Antimicrobial resistance and treatment failures are the biggest challenges
The publication of national treatment guidelines does not usually generate headlines in national newspapers. However, the recent release of draft management guidelines for Mycoplasma genitalium infection was accompanied by high profile media coverage suggesting that it is the next sexually transmitted “superbug.” So what are the facts behind these headlines, and how concerned should we be?
First isolated in 1981, M genitalium is the smallest known self replicating bacterium. Most infections are probably asymptomatic and have no adverse health outcomes. Nonetheless, evidence that M genitalium is associated with serious genitourinary and reproductive health morbidity is accumulating.
In men, there is an unequivocal association with non-gonococcal urethritis, and it is detected in up to 40% of men with persistent and recurrent urethritis. In women, a recent meta-analysis found significant associations with a range of clinical syndromes and adverse reproductive health outcomes, including cervicitis, postcoital bleeding, pelvic inflammatory disease, preterm birth, and spontaneous abortion, and a weak association with infertility.
The main concern is M genitalium’s increasing resistance to azithromycin and moxifloxacin, the recommended first and second line treatments in Europe, North America, and Australia, especially in the Asia-Pacific region. For example, single nucleotide polymorphisms in region V of the 23S rRNA gene, which confer macrolide resistance, were found in over 60% of M genitalium specimens from people attending STI clinics in Australia in 2015. Furthermore, selective pressure can lead to the emergence of macrolide resistance after exposure to suboptimal levels of drug.
Importantly, resistance markers are highly correlated with treatment failure, especially when the organism load is high.
Annual report of HIV infections in the United Kingdom in 2001 published by Health Protection Agency (HPA) show that for the first time in many years newly diagnosed infections were higher in men who have sex with men (MSM) than transmission through heterosexual intercourse.
By the end of 2011, there were an estimated 96,000 (95% credible interval 90,800 – 102,500) people were living with HIV in the UK. Approximately one quarter (22,600, 24% [19%- 28%]) of these were undiagnosed and unaware of their infection. Fig 1
This is an increase from the 91,500 people estimated to have been living with HIV by the end of 2010. The estimated prevalence of HIV in 2011 was 1.5 per 1,000 (1.5-1.6) population of all ages, 2.1 per 1,000 (1.9 – 2.3) men and 1.0 per 1,000 (1.0 – 1.1) women.
The rise in new diagnosis in MSM (Fig 2) is particularly worrying as nearly half the patients (47%) are diagnosed late when their immune system is already compromised increasing the chance of a fatal outcome within one year of diagnosis ten fold. These deaths are totally avoidable with the use of anti-viral therapy early in the infection.
In this year’s funding round we received six applications. After sending them for external peer review by experts, the Scientific Committee approved two projects for funding in 2013 which was submitted to the Trustees.
Project 1: Chlamydia trachomatisis the most common sexually transmitted infection effecting young people in the UK. It infects one in ten of all women aged 15-25 and can cause serious long term complications such as pelvic inflammatory disease and infertility. According to the Health Protection Agency in 2011 in England and Wales 147,594 infections were diagnosed in 15 to 24 year olds.
Recent evidence for emergence of resistance to the commonly used antibotics used in eradicating chlamydia is very worrying. We are delighted to fund Emma Hathorn as part of a multi-centre study to evaluate the incidence of chlamydia resistance in people attending a clinic for sexually transmitted infections.
Antimicrobial resistance in Chlamydia trachomatis: is it a reality? STIRF-022
Project 2: There is increasing focus on involving patients and what they perceive are their actual needs when delivering clinical services in the NHS. This is particularly important in the fast developing field of HIV where new management strategies and new treatments take place within the background of shrinking funding. These clearly call for new ways of delivering these services more efficiently as well as more effectively. It is with this in mind that STIRF decided to fund the nurse-led project by Lucy Land that is taking steps to objectively define these priorities as seen from the HIV-infected patients perspective.
Development of a weighting scale to evaluate the relative importance of items in a validated HIV patient satisfaction questionnaire. STIRF-020
This study aims to refine a questionnaire they developed and validated with the help of HIV-infected patients to find issues that are more important and therefore need to be prioritised in development of HIV services.
