Ian Cropley

Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection

Background: Serious treatment associated adverse events are thought to occur more frequently in individuals with tuberculosis (TB) who are co-infected with HIV. A study was undertaken to assess the frequency of serious (grade III/IV) adverse events and interruption of anti-TB treatment in the era of effective antiretroviral therapy. Methods: The incidence of serious adverse events was retrospectively compared in 312 individuals treated for TB, 156 of whom were co-infected with HIV. Results: 111 HIV infected individuals (71%) received highly active antiretroviral therapy at the same time as anti-TB treatment. Serious adverse events were recorded in 40% HIV infected and 26% HIV uninfected individuals (p = 0.008). Peripheral neuropathy and persistent vomiting were more common in co-infected patients (p<0.001; p = 0.006), although all cause interruption of anti-TB treatment occurred with similar frequency in the two groups (13% in HIV infected patients and 15% in HIV uninfected patients; p = 0.74). In 85% of HIV infected patients and 87% of HIV uninfected individuals this was due to hepatotoxicity, which typically presented within 2 months of starting treatment. The median delay in restarting treatment was 4 weeks, so most individuals required full TB re-treatment. Conclusion: Despite a greater rate of serious (grade III/IV) adverse events among HIV infected individuals, discontinuation of anti-TB treatment occurred with a similar frequency in HIV infected and HIV uninfected individuals.

Factors Influencing Increases in CD4 Cell Counts of HIV-Positive Persons Receiving Long-Term Highly Active Antiretroviral Therapy

BACKGROUND Highly active antiretroviral therapy (HAART) results in an improvement in immunologic function. We sought to investigate the factors associated with increases in CD4 cell count among human immunodeficiency virus (HIV)-positive antiretroviral-naive patients starting HAART. METHODS Five hundred ninety-six subjects were followed for a median of 2.5 years (interquartile range, 1.0-4.0 years). Factors associated with changes in CD4 cell counts in the first 3 months of HAART and from 3 months onwards were analyzed. RESULTS After 6, 12, and 24 months of HAART, the median increases in CD4 cell counts were 114, 181, and 248 cells/mm3, respectively; 84%, 84%, and 80% of subjects had a virus load of <400 copies/mL during the same periods. White ethnicity, higher pre-HAART virus load, and lower pre-HAART CD4 and CD8 cell counts were associated with greater increases in CD4 cell counts during the first 3 months of HAART. From 3 months onward, a greater cumulative proportion of time spent with virus load <400 copies/mL was associated with a more favorable change in CD4 cell count (an average increase of 5.2 cells/mm3/year [95% confidence interval [CI], 3.8-6.7 cells/mm3/year] for each extra 10% cumulative time spent with a virus load <400 copies/mL) (P<.0001). For every 100 cells/mm3 higher in baseline CD4 cell count, the increase was 6 cells/mm3/year less (95% CI, 2-11 cells/mm3/year) (P=.02). Sex, risk group, age, and HAART regimen were not associated with increases in CD4 cell counts. CONCLUSIONS These findings emphasize the importance of maintaining virological suppression and suggest other factors that influence long-term CD4 cell response.

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.

Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy

Objectives:To assess whether highly active anti-retroviral therapy (HAART) contributes to the presentation of active tuberculosis (TB). Design:Retrospective single-centre cohort study. Methods:A total of 111 HIV-infected individuals with active TB were identified at an urban teaching hospital between February 1997 and April 2004. Those receiving HAART at the time of TB diagnosis were assessed. Results:Nineteen of 111 (17%) were receiving HAART when TB developed. Within this group there appeared to be two distinct populations. Thirteen of 19, 12 from ethnic or social groups with high background rates of TB, developed disease a median of 41 days (range, 7–109) after starting HAART (‘early TB’ group). In six of 19 (‘late TB’ group), TB occurred a median of 358 days after HAART initiation (range, 258–598). The ‘early TB’ group had lower CD4 cell counts when starting HAART in comparison with the ‘late TB’ group (median; 87 versus 218 × 106 cells/l; P = 0.04); however no difference was observed in the rate of change of CD4 cell count (P = 0.5) or HIV load. Paradoxical reaction rate in the ‘early TB’ group was significantly greater than in the ‘late-TB’ group (62 versus 0%, P = 0.02) and greater than in a similar control population who started HAART while taking anti-TB therapy (62 versus 30%, P = 0.05). Conclusions:These data suggest anti-HIV treatment may amplify the presentation of active TB. This has implications for antiretroviral programmes in countries with high TB rates and warrants prospective investigation of a larger cohort.

Virological Response to Highly Active Antiretroviral Therapy Is Unaffected by Antituberculosis Therapy

We compared 156 human immunodeficiency virus (HIV)-infected patients who had tuberculosis with control populations of similar size. Of 111 patients with HIV infection and tuberculosis who received highly active antiretroviral therapy (HAART) and therapy for tuberculosis concurrently, 92 (83%) achieved or maintained virus loads of <50 copies/mL, and 99 (89%) achieved or maintained a >or=2 log10 reduction in virus load after 6 months. Virological response and changes in CD4 cell count were equivalent to those in 111 matched HIV-infected subjects without tuberculosis starting HAART. Tuberculosis recurrence rates were similar to those found in an HIV-uninfected population of 156 subjects (3% and 1%, respectively). Treatment for HIV and tuberculosis does not compromise outcomes for either disease.

Post-exposure prophylaxis against Ebola virus disease with experimental antiviral agents: A case-series of health-care workers

BACKGROUND Although a few international health-care workers who have assisted in the current Ebola outbreak in west Africa have been medically evacuated for treatment of Ebola virus disease, more commonly they were evacuated after potential accidental exposure to Ebola virus. An urgent need exists for a consensus about the risk assessment of Ebola virus transmission after accidental exposure, and to investigate the use of post-exposure prophylaxis (PEP). Experimental vaccines have occasionally been used for Ebola PEP, but newly developed experimental antiviral agents have potential advantages. Here, we describe a new method for risk assessment and management of health-care workers potentially exposed to Ebola virus and report the use of experimental antiviral therapies for Ebola PEP in people. METHODS We devised a risk assessment and management algorithm for health-care workers potentially exposed to Ebola virus and applied this to eight consecutive individuals who were medically evacuated to the UK from west Africa between January, and March, 2015. PEP with antiviral agents was given to health-care workers assessed to have had substantial risk exposures to Ebola virus. Participants were followed up for 42 days after potential exposure. FINDINGS Four of eight health-care workers were classified as having had low risk exposures and managed by watchful waiting in the community. None of these health-care workers developed Ebola virus disease. The other four health-care workers had intermediate or maximum risk exposures and were given PEP with antiviral agents. PEP was well tolerated with no serious adverse effects. None of these four health-care workers, including two with maximum risk exposures from penetrating injuries with freshly used hollow-bore needles, developed Ebola virus disease. INTERPRETATION Standardised risk assessment should be adopted and consensus guidelines developed to systematically study the efficacy and safety of PEP with experimental agents. New experimental antiviral treatments are a viable option for PEP against Ebola. FUNDING Royal Free London NHS Foundation Trust.

Rapid Diagnosis of Smear-Negative Tuberculosis Using Immunology and Microbiology with Induced Sputum in HIV-Infected and Uninfected Individuals

Rationale and Objectives Blood-based studies have demonstrated the potential of immunological assays to detect tuberculosis. However lung fluid sampling may prove superior as it enables simultaneous microbiological detection of mycobacteria to be performed. Until now this has only been possible using the expensive and invasive technique of broncho-alveolar lavage. We sought to evaluate an immunoassay using non-invasive induced-sputum to diagnose active tuberculosis. Methods and Results Prospective cohort study of forty-two spontaneous sputum smear-negative or sputum non-producing adults under investigation for tuberculosis. CD4 lymphocytes specific to purified-protein-derivative of Mycobacterium tuberculosis actively synthesising interferon-gamma were measured by flow cytometry and final diagnosis compared to immunoassay using a cut-off of 0.5%. Sixteen subjects (38%) were HIV-infected (median CD4 count [range] = 332 cells/µl [103–748]). Thirty-eight (90%) were BCG-vaccinated. In 27 subjects diagnosed with active tuberculosis, the median [range] percentage of interferon-gamma synthetic CD4+ lymphocytes was 2.77% [0–23.93%] versus 0% [0–2.10%] in 15 negative for active infection (p<0.0001). Sensitivity and specificity of the immunoassay versus final diagnosis of active tuberculosis were 89% (24 of 27) and 80% (12 of 15) respectively. The 3 positive assays in the latter group occurred in subjects diagnosed with quiescent/latent tuberculosis. Assay performance was unaffected by HIV-status, BCG-vaccination or disease site. Combining this approach with traditional microbiological methods increased the diagnostic yield to 93% (25 of 27) alongside acid-fast bacilli smear and 96% (26 of 27) alongside tuberculosis culture. Conclusions These data demonstrate for the first time that a rapid immunological assay to diagnose active tuberculosis can be performed successfully in combination with microbiological methods on a single induced-sputum sample.

Clinical application of a rapid lung-orientated immunoassay in individuals with possible tuberculosis

Background: Immunological ex vivo assays to diagnose tuberculosis (TB) have great potential but have largely been blood-based and poorly evaluated in active TB. Lung sampling enables combined microbiological and immunological testing and uses higher frequency antigen-specific responses than in blood. Methods: A prospective evaluation was undertaken of a flow cytometric assay measuring the percentage of interferon-γ synthetic CD4+ lymphocytes following stimulation with purified protein derivative of Mycobacterium tuberculosis (PPD) in bronchoalveolar lavage fluid from 250 sputum smear-negative individuals with possible TB. A positive assay was defined as >1.5%. Results: Of those who underwent lavage and were diagnosed with active TB, 95% (106/111) had a positive immunoassay (95% CI 89% to 98%). In 139 individuals deemed not to have active TB, 105 (76%) were immunoassay negative (95% CI 68% to 82%). Of the remaining 24% (34 cases) with a positive immunoassay, a substantial proportion had evidence of untreated TB; in two of these active TB was subsequently diagnosed. Assay performance was unaffected by HIV status, disease site or BCG vaccination. In culture-positive pulmonary cases, response to PPD was more sensitive than nucleic acid amplification testing (94% vs 73%). The use of early secretory antigen target-6 (ESAT-6) responses in 71 subjects was no better than PPD, and 19% of those with culture-confirmed TB and a positive PPD immunoassay had no detectable response to ESAT-6. Conclusions: These findings suggest that lung-orientated immunological investigation is a potentially powerful tool in diagnosing individuals with sputum smear-negative active TB, regardless of HIV serostatus.

Detection of mycobacterial antigen responses in lung but not blood in HIV-tuberculosis co-infected subjects

Forty-seven HIV-infected adults had broncho-alveolar lavage stimulated with purified protein derivate of Mycobacterium tuberculosis. Eighteen of 19 (95%) with tuberculosis co-infection had interferon-gamma synthetic CD4 lymphocyte responses > 1% versus three of 28 (11%) without (P < 0.0001). Lung response was unrelated to blood CD4 cell count. BAL HIV tuberculosis responses were similar in 25 HIV-uninfected tuberculosis patients. Responses in matched blood samples were often undetectable. Therefore, immunological tuberculosis assays seem less affected by HIV co-infection when lung-based.

Amikacin treatment for multidrug resistant tuberculosis: how much monitoring is required?

To the Editor: Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem. The World Health Organization (WHO) guidelines state that all patients suspected of MDR-TB should be given a group 2 injectable agent, usually an aminoglycoside. However, when taken for extended periods, these can cause nephrotoxicity, neurotoxicity and irreversible ototoxicity [1, 2]. Aminoglycoside-associated progressive hearing loss, from high to low conversational frequency sounds (0.5–2 KHz), affects at least 19% of MDR-TB patients [3, 4]. Most assessments are based on self-reported hearing loss, which is likely to significantly under-estimate the true proportion affected. Although both cochlear and vestibular functions can be impaired, the cochlea is predominantly damaged. This makes audiology testing, in particular serial audiograms that detect tone threshold changes, a useful way to assess ototoxicity, especially for non-conversational ultra-high frequency losses [3–5]. Despite this, there is no widely accepted protocol to monitor for ototoxicity in aminoglycoside-treated MDR-TB patients. Weekly to fortnightly audiograms are recommended after baseline evaluation, though financial and logistical barriers can limit this to monthly assessment [4]. We sought to determine the practicality of intensive assessments in subjects using long-term amikacin, and whether we detected early changes in high frequency hearing loss that could assist in clinical management and so avoid subjective ototoxicity. A retrospective data review of all MDR-TB patients treated with amikacin at a single site London MDR-TB service between 2009 and 2011 was performed. This included information on audiology testing, renal assessments and serum trough level drug concentration. Amikacin was administered intravenously at 15 mg·kg−1 …