Background: Anal intraepithelial neoplasia (AIN) is associated with high-risk human papillomavirus (hrHPV) infection and is a precursor to anal cancer. Factors other than hrHPV are likely to be involved in causing AIN and further study of cofactors is required. Methods: A surgical database of patients having anal warts removed was established at Royal Perth Hospital in 1995 and epidemiological information concerning age, sex, sexual preference, history or clinical evidence of gonorrhoea or chlamydia infection and serological evidence of HIV-1, HSV-2, hepatitis B or C virus infection and syphilis has been prospectively collected since then. Three hundred and fourteen patients underwent 457 operations from June 1995 to November 2016. Histopathology and hrHPV testing using the Digene Hybrid Capture 2 (HC2) method were performed at the time of surgery. Results: hrHPV alone was associated with high-grade squamous epithelial lesions (HSIL) (OR=4.65, p<0.001). Amplification of HSIL risk was found when hrHPV infection occurred with HIV-1 (OR=11.1) or HSV-2 (OR=7.85) infection; current or previous gonorrhoea (OR=6.45) or syphilis (OR=5.58); and some other infections. Conclusions: HrHPV is a sufficient cause of anal HSIL but seropositivity for HIV-1, HSV-2, T. pallidum, HBV, HCV infections and a history of gonorrhoea or chlamydia exert a powerful amplifying factor increasing the risk of HSIL above the risk with hrHPV alone. This pattern of disease in patients with warts is characteristic of a syndemic with potential increased risk of anal carcinoma in men because of rising rates of sexually-transmitted infections.

BACKGROUND:Anal intraepithelial neoplasia is associated with high-risk human papillomavirus (hrHPV) as a precursor to anal cancer. However, factors other than hrHPV are likely to be involved and further study of cofactors is required because of the possibility of syndemic interactions.METHODS:Three hundred and fourteen patients underwent 457 operations. Histopathology and hrHPV testing using the Digene Hybrid Capture 2 (HC 2) method were performed. Demographic factors and sexually transmissible infections (STIs) were recorded.RESULTS:Results showed that hrHPV alone was associated with HSIL (OR = 4.65, p < 0.001). None of the other STIs were alone associated with HSIL but amplification of risk was found when hrHPV infection occurred with HIV (OR = 11.1); syphilis (OR = 5.58); HSV 2 (OR = 7.85); gonorrhoea (OR = 6.45) and some other infections.CONCLUSIONS:These results suggest that hrHPV is a sufficient cause of anal HSIL. Seropositivity for HIV, HSV 2, T. pallidum, HBV and HCV and a history of gonorrhoea or chlamydia exert a powerful amplifying factor increasing the risk of HSIL above the risk with hrHPV alone. Other co-factors which are associated with an increased risk of HSIL are increased age, male gender, MSM behaviour and self-reported history of more than 50 sexual partners. This pattern of disease in patients with warts is characteristic of a syndemic with potential serious increased risk of anal carcinoma.

On 16 April 2009, a boat carrying 47 Afghan asylum seekers and 2 Indonesian crew exploded in Australian waters, resulting in mass casualties. Of these casualties, 23 persons who suffered significant burns were transferred to Royal Perth Hospital, Perth, Western Australia. One patient was subsequently shown to be a hepatitis B virus (HBV) carrier at the time of the explosion. Over the following months, 3 other patients received a diagnosis of acute hepatitis B, and an additional 4 patients showed serological evidence of recent HBV infection, including 1 patient who was transferred to another Australian city. Molecular typing determined that the strains from the HBV carrier and the acute and recent case patients formed a closely related cluster, and the investigation suggested that transmission occurred at or around the time of the boat explosion. This is the first report of confirmed transmission of HBV following a disaster, and it reinforces the importance of postexposure prophylaxis for HBV in mass casualty situations.

