A population-based study of the prevalence and risk factors of low-grade Plasmodium falciparum malaria infection in children aged 0-15 years old in northern Tanzania.

OBJECTIVES: Northern Tanzania experiences significant malaria-related morbidity and mortality, but accurate data are scarce. We update the data on patterns of low-grade Plasmodium falciparum malaria infection among children in northern Tanzania. METHODS: Plasmodium falciparum malaria prevalence (pfPR) was assessed in a representative sample of 819 children enrolled in 94 villages in northern Tanzania between October 2015 and August 2016, using a complex survey design. Individual- and household-level risk factors for pfPR were elicited using structured questionnaires. pfPR was assessed using rapid diagnostic tests (RDTs) and thick film microscopy (TFM). Associations with pfPR, based on RDT, were assessed using adjusted odds ratios (aOR) and confidence intervals (CI) from weighted survey logistic regression models. RESULTS: Plasmodium falciparum malaria prevalence (pfPR) was 39.5% (95% CI: 31.5, 47.5) by RDT and 33.4% (26.0, 40.6) by TFM. pfPR by RDT was inversely associated with higher-education parents, especially mothers (5-7 years of education: aOR 0.55; 95% CI: 0.31, 0.96, senior secondary education: aOR 0.10; 95% CI: 0.02, 0.55), living in a house near the main road (aOR 0.34; 95% CI: 0.15, 0.76), in a larger household (two rooms: aOR 0.40; 95% CI: 0.21, 0.79, more than two rooms OR 0.35; 95% CI: 0.20, 0.62). Keeping a dog near or inside the house was positively associated with pfPR (aOR 2.01; 95% CI: 1.26, 3.21). pfPR was not associated with bed-net use or indoor residual spraying. CONCLUSIONS: Nearly 40% of children in northern Tanzania had low-grade malaria antigenaemia. Higher parental education and household metrics but not mosquito bed-net use were inversely associated with pfPR.

OBJECTIFS: La Tanzanie connaît une morbidité et une mortalité importantes liées au paludisme, mais les données précises sont rares. Nous mettons à jour les données sur les profils en matière d'infection par le paludisme à Plasmodium falciparum de faible grade chez les enfants dans le nord de la Tanzanie. MÉTHODES: La prévalence du paludisme à P. falciparum (pfPR) a été évaluée sur un échantillon représentatif de 819 enfants inscrits dans 94 villages dans le nord de la Tanzanie entre octobre 2015 et août 2016, à l'aide d'un plan d'enquête complexe. Des facteurs de risque de pfPR au niveau individuel et au niveau du ménage ont été déterminés à l'aide de questionnaires structurés. La pfPR a été évaluée à l'aide de tests de diagnostic rapides (TDR) et de microscopie à film épais (TFM). Les associations avec la pfPR, sur la base des TDR, ont été évaluées à l'aide des rapports de cotes ajustés (aOR) et des intervalles de confiance (IC) de modèles de régression logistique de surveillances pondérées. RÉSULTATS: La pfPR était de 39,5% (IC95%: 31,5-47,5) avec les TDR et de 33,4% (26,0-40,6) avec la TFM. La pfPR par les TDR était inversement associée aux parents avec un niveau d'éducation plus élevé, en particulier les mères (5-7 ans d'études: aOR: 0,55; IC95%: 0,31-0,96, enseignement secondaire supérieur: aOR: 0,10; IC95%: 0,02-0,55), vivre dans une maison proche de la route principale (aOR: 0,34; IC95%: 0,15-0,76), dans un ménage plus grand (2 chambres: aOR: 0,40; IC95%: 0,21-0,79, plus de 2 pièces aOR: 0,35; IC95%: 0,20-0,62). Garder un chien près ou à l'intérieur de la maison était positivement associé à la pfPR (aOR: 2,01; IC95%: 1,26-3,21). La pfPR n'était pas associée à l'utilisation de moustiquaire ou à la pulvérisation de résidus à l'intérieur. CONCLUSIONS: Près de 40% des enfants dans nord de la Tanzanie présentaient une antigénémie paludéenne de faible grade. Un niveau d'éducation parentale plus élevé et les indicateurs du ménage, mais pas l'utilisation de moustiquaires, étaient inversement associés à la pfPR.

Admixture analysis of spontaneous hepatitis C virus clearance in individuals of African descent.

Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75-85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African descent have lower rates of clearance compared with individuals of European descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression, we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18 × 10(-8)) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.

Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins.

BACKGROUND: Adolescent/young adult Hodgkin lymphoma (AYAHL) survivors report fewer exposures to infections during childhood compared with controls, and they have functional lymphocyte aberrations. The gut microbiota plays a central role in immunity. METHODS: We investigated whether fecal microbial diversity differed between 13 AYAHL survivors and their unaffected co-twin controls. Pyrosequencing of fecal bacterial 16S rRNA amplicons yielded 252 943 edited reads that were assigned to species-level operational taxonomic units (OTUs) and standardised for sequencing depth by random sampling. Microbial diversity was compared within vs between twin pairs and by case-control status. RESULTS: The number of unique OTUs was more similar within twin pairs compared with randomly paired participants (P=0.0004). The AYAHL cases had fewer unique OTUs compared with their co-twin controls (338 vs 369, P=0.015); this difference was not significant (169 vs 183, P=0.10) when restricted to abundant OTUs. CONCLUSION: In this small study, AYAHL survivors appear to have a deficit of rare gut microbes. Further work is needed to determine if reduced microbial diversity is a consequence of the disease, its treatment, or a particularly hygienic environment.

A case-control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A.

Several genes that modify risk of factor VIII (FVIII) inhibitors in haemophilia A patients have been identified. Aside from the underlying mutations that cause haemophilia A, inhibitor risk appears to be modified by polymorphisms in various cytokines and immunomodulators including IL10, TNFα and CTLA4. HLA haplotypes have not been strong determinants of inhibitor risk. We sought to confirm previous observations on FVIII inhibitor risk-modifying genes and to test new candidate genes encoding various otherTH1/TH2 cytokines. We also sought to determine whether normal FVIII gene polymorphisms affect inhibitor risk in caucasians. We studied 915 caucasian, severe haemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls). Genes were analysed using 368 tagging single nucleotide polymorphisms starting 20 kb 5' and ending 10 kb 3' of each gene's coding sequence; four other polymorphisms (factor V Leiden & prothrombin 20210 polymorphisms and two in HFE) were also evaluated. Haplotypes that increased inhibitor risk were found in IL10 (OR = 1.33, P = 0.04), IL12 (OR = 1.31, P = 0.04) and IL1α (OR = 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR = .69, P = 0.008) and IL1ß (OR = 0.75, P = 0.02). One rare haplotype in the FVIII gene increased the risk of inhibitor development by nearly fourfold (OR = 3.8, P = 0.004). We replicate previous findings for IL10; identify new associations with IL1, IL2 and IL12; and identify a rare FVIII haplotype in caucasians that is associated with increased inhibitor risk.

Delayed-type hypersensitivity in classic Kaposi sarcoma patients and controls.

BACKGROUND: Immune perturbation likely affects the development of Kaposi sarcoma (KS) among people infected with the KS-associated herpesvirus (KSHV). We tested whether KSHV-seropositive individuals or cases of classic KS (cKS), which typically originates in the leg, had differing delayed-type hypersensitivity (DTH) in the forearm or leg. METHODS: Mantoux DTH with three antigens (Candida, tetanus, PPD) was performed on the forearm and leg of 15 cKS cases, 14 KSHV-positives without KS, and 15 KSHV-negative controls. The diameters of induration responses were compared by group and body site. RESULTS: Leg DTH was greater than forearm DTH among controls (mean difference 5.6 mm, P=0.0004), whereas this was not observed in cKS cases (-2.2 mm, P=0.32) or KSHV-positives (0.5 mm, P=0.56). Leg-minus-forearm DTH difference was greater in controls compared with cKS cases (P=0.004) and KSHV-positives (P=0.002). Leg-plus-forearm DTH was similar in controls (mean 28.2 mm) and cKS cases (24.5 mm, P=0.60), but it was reduced in KSHV-positives (11.8 mm, P=0.02), particularly in the leg (P=0.004) and marginally in the forearm (P=0.07). CONCLUSION: KS cases had weaker DTH only in the leg, whereas both body sites appeared weaker in KSHV-positives without KS. Both systemic and regional immune alterations may influence the development of this malignancy.

Correlates of high hepatitis C virus RNA load in a cohort of HIV-negative and HIV-positive individuals with haemophilia.

