DOI: 10.1111/hiv.12245 HIV Medicine (2015)
© 2015 British HIV Association
Evaluation of screening and treatment of cryptococcal antigenaemia among HIV-infected persons in Soweto, South Africa* NP Govender,1,2 M Roy,3 JF Mendes,2,4 TG Zulu,1 TM Chiller3 and AS Karstaedt2,5 National Institute for Communicable Diseases (Centre for Opportunistic, Tropical and Hospital Infections), a Division of the National Health Laboratory Service, Johannesburg, South Africa, 2Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, 3Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA, 4Department of Community Health, Gauteng Department of Health, Johannesburg, South Africa and 5Division of Infectious Diseases, Department of Medicine, Chris Hani Baragwanath Hospital, Soweto, South Africa
We retrospectively evaluated clinic-based screening to determine the prevalence of cryptococcal antigenaemia and management and outcome of patients with antigenaemia. Methods
Cryptococcal antigen (CrAg) screening of HIV-infected adults who attended the HIV clinic at Chris Hani Baragwanath Hospital was conducted over 19 months. Data collected from CrAg-positive patients included CD4 T-lymphocyte count at screening, prior or subsequent cryptococcal meningitis (CM), antifungal and antiretroviral treatment and outcome after at least 8 months. Results
Of 1460 patients with no prior CM, 30 (2.1%) had a positive CrAg test. The prevalence of antigenaemia among patients with a CD4 count < 100 cells/μl and no prior CM was 2.8% (20 of 708). Of 29 evaluable CrAg-positive patients with no prior CM, 14 (48%) did not return for post-screening follow-up. Of these 14, five developed CM and one (7%) was known to be alive at follow-up. Of 15 patients who returned for follow-up, two already had evidence of nonmeningeal cryptococcosis. Overall, 11 received fluconazole, one did not and fluconazole treatment was unknown for three. Among these 15, one developed CM and 10 (67%) were known to be alive at follow-up. Overall, 18 (62%) of 29 CrAg-positive patients died or were lost to follow-up. Seven (0.5%) of 1430 CrAg-negative patients developed CM a median of 83 days post-screening (range 34 to 219 days). Conclusions
Loss to follow-up is the major operational issue relevant to scale-up of screen-and-treat. Patient outcomes may be improved by rapid access to CrAg results and focus on linkage to and retention in HIV care. Keywords: cryptococcal antigen, cryptococcal meningitis, evaluation, screen-and-treat, South
Africa Accepted 25 November 2014
Correspondence: Dr Nelesh P. Govender, National Institute for Communicable Diseases – Centre for Opportunistic, Tropical and Hospital Infections, Private Bag X4, Sandringham, 2132, South Africa. Tel: +27 11 555 0353; fax: +27 11 555 0435; e-mail: [email protected]
*This work was presented, in part, at the 16th International Conference on AIDS and STIs in Africa (ICASA), Addis Ababa, Ethiopia, 4–8 December 2011 (Abstract TUAB0503).
