf73 antibodies. KSHV viremia was determined by quantitative PCR and CD3, 4 and 8 lymphocyte counts were determined with flow cytometry. Of the 404 participants, 193 (48%) tested positive for KSHV at ART initiation; with 76 (39%) reactive to lytic K8.1, 35 (18%) to latent Orf73 and 82 (42%) to both. One individual presented with clinical KS at ART initiation. The KSHV infected group was similar to those without KSHV in terms of age, race, gender, ethnicity, smoking and alcohol use. KSHV infected individuals presented with slightly higher median CD3 (817 vs. 726 cells/mm3) and CD4 (90 vs. 80 cells/mm3) counts than KSHV negative subjects. We found no associations between KSHV seropositivity and body mass index, tuberculosis status, WHO stage, HIV RNA levels, full blood count or liver function tests at initiation. Those with detectable KSHV viremia (n = 19), however, appeared to present with signs of more advanced HIV disease including anemia and WHO stage 3 or 4 defining conditions compared to those in whom the virus was undetectable. Conclusions We demonstrate a high prevalence of KSHV among HIV-infected adults initiating ART in a large urban public-sector HIV clinic. KSHV viremia but not KSHV seropositivity may be associated with markers of advanced HIV disease.

Comparison of treatment outcomes of new smear-positive pulmonary tuberculosis patients by HIV and antiretroviral status in a TB/HIV clinic, Malawi

BACKGROUND Smear-positive pulmonary TB is the most infectious form of TB. Previous studies on the effect of HIV and antiretroviral therapy on TB treatment outcomes among these highly infectious patients demonstrated conflicting results, reducing understanding of important issues. METHODS All adult smear-positive pulmonary TB patients diagnosed between 2008 and 2010 in Malawi's largest public, integrated TB/HIV clinic were included in the study to assess treatment outcomes by HIV and antiretroviral therapy status using logistic regression. RESULTS Of 2,361 new smear-positive pulmonary TB patients, 86% had successful treatment outcome (were cured or completed treatment), 5% died, 6% were lost to follow-up, 1% failed treatment, and 2% transferred-out. Overall HIV prevalence was 56%. After adjusting for gender, age and TB registration year, treatment success was higher among HIV-negative than HIV-positive patients (adjusted odds ratio 1.49; 95% CI: 1.14-1.94). Of 1,275 HIV-infected pulmonary TB patients, 492 (38%) received antiretroviral therapy during the study. Pulmonary TB patients on antiretroviral therapy were more likely to have successful treatment outcomes than those not on ART (adjusted odds ratio : 1.83; 95% CI: 1.29-2.60). CONCLUSION HIV co-infection was associated with poor TB treatment outcomes. Despite high HIV prevalence and the integrated TB/HIV setting, only a minority of patients started antiretroviral therapy. Intensified patient education and provider training on the benefits of antiretroviral therapy could increase antiretroviral therapy uptake and improve TB treatment success among these most infectious patients.

Elevated AST-to-platelet ratio index is associated with increased all-cause mortality among HIV-infected adults in Zambia.

BACKGROUND AND AIMS We investigated the association between significant liver fibrosis, determined by AST-to-platelet ratio index (APRI), and all-cause mortality among HIV-infected patients prescribed antiretroviral therapy (ART) in Zambia METHODS: Among HIV-infected adults who initiated ART, we categorized baseline APRI scores according to established thresholds for significant hepatic fibrosis (APRI ≥1.5) and cirrhosis (APRI ≥2.0). Using multivariable logistic regression we identified risk factors for elevated APRI including demographic characteristics, body mass index (BMI), HIV clinical and immunologic status, and tuberculosis. In the subset tested for hepatitis B surface antigen (HBsAg), we investigated the association of hepatitis B virus co-infection with APRI score. Using Kaplan-Meier analysis and Cox proportional hazards regression we determined the association of elevated APRI with death during ART. RESULTS Among 20,308 adults in the analysis cohort, 1,027 (5.1%) had significant liver fibrosis at ART initiation including 616 (3.0%) with cirrhosis. Risk factors for significant fibrosis or cirrhosis included male sex, BMI <18, WHO clinical stage 3 or 4, CD4+ count <200 cells/mm(3) , and tuberculosis. Among the 237 (1.2%) who were tested, HBsAg-positive patients had four times the odds (adjusted odds ratio, 4.15; 95% CI, 1.71-10.04) of significant fibrosis compared HBsAg-negatives. Both significant fibrosis (adjusted hazard ratio 1.41, 95% CI, 1.21-1.64) and cirrhosis (adjusted hazard ratio 1.57, 95% CI, 1.31-1.89) were associated with increased all-cause mortality. CONCLUSION Liver fibrosis may be a risk factor for mortality during ART among HIV-infected individuals in Africa. APRI is an inexpensive and potentially useful test for liver fibrosis in resource-constrained settings. This article is protected by copyright. All rights reserved.