Hepatitis C virus (HCV) treatment failure and disease progression are more likely with high HCV-RNA load. Correlates of high HCV-RNA load in individuals with haemophilia are largely unknown. Among 1266 interferon naïve HCV-infected individuals with haemophilia, we compared those with high (> 2 x 106 HCV-RNA copies/mL) to lower viral load, overall and stratifying on HIV co-infection status using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Overall, high HCV load was independently associated with longer duration of HCV infection (P(trend)=0.0001), body mass index ≥ 25 kg/m² (OR=1.4, 95% CI=1.1-1.9), and HIV co-infection (OR=1.4, 95% CI=1.0-1.8). Among 795 HIV-negative participants, high HCV-RNA load was associated with older age at HCV acquisition (OR=1.9 for > 15 years vs ≤ 2 years, P(trend)=0.008), and lower AST/platelet ratio (P(trend)=0.01), in addition to longer duration of HCV infection (P(trend)=0.0008), and body mass index ≥ 25 kg/m² (OR=1.6, P=0.005). Among 471 HIV-positive individuals, anti-retroviral therapy (ART) was the only variable associated with high HCV-RNA load (OR=1.8, CI=1.1-2.9 for combination ART; OR=1.8, CI=0.9-3.4, for other ART vs no treatment). High HCV-RNA load with haemophilia is more likely with longer duration of infection, older age at infection, higher body mass index, and antiretroviral therapy. These findings may help identify individuals at increased risk of HCV treatment failure and progression to end-stage liver disease.

Hepatitis B viral load and risk for liver cirrhosis and hepatocellular carcinoma in The Gambia, West Africa.

The main objectives of this study were to define the occurrence and levels of hepatitis B virus (HBV) DNA in asymptomatic HBV carriers, cirrhosis patients and hepatocellular carcinoma (HCC) cases from The Gambia, and to evaluate the risk for cirrhosis or HCC associated with HBV viremia. We used sensitive real-time quantitative PCR assays to measure HBV DNA in samples from a case-control study consisting of 60 asymptomatic HBV carriers, 53 cirrhotic patients and 129 HCC cases. Logistic regression was used to estimate the risks of cirrhosis and HCC associated with HBV-DNA levels and HBV e antigenemia (HBeAg) detection (a surrogate marker for viral replication). Detectable HBV viremia and HBeAg positivity were both significantly associated with cirrhosis (increasing risk by fourfold and 11-fold respectively) and with HCC (increasing risk by sixfold and threefold respectively). HBV-DNA levels were significantly higher in both HCC cases and cirrhotic patients compared to asymptomatic carriers (P < 0.01 for both). High-level HBV DNA (>10,000 copies/mL) was strongly associated with both HCC and cirrhosis (17- and 39-fold increased risk). Lower level HBV viremia (200-10,000 copies/mL) conferred a significant risk of HCC, although the association with cirrhosis was not significant. In conclusion, we find that high HBV-DNA levels are strongly associated with the serious sequelae of HBV infection, independent of HBeAg status. While risk for cirrhosis and for HCC notably increases at HBV-DNA levels >or=10,000 copies/mL, low-level viremia was also associated with significant risk for HCC.

Extended IL10 haplotypes and their association with HIV progression to AIDS.

Interleukin-10 (IL-10) is a pleiotropic cytokine with both immunosuppressive and immunostimulatory functions. Its roles in infections and autoimmunity may have resulted in selective pressures on polymorphisms within the gene, leading to genomic coexistence of several semi-conserved haplotypes involved with diverse pathogen interactions during genomic evolution. Previous studies focused either exclusively on promoter haplotypes or on individual SNPs. We genotyped 21 single nucleotide polymorphisms in the human IL10 gene and examined this variation compared to other mammalian species sequences. Haplotype heterogeneity in human populations is centered around 'classic' 'proximal' promoter polymorphisms: -592, -819 and -1082. High-producing GCC haplotypes are by far the most numerous and diverse group, the intermediate IL-10 producing ACC-inclusive haplotypes seem to be related most closely to the ancestral haplotype, and the ATA-inclusive haplotypes cluster a separate branch with strong bootstrap support. We looked at associations of corresponding haplotypes with HIV progression. A haplotype trend regression confirmed that individuals carrying the low-producing ATA-inclusive haplotypes in European Americans progress to AIDS faster, and most likely explain the role of IL10. Our findings are consistent with the hypothesis that existing polymorphisms in this gene may reflect a balance of historic adaptive responses to autoimmune, infectious and other disease agents.