Thanks to all the researchers who submitted and to the reviewers who gave their valuable time for free.
A STIRF funded project (STIRF-012) has been completed successfully. Professor Jonathan Ross, Consultant in HIV medicine at University Hospital Birmingham and Lucy Land, Reader in Nursing at Birmingham City University have developed a questionnaire that will give patients attending an HIV clinic the opportunity to feedback their experiences of care.
A systematic review of the medical literature provided background information on what factors were important to patients attending a HIV clinic. Current users of the service were then involved in verifying this information and added their views about the issues that were important to them. For example being afforded respect, dignity and autonomy, together with an expectation of expert medical care were considered essential to a good service.
A draft questionnaire was constructed to include questions around these issues as well as others that were relevant and important to patients with HIV. This draft was tested with a group of patients and refined further. The final questionnaire was piloted on 100 clinic patients and showed that the feedback from the questionnaire could provide an accurate reflection of patients’ experiences. In the future, an annual survey using this questionnaire will be conducted and the data will be used to measure the quality of care and inform improvements in HIV clinic services.
Pneumocystis jirovecii pneumonia (PCP) is a leading cause of morbidity and mortality in HIV and other immunocompromised patients. Currently the commonly used PCR for diagnosing P. jirovecii will miss some organisms by staining methods. The authors of a study published in Clinical Microbiology and Infection developed a new assay using the same targeted genes.
This assay was compared with the currently used PCR and other conventional assays (Giemsa staining and immunofluorescence assay). Brochoalveolar lavage (BAL) sample collected from human immunodeficiency virus (HIV)-infected (n = 66) and non-HIV (n = 36) immunocompromised patients presenting with fever, dyspnoea, cough and pulmonary infiltrates was tested by all the assays. Pneumocystis jirovecii was diagnosed with Giemsa-stained smear, immunofluorescence assay, conventional single-round and nested PCR, and the new PCR in 46 (45.1%), 53 (52.0%), 69 (67.6%), 74 (72.6%), 87 (85.3%) and 91 (89.2%) patients, respectively.
The new PCR could detectP. jirovecii DNA in BAL fluids two to three orders of magnitude more dilute than conventional PCR. Although both conventional and new PCR assays were highly specific for diagnosing P. jirovecii, the new PCR yielded more positive results than conventional PCR among BAL samples that were negative by both Giemsa stain and immunofluorescence assay. Hence, the new PCR offered a more sensitive detection of P. jirovecii infection and colonization than conventional PCR.
According to an editorial by Salim Abdool Karim in the Lancet a defining moment in the global AIDS response has been reached. The discourse is no longer about HIV prevention or HIV treatment; it is now about HIV control through the implementation of antiretroviral treatments as key components of combination interventions.
Barely a year ago, visions of HIV control would have been considered far-fetched. The impetus for this change in mindset, which has been building since the XVIII International AIDS Conference in Vienna last year, emanates from the compelling evidence that antiretroviral drugs prevent HIV infection in the general heterosexual population, which is released this week and presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome by the Partners PrEP and Botswana TDF2 trials.
The Partners PrEP trial, involving 4758 HIV discordant couples from Kenya and Uganda, found that daily oral tenofovir disoproxil fumarate (TDF) and TDF-emtricitabine reduced HIV transmission by 62% and 73%, respectively. The Bostwana TDF2 trial, in 1200 heterosexual men and women from the general population, found that daily oral TDF-emtricitabine reduced HIV transmission by 63%.
Both these are of a similar order of magnitude to that seen with male circumcision and is probably caused by a significant reduction of HIV in the genital tract.
see fig 1 for comparison between different prevension strategies
Several issues were raised by the authors that need further research. There is now no doubt that antiretroviral drugs prevent HIV infection. However, important scientific questions remain. Does the inclusion of emtricitabine in pre-exposure prophylaxis (PrEP) formulations provide sufficient additional benefit to warrant the additional costs and side-effects? Are levels of effectiveness and safety similar for daily use and use-with-sex of PrEP? Do the safety, effectiveness, cost, and acceptability profiles of oral and topical PrEP merit implementation of both formulations? Does PrEP lead to masking of HIV acquisition that is then revealed once PrEP is withdrawn?