The role of pro-fibrogenic cytokines in the outcome of infections with hepatitis C virus (HCV) and the response to treatment with pegylated interferon-alpha (pegIFNα) and ribavirin remains unclear. To address this issue, we assessed hepatic fibrosis and plasma markers pertinent to T-cell mediated fibrogenesis and inflammation at the start of treatment. Levels of soluble (s)CD30, interleukin-13 receptor alpha 2 (IL-13Rα2), total and active transforming growth factor-beta 1 (TGFβ1), interleukin-18 (IL-18) and interferon-gamma inducible protein-10 (IP-10, CXCL10) were correlated with the severity of fibrosis and with treatment outcome using multiple logistic regression modelling. The Hepascore algorithm was confirmed as a marker of fibrosis, but was a poor predictor of treatment outcome. Inclusion of all immunological markers improved prediction based on Hepascore alone (p = 0.045), but optimal prediction was achieved with an algorithm (“TIPscore”) based on TGFβ1 (total), IP-10, age, sex and HCV genotype (p = 0.003 relative to Hepascore). Whilst this was only marginally more effective than predictions based on HCV genotype age and sex (p = 0.07), it associates high TGFβ1 and low IP-10 levels with a failure of therapy.

Natural killer (NK) cells are implicated in the regulation of a protective immune response in patients chronically infected with hepatitis C virus (HCV), but effects of interferon-alpha/ribavirin therapy on NK cell subsets and the consequences of viral clearance during therapy remain unclear. Samples were collected from chronically infected patients (n = 34) at baseline and from a subset after 3-10 months on pegylated interferon-a and ribavirin therapy (n = 19). NK cells present in cryopreserved PBMC were characterized by flow cytometry. Before therapy, the frequency of CD3-CD56+ NK cells was lower in patients than uninfected controls. Therapy increased proportions of CD56(bright) NK cells. Frequencies of CD56(dim) NK cells declined slightly while perforin and CD16 expression on CD56(dim) NK cells decreased compared to baseline samples. Evaluation of NK cell subsets at baseline did not identify patients able to achieve sustained virological response following therapy. However, therapy may promote the expansion of NK cells able to produce interferon-gamma, while minimizing cytotoxicity to limit liver damage. J. Med. Virol. 82:568-574, 2010. (C) 2010 Wiley-Liss, Inc.

Toll-like receptor (TLR) expression on T-cells and the signalling pathways that lead to the production of cytokines may limit antigen-specific T-cell responses. Here, expression of TLR and retinoic acid inducible gene I (RIG-I) on T-cells were evaluated in patients chronically infected with hepatitis C virus (HCV), before and during pegylated interferon-alpha and ribavirin therapy. Expression of TLR2,3,4,7,9 and retinoic acid inducible gene (RIG)-I on different CD4(+) and CD8(+) T-cell sub-populations (naïve: CD45RA(+)CD57(-); central memory: T(CM) CD45RA(-)CD57(-); effector memory: T(EM) CD45RA(-)CD57(+) and terminally differentiated effector memory: T(EMRA) CD45RA(+)CD57(+)) were measured by flow cytometry. TLR7, TLR9 and RIG-I expression on CD4(+) T-cells and RIG-I expression on CD8(+) T-cells was higher in patients than healthy controls. Therapy increased expression of TLR2, TLR4 and TLR9 and this was observed for all T-cell sub-populations. Evaluation of TLR expression at baseline did not identify patients able to achieve sustained virological response following therapy.

Rapid progression of hepatitis C virus (HCV) disease in patients with HIV/HCV may reflect different cytokine responses and be influenced by HCV genotype. This is addressed by a study of patients with HIV/HCV coinfection and infection with HCV genotype 2 or 3 (2/3). They are compared with coinfected patients infected with genotype 1 and HCV monoinfected patients matched for HCV genotype. IFN-γ, IL-10, IL-4 and IL-4δ2 mRNA were quantified by real-time PCR in unstimulated PBMC and after in vitro stimulation with HCV core or nonstructural 3/4A antigen. In unstimulated PBMC, levels of IFN-γ and IL-4 mRNA were lowest in HIV/HCV genotype 1 patients, intermediate in HIV/HCV genotype 2/3 patients and highest in HCV genotype 2/3 patients. Neither HCV genotype nor HIV affected levels of IL-10 mRNA in unstimulated PBMC or IFN-γ, IL-4 and IL-10 mRNA in PBMC stimulated with HCV antigens. Levels of IL-4 and IL-4δ2 mRNA correlated in mitogen-stimulated PBMC from all patient groups but both were low in HIV/HCV genotype 1 patients. Serum soluble CD30 levels (a putative marker of a T2 cytokine environment) did not differ between patient groups. The data do not suggest a shift in the T1/T2 balance driven by HIV coinfection or HCV genotype but either may affect IL-4 bioavailability.