Breast cancer risk in elderly women with systemic autoimmune rheumatic diseases: a population-based case-control study.

Systemic autoimmune rheumatic diseases (SARDs) are chronic inflammatory and immuno-modulatory conditions that have been suggested to affect cancer risk. Using the Surveillance, Epidemiology and End Results-Medicare-linked database, women aged 67-99 years and diagnosed with incident breast cancer in 1993-2002 (n=84 778) were compared with an equal number of age-matched cancer-free female controls. Diagnoses of SARDs, including rheumatoid arthritis (RA, n=5238), systemic lupus erythematosus (SLE, n=340), Sjogren's syndrome (n=374), systemic sclerosis (n=128), and dermatomyositis (n=31), were determined from claim files for individuals from age 65 years to 1 year before selection. Associations of SARD diagnoses with breast cancer, overall and by oestrogen receptor (ER) expression, were assessed using odds ratio (OR) estimates from multivariable logistic regression models. The women diagnosed with RA were less likely to develop breast cancer (OR=0.87, 95% confidence interval (CI)=0.82-0.93). The risk reduction did not differ by tumour ER-status (OR=0.83, 95% CI=0.78-0.89 for ER-positive vs OR=0.91, 95% CI=0.81-1.04 for ER-negative, P for heterogeneity=0.14). The breast cancer risk was not associated with any of the other SARDs, except for a risk reduction of ER-negative cases (OR=0.49, 95% CI=0.26-0.93) among women with SLE. These findings suggest that systemic inflammation may affect breast epithelial neoplasia.

Treatment of classic Kaposi sarcoma with a nicotine dermal patch: a phase II clinical trial.

BACKGROUND: Kaposi sarcoma (KS), a malignancy of dermal endothelial cells that is caused by human herpesvirus 8 (HHV8) infection, is sensitive to perturbations of immunity. Nicotine might be effective against KS because of its immunologic and vascular effects and because smoking is associated with a low risk of KS. OBJECTIVE AND STUDY DESIGN: We conducted a masked, randomized phase 2 clinical trial of transdermal nicotine and placebo patches to assess the safety and efficacy of nicotine against classic KS (cKS). SUBJECTS AND METHODS: Three cKS lesions, predominantly nodules, in each of 24 non-smoking patients were randomly assigned to 15 weeks continuous treatment with nicotine patch (escalated to 7 mg), identical masked placebo patch or no patch. Changes in lesion area and elevation from baseline through six follow-up visits, by direct measurement and by two independent readers using digital photographs of the lesions, were compared using non-parametric and regression methods. Changes in longitudinal levels of HHV8 antibodies and DNA in blood cells were similarly assessed. RESULTS: There were no systemic or serious adverse events, and compliance was good. One patient resumed smoking and discontinued patches, and two patients withdrew at week 12 for unrelated indications. Six (29%) of the remaining 21 suspended use of patches to relieve local skin irritation; four of these six completed the trial at reduced dose. Treatment assignment was not associated with significant or consistent changes in cKS lesion area or elevation, HHV8 viral load or antibodies. CONCLUSION: Transdermal nicotine and placebo patches caused no serious toxicities but had no demonstrable effect on nodular cKS lesions or HHV8 levels.

Detecting AIDS restriction genes: from candidate genes to genome-wide association discovery.

The screening of common genetic polymorphisms among candidate genes for AIDS pathology in HIV exposed cohort populations has led to the description of 20 AIDS restriction genes (ARGs), variants that affect susceptibility to HIV infection or to AIDS progression. The combination of high-throughput genotyping platforms and the recent HapMap annotation of some 3 million human SNP variants has been developed for and applied to gene discovery in complex and multi-factorial diseases. Here, we explore novel computational approaches to ARG discovery which consider interacting analytical models, various genetic influences, and SNP-haplotype/LD structure in AIDS cohort populations to determine if these ARGs could have been discovered using an unbiased genome-wide association approach. The procedures were evaluated by tracking the performance of haplotypes and SNPs within ARG regions to detect genetic association in the same AIDS cohort populations in which the ARGs were originally discovered. The methodology captures the signals of multiple non-independent AIDS-genetic association tests of different disease stages and uses association signal strength (odds ratio or relative hazard), statistical significance (p-values), gene influence, internal replication, and haplotype structure together as a multi-facetted approach to identifying important genetic associations within a deluge of genotyping/test data. The complementary approaches perform rather well and predict the detection of a variety of undiscovered ARGs that affect different stages of HIV/AIDS pathogenesis using genome-wide association analyses.

Human herpesvirus 8 seroprevalence among prostate cancer case patients and control subjects.

To investigate a possible association between human herpesvirus 8 (HHV-8) and prostate cancer, we evaluated HHV-8 seroprevalence in 2 case-control studies. HHV-8 antibodies were detected by immunofluorescence with cells expressing lytic viral proteins and by enzyme immunoassays with recombinant viral structural protein (K8.1) and latent protein (latency-associated nuclear antigen-1; open reading frame 73), respectively. HHV-8 seroprevalence tended to be lower in patients with prostate cancer than in control subjects, but there was no significant difference in either study. These data imply that HHV-8 is not a major prevalent cause of prostate cancer.

Upper gastrointestinal bleeding in haemophiliacs: incidence and relation to use of non-steroidal anti-inflammatory drugs.

This multicentre study sought to estimate the incidence of upper gastrointestinal (UGI) bleeding in haemophiliacs and its relationship to use of non-steroidal anti-inflammatory drugs (NSAIDs). Cox models were used to estimate relative hazards (RH) with 95% confidence intervals (CI) for postulated risk factors. Conditional logistic regression and stored sera were used to assess UGI bleeding risk with Heliobacter pylori seropositivity in cases compared with closely matched controls. During a mean of 17.4 months (range 2-34), 2285 participants, ages 13-89 (mean 36.5) were followed for 3309 person-years (py). Forty-two experienced a UGI bleeding event (incidence 1.3 per 100 py), most from ulcer (11), gastritis (four), varices (five) and Mallory Weiss tears (eight). RH was significantly increased with traditional NSAID use for <1 month (OR: 3.66; 95% CI: 1.1-11.9), but not with coxibs use. RH was significantly and independently increased with age >46 years (3.5; 95% CI: 1.1-10.6) and hepatic decompensation (4.4; 95% CI: 1.7-11.6). Likelihood of bleeding was substantially but not significantly increased (OR: 4.6; 95% CI: 0.3-83.9) with H. pylori seropositivity. These findings suggest that coxibs are a safer alternative than traditional NSAIDs in the treatment of haemophilic arthropathy.

Risk of breast, ovary, and uterine corpus cancers among 85,268 women with AIDS.

By linking HIV/AIDS and cancer surveillance data in 12 US regions, breast and reproductive cancer risks with AIDS were compared to those in the general population. Trends in standardized incidence ratios (SIRs) were assessed by CD4 count, AIDS-relative time, and calendar time. Standardized incidence ratios were indirectly adjusted for cancer risk factors using data from AIDS cohort participants and the general population. With AIDS, 313 women developed breast cancer (SIR 0.69, 95% confidence interval (CI) 0.62-0.77), 42 developed ovary cancer (SIR 1.05, 95% CI, 0.75-1.42), and 31 developed uterine corpus cancer (SIR 0.57, 95% CI, 0.39-0.81). Uterine cancer risk was reduced significantly after age 50 (SIR 0.33). Breast cancer risk was reduced significantly both before (SIR 0.71) and after (SIR 0.66) age 50, and was lower for local or regional (SIR 0.54) than distant (SIR 0.89) disease. Breast cancer risk varied little by CD4 count (Ptrend=0.47) or AIDS-relative time (Ptrend=0.14) or after adjustment for established cancer risk factors. However, it increased significantly between 1980 and 2002 (Ptrend=0.003), approaching the risk of the general population. We conclude that the cancer deficit reflected direct or indirect effects of HIV/AIDS and that anti-HIV therapy reduced these effects.

Prevalence of serologic reactivity against four strains of mouse mammary tumour virus among US women with breast cancer.