2 NP Govender et al.
Introduction Cryptococcus neoformans is the most common cause of microbiologically confirmed meningitis among HIVinfected adults in southern and eastern Africa [1–3]. Among persons initiating antiretroviral therapy (ART) in sub-Saharan Africa, cryptococcal meningitis (CM) accounted for approximately 20% of all deaths that occurred in the first year post ART initiation [4,5]. Earlier diagnosis of HIV infection and ART initiation prior to AIDS onset are the most important interventions to reduce the incidence of CM and associated deaths. However, these require major improvements in health system infrastructure and population-level changes in health-seeking behaviour. A large proportion of South African patients still initiate ART with a CD4 T-lymphocyte count < 100 cells/μl [6,7]. As a strategy to reduce deaths associated with CM, primary fluconazole prophylaxis is not routinely recommended by the World Health Organization (WHO) unless a prolonged delay to ART is likely, because of limited improvements in survival and cost-effectiveness [8,9]. However, screening for cryptococcal antigenaemia, followed by pre-emptive antifungal treatment, among patients with a CD4 count < 100 cells/μl is an attractive strategy to prevent deaths in a targeted manner [10–12]. Data from Africa and Asia suggest that screening-andtreatment is more cost-effective than primary prophylaxis and may be comparable to trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis and bacterial infections or isoniazid prophylaxis for tuberculosis [13,14]. Although the feasibility of the cryptococcal screen-and-treat intervention has been retrospectively evaluated in a research setting in South Africa , there are few published studies of prospective implementation in a real-world setting. This information is important as the screen-and-treat intervention has been included in the South African National Strategic Plan on HIV, sexually transmitted infections (STI) and tuberculosis (TB) and in updated national consolidated HIV guidelines; the intervention is also currently being phased in at > 180 government facilities in Gauteng and Free State provinces [15,16]. Prior to the government programme, we evaluated cryptococcal screen-and-treat at an out-patient HIV clinic in Soweto to determine the prevalence of cryptococcal antigenaemia, management and outcome of patients with antigenaemia and operational barriers to scale-up.
Methods Setting Routine serum cryptococcal antigen (CrAg) screening of ART-naïve HIV-infected adults who attended the out-
© 2015 British HIV Association
patient HIV clinic at Chris Hani Baragwanath Hospital (CHBH) began in January 2009, regardless of baseline CD4 count or eligibility for ART. CHBH is a 2700-bed publicsector and university-affiliated hospital in Soweto. The clinic provides ART through the national programme initiated in 2004; approximately 6859 patients had initiated ART at this clinic by 2010. During the evaluation, approximately 2000 patients were seen at the clinic each month. Patients were initiated on ART if the following criteria were met: CD4 count < 200 cells/μl irrespective of clinical stage or WHO stage IV AIDS-defining illness irrespective of CD4 count and a willingness to adhere to ART . The firstline regimen was comprised of stavudine, lamivudine and either efavirenz or nevirapine .
Inclusion criteria and laboratory testing Patients were included in the study if they had registered at the clinic from 20 January 2009 to 31 July 2010 and/or had been screened for cryptococcal disease. Serum was shipped to the National Institute for Communicable Diseases and tested with the Cryptococcal Antigen Latex Agglutination System (Meridian Bioscience, Inc., Cincinnati, OH) or the Latex-Cryptococcus Antigen Detection System (ImmunoMycologics, Inc., Norman, OK) according to the manufacturers’ instructions [cost per specimen dilution tested, ZAR 41.00 (US$ 3.75)]. Titres up to 1024 were determined on CrAg-positive specimens. CrAg test results were communicated to the clinic within 48 h of the sample being drawn.
Clinical management There was no written protocol for management of CrAgpositive patients at the clinic during the period of evaluation, although guidance was provided by the clinic head (A.S.K.). In general, CrAg-positive patients were contacted to return to the clinic using details provided at registration. If a patient could not be immediately contacted, that patient’s next appointment was flagged as high priority. CrAg-positive patients were assessed for signs of CM; patients with clinical illness consistent with CM were admitted to the adjoining hospital for lumbar puncture (LP). Patients with asymptomatic cryptococcal antigenaemia were also offered an LP; those without detectable cerebrospinal fluid (CSF) CrAg were treated as out-patients, at the clinician’s discretion, with doses of fluconazole ranging from 400 to 800 mg per day for at least 3 months; patients with detected CrAg in CSF were treated for CM. Patients who refused consent for LP or hospital admission were treated with oral fluconazole, monitored frequently as out-patients and advised to immediately return to clinic if symptoms of CM developed.
HIV Medicine (2015)
Cryptococcal screen-and-treat evaluation 3
HIV-infected patients screened n = 1494 Known CD4 count n = 1486 (7 missing results)
CrAg-positive n = 60 (4%)
CrAg-negative n = 1434