Sanjay Bhagani

Recent epidemic of acute hepatitis C Virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours.

Objective:To characterize the mode of hepatitis C virus (HCV) transmission in a recent epidemic of acute HCV in HIV-infected individuals using linked molecular and clinical epidemiological studies. Design:Individuals diagnosed with acute HCV between 1999 and 2005 at three urban HIV units in the UK were enrolled into a phylogenetic and case–control study. Phylogenetic trees were constructed from the amplified sequences of the E1/E2 region of the HCV genome and were used to compare cases with unrelated sequences. A questionnaire-based, case–control study using matched controls recruited from each HIV unit identified putative transmission factors. Results:One hundred and eleven HIV-positive men who have sex with men with acute HCV (genotype 1: 84%) were enrolled. Phylogenetic analysis of 93 E1/E2 sequences revealed seven monophyletic clusters signifying multiple independent HCV lineages co-circulating in the HIV-positive population. Permucosal rather than percutaneous transmission factors were associated with case/control status. Cases (n = 60) had more sexual partners, increased levels of high-risk sexual behaviour and were more likely to have shared drugs via a nasal or anal route in the preceding year in comparison with controls (n = 130). Sex in a group of more than two people was the strongest predictor of case/control status; odds ratios associated with participation in two or at least three types of high-risk sexual behaviour in a group were 9.16 (95% confidence interval, 3.51–23.90) and 23.50 (95% confidence interval, 9.47–58.33), respectively. Conclusion:The identified co-circulating HCV lineages belong to different subtypes and genotypes, implying that rather than viral change, the epidemic is due to permucosal transmission factors that should be the focus of public health interventions.

European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults

With the decline in HIV‐associated morbidity and mortality following the introduction of highly active antiretroviral therapy (HAART), liver disease has emerged as a major cause of death in HIV/hepatitis B virus (HBV) and HIV/hepatitis C virus (HCV) coinfected persons. Therefore, screening for underlying viral hepatitis coinfection and the provision of management and treatment recommendations for patients with chronic viral hepatitis are of great importance in preventing, as far as possible, the development of liver disease. With the introduction of new agents for the treatment of hepatitis B and increased knowledge of how best to manage hepatitis C, an update of current guidelines for management of HBV and HCV coinfection with HIV is warranted.

Late Ebola virus relapse causing meningoencephalitis: a case report

Summary Background There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. Funding Royal Free London NHS Foundation Trust.

Increase in diagnosed newly acquired hepatitis C in HIV-positive men who have sex with men across London and Brighton, 2002–2006: is this an outbreak?

Objectives: To determine the incidence of diagnosed newly acquired hepatitis C virus (HCV) in HIV-positive men who have sex with men (MSM) across London and Brighton in order to inform public health interventions. Methods: Cases were defined as MSM attending London and Brighton HIV/genitourinary medicine clinics from January 2002 to June 2006, with HCV PCR RNA or antibody positive, and a negative HCV test in the previous three years. The yearly number of cases and HCV screening policy in MSM were examined. A negative binomial regression model was used to estimate HCV incidence density rate ratio and 95% CI. Results: 20 out of 38 clinics provided information, covering 84% of the HIV-positive MSM workload in London and 100% in Brighton. The estimated overall incidence was 9.05 per 1000 HIV-positive MSM patient-years. It increased from 6.86 per 1000 in 2002 to 11.58 per 1000 during January–June 2006. Incidence at clinics ranged from 0 to 15.4 (median 6.52) per 1000 HIV-positive MSM patient-years. There was some evidence of difference in the incidence and trend (p = 0.02) in each clinic. The average annual rise in incidence of HCV was 20% (95% CI 4% to 39%, p = 0.001). There was little evidence of such transmission among MSM with negative or unknown HIV status. Conclusions: HCV incidence clearly increased among HIV-positive MSM in London and Brighton during January 2002 to June 2006. Prospective enhanced surveillance of HCV in MSM, including HIV status and behavioural risk factors, is recommended to help inform control measures and better determine the frequency of transmission in all MSM.