Mouse mammary tumour virus (MMTV) causes breast cancer in mice, and MMTV-specific antibodies develop to high titers among mice infected as adults. Whether MMTV or a related virus infects humans is uncertain, because MMTV DNA sequences have been detected inconsistently and because serologic methods have varied widely. The current study used immunoblot and immunoprecipitation with four strains of MMTV (RIII, FM, C3H, and LA) to detect specific antibodies in 92 sera from US women with breast cancer and in masked dilutions of monoclonal hybridoma and hyperimmunised goat positive-control reagents. In these positive controls, MMTV antibodies of the expected molecular weights were detected at high titer (1 : 100 in the monoclonal reagent, 1 : 10000 in the hyperimmunised goat serum). Nearly 30% of the sera from women with breast cancer had at least one faint band on an immunoblot, but none of these matched the molecular weight of bands revealed by probing the same blot strips with the goat serum. The goat serum readily immunoprecipitated MMTV antigens from all four strains of MMTV, but MMTV antigens were not immunoprecipitated by any of the six breast cancer sera that had four or more nonspecific immunoblot bands. Thus, among women with breast cancer, we found no MMTV-specific antibodies. The upper 95% confidence limit implies that MMTV seroprevalence among breast cancer patients does not exceed 3%.

Prevalence of conditions associated with human immunodeficiency and hepatitis virus infections among persons with haemophilia, 2001-2003.

Before the mid-1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV-seropositive patients, age 13-88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross-sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV-1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV-1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV-1-positive participants had > or = 200 CD4+ cells microL(-1), only 59% were on HAART. HIV-1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti-HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV-1-positive than HIV-1-negative participants (85% vs. 70%, P < 0.0001). HIV-1-positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV-negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self-reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non-Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV-1, HCV or both.

Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study.

The stromal-derived factor-1 (SDF-1) chemokine gene encodes the only natural ligand for CXCR4, the coreceptor for the pathogenic X4 HIV-1 strains. A single-nucleotide polymorphism (SNP) in the 3' untranslated region (SDF1-3'A=rs1801157) of SDF-1 was reported to be protective against infection and progression in some, but not other, epidemiological studies. To identify additional alleles that may influence HIV-1 infection and progression to AIDS, nine SNPs (including rs1801157) spanning 20.2 kb in and around the SDF-1 gene were genotyped in over 3000 African American (AA) and European American (EA) participants enrolled in five longitudinal HIV-1/AIDS natural cohort studies. Six or five haplotypes were present at frequencies greater than 5% in AA or EA, respectively. Six of the nine SNPs occur on only one common haplotype (>5%), while the remaining three SNPs were found on multiple haplotypes, suggesting a complex history of recombination. Among EA, rs754618 was associated with an increased risk of infection (OR=1.50, P=0.03), while rs1801157 (=SDF1-3'A) was associated with protection against infection (OR=0.63, P=0.01). In the MACS cohort, rs1801157 was associated with AIDS-87 (RH=0.31, P=0.02) and with death (RH=0.18, P=0.02). Significant associations to a single disease outcome were found for two SNPs and one haplotype in AA.

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance.

Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (+/-300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P=0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P=0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.

Human immunodeficiency and hepatitis virus infections and their associated conditions and treatments among people with haemophilia.

Treatment with contaminated plasma products before 1990 resulted in extraordinary prevalence rates of human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV, HCV). In the Second Multicentre Haemophilia Cohort Study (MHCS-II) during 2001-03, 30% of HCV-seropositive survivors had HIV and 4.6% were HBV carriers. Highly active antiretroviral therapy (HAART) radically altered the consequences of HIV/HCV coinfection. Whereas opportunistic infections predominated previously, current major complications are liver failure and bleeding (exacerbated by decreased clotting factor synthesis, hypersplenic thrombocytopenia, and oesophageal varices). Most HIV-positives in MHCS-II were HIV RNA-negative and had > 200 CD4(+) cells microL(-1), but only 59% were on HAART. With HIV, especially after 41 years of age, liver disease was apparent (jaundice in 5%, ascites 7%, hepatomegaly 9%, splenomegaly 19%). HAART increases survival but may contribute to various comorbidities. Without HIV, sustained HCV clearance is obtained in > 50% with combined pegylated interferons plus ribavirin, but data in haemophilic populations, especially with HIV, are limited. In MHCS-II, HCV RNA negativity was 41% following standard interferon plus ribavirin; among interferon-naive participants (implying spontaneous HCV clearance), HCV RNA negativity was 12% with and 25% without HIV. Without HIV, spontaneous HCV clearance was much more likely with early age at infection and particularly with recent birth (late 1970s or early 1980s) but not with bleeding propensity or its treatment. Most (72%) participants had received no anti-HCV therapy. Hepatic and haematological conditions are likely to increase during the coming years unless most adult haemophiliacs are successfully treated for HIV, HCV or both.

Liver biopsy in patients with inherited disorders of coagulation and chronic hepatitis C.

Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.