Hepatitis C: recent advances and practical management.

Hepatitis B virus and hepatitis C virus (HCV) remain leading causes of disability and premature death worldwide. In May 2016, the UK, as a member of the World Health Assembly, adopted the Global Health Sector Strategy and its targets to eliminate viral hepatitis as a public health threat by 2030. In pursuit of this goal, there have been a number of recent advances in viral hepatitis care. Perhaps most notable is the availability of short courses of all-oral curative direct acting antivirals for hepatitis C. However, while access to treatment has been scaled up across the UK, an estimated 93 000 people were still living with HCV at the end of 2021 of which three-quarters remained unaware of their infection. This review article will summarise key advances in hepatitis C treatment and prevention and provide a practical approach to the management of individuals living with hepatitis C infection.

Rate and determinants of antiviral treatment initiation for patients with HBeAg-negative chronic hepatitis B.

Most clinic attenders with chronic hepatitis B (CHB) are serum HBeAg-negative, and a minority will require suppressive antiviral treatment. Expert guidelines propose schedules for the monitoring of untreated patients, but the recommended frequency of patient review does not reflect recognised demographic determinants of HBeAg-negative chronic hepatitis. Also, the impact of patient ethnicity on risk has not been defined. The aim of our study was to determine the rates and determinants of antiviral treatment initiation in a large multi-ethnic cohort of CHB patients attending a single centre. We undertook a retrospective study using entirely electronic sources of patient information. Treatment initiation dates were identified from electronic pharmacy records. Crude and time-dependent statistical analyses were undertaken to identify rate and risk factors for treatment initiation. Treatment was initiated for 232/1256 (18.5%) patients with rates of 23.2% and 33.2% at 5 and 10 years. An increased risk of treatment was associated with male sex (RR 1.803), older age at presentation (RR 1.027 per year increase) and with non-Black ethnicity (RR 1.654). Patient sex, baseline age and ethnicity also determined risk for treatment in the subset of patients with normal serum ALT and low HBV DNA at baseline, though overall treatment rate in this group was low (only 2% per annum). Thus, patient demographics permit risk stratification for treatment initiation and could determine to a significant extent the frequency of review required for untreated HBeAg-negative patients. Black ethnicity is associated with a significant reduction in risk of treatment initiation.

Hepatitis B e antigen and e antibody in a multi-ethnic cohort of adult chronic hepatitis B virus patients followed at a single liver unit for a period of 20 years.

Hepatitis B virus e antigen (HBeAg) loss and the appearance of antibodies to HBeAg (anti-HBe) are favourable events in the history of chronic hepatitis B virus (CHB) infection. Most CHB patients have the HBeAg/anti-HBe profiles +/- or -/+, and little is published on the derivation or fate of the +/+ and -/- profiles. We have used electronically accessible patient data to study the HBeAg and anti-HBe profiles of a multi-ethnic cohort of adult HBV patients seen at a single centre over a period of more than 20 years. 3594 HBsAg-positive patients were identified and patients with viral coinfection or acute HBV infection were excluded. Cross-sectional and longitudinal analyses of HBeAg/anti-HBe status were undertaken. Compared with White or Black patients, Chinese and Asian patients are more likely to be HBeAg positive during child-bearing years. Patients with +/+ profile are likely to undergo HBeAg loss and seroconversion during relatively short follow-up. Chinese patients have a relatively increased rate of seroconversion. For HBeAg-positive patients, the risk of seroconversion diminishes with advancing age. Despite HBeAg loss, seroconversion is seldom observed after age 60 years. The proportion of HBV patients with -/- increases with age, and most acquire this profile by HBeAg loss but without antecedent seroconversion. -/- patients can lose HBsAg and develop anti-HBs. It was not possible to demonstrate a favourable impact of antiviral treatment on the rate of HBeAg seroconversion.

Whole-genome sequencing of Chlamydia trachomatis isolates from persistently infected patients.

BACKGROUND: Current understanding of the causes of treatment failure in Chlamydia trachomatis is poor and antimicrobial susceptibility data are lacking. We used genome sequencing to seek evidence of antimicrobial resistance in isolates sourced from patients who were persistently infected. METHODS: Genomic DNA was extracted from C. trachomatis isolates cultured in McCoy cell monolayers. Sequencing libraries were prepared using the SureSelectXT Illumina paired-end protocol. Paired reads were mapped against a reference genome and single nucleotide variants (SNVs) were identified. RESULTS: Seven isolates from persistently infected patients and five isolates from successfully treated patients were sequenced. No previously reported SNVs associated with antimicrobial resistance were found. A unique SNV was identified in the gyrA gene of one treatment failure isolate but was located outside of the quinolone resistance determining region; this SNV has been previously reported in other members of the Chlamydiaceae family. CONCLUSION: No genomic evidence was found to explain the differences in clinical outcome for our two groups of patients. A mutation unrelated to antimicrobial susceptibility was found in an isolate from a persistently infected patient. The cause of these persistent infections with C. trachomatis remains unclear.

Phenotypic antimicrobial susceptibility testing of Chlamydia trachomatis isolates from patients with persistent or successfully treated infections.

Objectives: Antimicrobial susceptibility data for Chlamydia trachomatis are lacking. Methodologies for susceptibility testing in C. trachomatis are not well-defined, standardized or performed routinely owing to its intracellular growth requirements. We sought to develop an assay for the in vitro susceptibility testing of C. trachomatis isolates from two patient cohorts with different clinical outcomes. Methods: Twenty-four clinical isolates (11 from persistently infected and 13 from successfully treated patients) were overlaid with media containing two-fold serial dilutions of azithromycin or doxycycline. After incubation, aliquots were removed from the stock inoculum (SI) and each antimicrobial concentration for total RNA extraction, complementary DNA generation and real-time PCR. The MIC was defined as the lowest antimicrobial concentration where a 95% reduction in transcription was evident in comparison with the SI for each isolate. Results: MICs of azithromycin were comparable for isolates from the two patient groups (82% ≤ 0.25 mg/L for persistently infected and 100% ≤ 0.25 mg/L for successfully treated patients). Doxycycline MICs were at least two-fold lower for isolates from the successfully treated patients (53.9% ≤ 0.064 mg/L) than for the persistently infected patients (100% ≥ 0.125 mg/L) (P = 0.006, Fisher's exact test). Overall, 96% of isolates gave reproducible MICs when re-tested. Conclusions: A reproducible assay was developed for antimicrobial susceptibility testing of C. trachomatis. MICs of azithromycin were generally comparable for the two different patient groups. MICs of doxycycline were significantly higher in the persistently infected patients. However, interpretation of elevated MICs in C. trachomatis is extremely challenging in the absence of breakpoints, or wild-type and treatment failure MIC distribution data.

Management of hepatitis C genotype 4 in the directly acting antivirals era.

Genotype 4 chronic hepatitis C (G4 HCV) accounts for 13% of worldwide HCV infections; with 10 million people infected with the virus across the world. Up to the end of 2013, the only treatment option for G4 HCV was treatment with pegylated interferon and ribavirin for 24-48 weeks. Since late 2013, treatment of G4 HCV has been transformed by the licensing of many directly acting antiviral agents (DAA). It is an exciting time to be involved in the management of HCV generally and G4 particularly. Interferon-free DAA regimens are now a reality for G4 HCV. This review will highlight these developments and discuss the data behind the use of these drugs. It will also highlight future regimens that are likely to be available over the coming years.

The Significance of Isolated Reactive Treponemal Enzyme Immunoassay in the Diagnosis of Early Syphilis.

BACKGROUND: The Treponemal test algorithm for syphilis screening is widely used. A diagnostic challenge between identifying early syphilis versus a false positive signal occurs in cases where the treponemal enzyme immunoassay (EIA) is reactive and confirmatory T. pallidum particle agglutination assay is negative. We investigated the diagnostic outcome of isolated reactive EIA in patients attending a sexual health clinic. METHODS: Results of syphilis serology tests carried out at Birmingham Whittall Street Clinic between August 10, 2010, and November 31, 2014, were reviewed. Cases with isolated EIA were routinely invited for repeat syphilis serology. Outcomes of patients with isolated EIA were reviewed and the proportion with confirmed positive syphilis serology on their repeat test identified. The number of isolated EIA cases needed to retest to identify 1 case of early syphilis was calculated. RESULTS: A total of 121,724 syphilis screening tests were performed. Among the 1561 individual patients with reactive EIA sera, 316 (20% of total reactive tests) had isolated reactive EIA. Repeat syphilis serology results of 163 patients were reviewed; 106 patients remained with isolated reactive EIA, 50 had negative EIA test and 7 (4.3%) had confirmed reactive EIA. Of the 7 patients, 2 had evidence of early syphilis infection. The number of isolated EIA needed to retest to identify 1 case of early syphilis was 81.5 (95% confidence interval, 22.9-671.4). CONCLUSIONS: Routine recall of patients with isolated EIA sera is not warranted. Risk of acquisition or presence of early syphilis should be assessed independently and irrespective of a negative syphilis screening test or isolated EIA.

A service evaluation of the Gen-Probe APTIMA nucleic acid amplification test for Trichomonas vaginalis: should it change whom we screen for infection?

OBJECTIVE: A service evaluation of the new Gen-Probe APTIMA nucleic acid amplification test was performed to determine the prevalence of Trichomonas vaginalis (TV) infection in a UK sexual health clinic and identify risk factors to inform an appropriate TV screening strategy. METHOD: Unselected patients presenting with a new clinical episode were offered TV testing with Gen Probe transcription-mediated amplification (TV TMA) in addition to routine sexually transmitted infection screening. Asymptomatic females provided a self-collected vulvovaginal specimen and asymptomatic men a first-void urine sample. Symptomatic patients were examined and a urethral swab taken from men and two posterior vaginal swabs from females; one for culture and one for TV TMA testing. Demographic and clinical data were collected on all patients positive for TV infection and 100 randomly selected TV-negative controls. RESULTS: 3503 patients underwent TV TMA testing during the evaluation period. The prevalence of TV infection was 21/1483, 1.4% (95% CI 0.9% to 2.2%) in men and 72/2020, 3.6% (95% CI 2.8% to 4.5%) in women. The rate of TV positivity was higher in Black Caribbean patients compared with Caucasian patients (men 5.4% vs 0.1%, p<0.001; women 9.0% vs 1.2%, p<0.001). TV TMA detected an additional 16 infections (38%) in symptomatic women compared with culture. CONCLUSIONS: While screening all patients with TV TMA will identify more TV infections, the UK prevalence remains low and this approach is unlikely to be cost effective. In addition to testing symptomatic patients, targeted testing of high-risk asymptomatic groups using TV TMA should be considered.

The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review.

BACKGROUND: A high level of resistance in Neisseria gonorrhoeae has developed against penicillins, sulphonamides, tetracyclines and quinolones, and recent surveillance data have shown a gradual reduction in sensitivity to current first-line agents with an upward drift in the minimum inhibitory concentration of ceftriaxone. Laboratory sensitivity testing suggests that gentamicin, an aminoglycoside, may be an effective treatment option for gonorrhoea infection when used as a single intramuscular dose. METHODS: A search of electronic reference databases and grey literature was used to identify randomised trials and well-conducted prospective studies with concurrent controls evaluating single-dose gentamicin against placebo or a comparator regimen in the treatment of uncomplicated gonorrhoea infection in men and women aged 16 years and over. The primary outcome was microbiological cure of N. gonorrhoeae. RESULTS: Eight hundred and thirty-nine studies were identified, of which five (1,063 total participants) were included. All five studies administered single-dose gentamicin via intramuscular injection to men with uncomplicated gonococcal urethritis. Three studies were randomised trials, one was quasi-randomised and one was non-randomised but included a comparator arm. Comparator antibiotics included an alternative aminoglycoside or antibiotic used in the syndromic management of male urethritis. Methodology was poorly described in all five included studies. The high risk of bias within studies and clinical heterogeneity between studies meant that it was inappropriate to pool data for meta-analysis. Cure rates of 62% to 98% were reported with gentamicin treatment. The relative risk of cure was comparable between gentamicin and comparator antibiotics. CONCLUSIONS: The studies identified provide insufficient data to support or refute the efficacy and safety of single-dose intramuscular gentamicin in the treatment of uncomplicated gonorrhoea infection. Additional randomised trials to evaluate gentamicin for this indication are therefore required. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002490.

The effectiveness of nonsteroidal anti-inflammatory agents in the treatment of pelvic inflammatory disease: a systematic review.

BACKGROUND: Pelvic inflammatory disease (PID) is the result of infection ascending through the endocervix to the uterus and fallopian tubes. Inflammation driven by infected host cells appears to be central to the development of tissue damage and associated reproductive complications. Nonsteroidal anti-inflammatory agents (NSAIDs) therefore have the potential to reduce the sequelae associated with pelvic infection. METHODS: A search of four electronic reference databases, an internet search for relevant grey literature and a review of the bibliographies of identified publications was used to identify studies evaluating NSAIDs in the management of PID. A predefined search strategy was used to identify studies that included women with PID aged over 16 and diagnosed after 1980. Randomized controlled trials, nonrandomized controlled trials, and cohort studies with comparison group data were included without language restriction. Two reviewers independently assessed the studies against agreed criteria and extracted relevant data using a standardized pro forma. A meta-analysis to calculate the relative risk associated with NSAID use was planned if appropriate. RESULTS: Forty-three studies were identified. After reviewing abstracts or full texts, two randomized controlled trials were found to meet the selection criteria for inclusion. The use of NSAIDs was reported to improve tubal patency, reduce pelvic adhesions and reduce suprapubic pain but the studies were of poor quality with a high risk of bias. Meta-analysis of the data was not performed. CONCLUSIONS: Insufficient data is available to support or refute the efficacy of NSAIDs in the prevention of short or long-term complications of PID.

What is the appropriate treatment for the management of rectal Chlamydia trachomatis in men and women?

BACKGROUND: There is no UK guidance specifically for the management of rectal Chlamydia trachomatis yet there is documented treatment failure with single-dose azithromycin suggesting that test of cure (TOC) and alternative treatment may be needed. OBJECTIVES: To evaluate the efficacy of single-dose azithromycin compared with 1 week of doxycycline in the treatment of rectal C trachomatis. METHODS: Data were collected prospectively on all patients diagnosed with rectal C trachomatis who received azithromycin 1 g stat between 1 January and 30 June 2010 and between 1 October 2010 and 31 March 2011 following a local change in treatment protocol to 1 week of doxycycline 100 mg twice a day. Information was collected on gender, concurrent sexually transmitted infections, treatment received, re-infection risk, re-treatment and TOC at 6 weeks. RESULTS: 11 patients (26.2%) had a positive TOC following treatment with stat azithromycin. The risk of re-infection was excluded in two, identifying nine of the 11 (81.8%) as treatment failures. Two patients had a positive TOC following treatment with 1 week of doxycycline, both were found to have a risk of re-infection. There was a significantly higher treatment failure rate in patients receiving azithromycin (p=0.0025). CONCLUSIONS: A higher treatment failure rate was found following azithromycin for rectal C trachomatis than previously published. If azithromycin is used for treatment of rectal C trachomatis, TOC may be required or alternative treatment with doxycycline may be preferable, but further data are required.

How to assess quality in your sexual health service.

Previous improvements in NHS have largely focused on increasing service capacity to ensure the provision of universal, comprehensive healthcare at the point of need in the UK. However, public expectations of the NHS are changing, triggered by increased access to information and media coverage of a series of lapses in quality and geographical inequity of care. The NHS also faces the challenges posed by a changing family structure, an ageing population, advancing technology and economic uncertainty. To meet these challenges, improvements in quality rather than just quantity have become a focus of the new NHS. This article provides an overview of quality and how to measure it in sexual health services.