Impact of HIV on Host-Virus Interactions during Early Hepatitis C Virus Infection

BACKGROUND Human immunodeficiency virus (HIV) may influence the outcome and natural history of hepatitis C virus (HCV) infection through an impact on acute HCV-specific T cell responses. METHODS Fifty-five HIV-positive males with acute HCV infection were identified; monoinfected individuals (n = 8) were used for peripheral blood mononuclear cell comparison. In 14 coinfected and 8 HCV-monoinfected patients, HCV-specific T cell responses against a range of HCV antigens were assessed using interferon (IFN)-gamma enzyme-linked immunospot (ELISpot) and proliferation assays. E1/E2 region genetic diversity and the selection pressure on the virus were measured in 8 coinfected patients by use of cloned sequences over time. RESULTS HCV persisted in 52 (95%) coinfected individuals. HCV/HIV coinfection significantly reduced IFN-gamma ELISpot responses versus those in HCV-monoinfected individuals, especially against nonstructural proteins (1/10 vs. 5/8; P = .008). In coinfected patients, increased HCV genetic diversity was observed between the first and subsequent time points, with no evidence for positive selection in the E1/E2 region sequenced. CONCLUSION HIV coinfection is associated with increased rates of HCV persistence and a lack of critical CD4 T cell responses, with no evidence of immune selection pressure during early HCV infection. Loss of key cellular immune responses against HCV during acute disease may contribute to the failure of early host control of HCV in HCV/HIV-coinfected patients.

Deaths in the era of HAART: contribution of late presentation, treatment exposure, resistance and abnormal laboratory markers

Objectives:To describe the characteristics of deaths that occur among HIV-positive individuals in the HAART era. Design:Observational database. Methods:Deaths were reviewed that occurred among HIV-positive individuals seen at the Royal Free Hospital, London between January 1998 and December 2003. Results:Over the study period, there were 121 deaths; death rates declined from approximately 2.0/100 person-years of follow-up in 1998–2000 to approximately 1.0/100 person-years of follow-up in 2001–2003. Approximately one half of deaths (45.5%) were from AIDS-related causes and 74 deaths (61.2%) occurred in individuals who had received HAART: patients had been exposed to a median of seven (range 2–14) antiretroviral drugs and two-fifths had started treatment in the pre-HAART era. Another 15 patients had received only non-HAART treatment regimens prior to death. The median pre-death CD4 cell counts were 68 and 167 cells/μl among those who had and had not received HAART; 23 (31.1%) and 4 (8.5%) had HIV RNA < 400 copies/ml, respectively. Of the patients exposed to HAART for at least 6 months and who experienced viral rebound, information was available on resistance for 26 (21.5% of the total deaths) and 19 of those tested had at least one resistance mutation (median 5, range, 1–16). Conclusions:While mortality rates among HIV-infected individuals at our centre have fallen since 1988, the deaths that do now occur are more diverse and are the result of a number of factors, including late presentation, delayed uptake of HAART and the previous use of treatment combinations that are now viewed as suboptimal.

Acute lung injury and other serious complications of Plasmodium vivax malaria.

Plasmodium vivax infection is classified among the so-called benign malarias, but it is increasingly recognised that serious and even life-threatening complications may occur. We present the case of a returning traveller with P vivax infection who developed acute lung injury 3 days into treatment, and discuss the serious complications of this infection. The case highlights the fact that P vivax infection is benign by name but not always by nature.

British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010

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Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study

Abstract Objectives To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. Design Multicentre cohort study. Setting Six large HIV treatment centres in southeast England. Participants All individuals seen for care between 1 January 1996 and 31 December 2002. Main outcome measures Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. Results Information is available on 16 593 individuals (13 378 (80.6%) male patients, 10 340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10 207 of the 16 593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of “viral load failure” with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. Conclusions The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients.

Predictors of Renal Outcome in HIV-Associated Nephropathy

BACKGROUND Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease. METHODS We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified. RESULTS From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end-stage renal disease (P < .001), and an index of chronic damage score >75 was associated with shorter renal survival (P < .001). CONCLUSIONS Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome.