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Clinical Science

A Prospective Evaluation of a Multisite Cryptococcal Screening and Treatment Program in HIV Clinics in Uganda

Nalintya, Elizabeth MBChB, MPH*; Meya, David B. MMed, PhD†,‡; Lofgren, Sarah MD§; Huppler Hullsiek, Kathy PhD; Boulware, David R. MD, MPH§; Rajasingham, Radha MD§

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: June 1, 2018 - Volume 78 - Issue 2 - p 231-238
doi: 10.1097/QAI.0000000000001669
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Abstract

INTRODUCTION

Cryptococcal meningitis continues to be a leading cause of AIDS-related mortality, accounting for approximately 15% of AIDS-related deaths in sub-Saharan Africa.1 Mortality from meningitis remains high at 50%–70% in sub-Saharan Africa because of delays in presentation to care, management requiring serial lumbar punctures, and difficulties with access and affordability of optimal antifungal medications.2–4 Cryptococcal antigen (CrAg) can be detected in the blood, weeks before onset of meningitis, and CrAg is an independent predictor of meningitis and death.5–7 Screening for CrAg among those with a reduced CD4 cell count, and treating those CrAg+ with fluconazole, has been evaluated in a randomized controlled trial in Zambia and Tanzania, and alongside adherence counseling demonstrated a 28% reduction in mortality.8 CrAg screening and preemptive treatment is now a recommendation by the World Health Organization (WHO) and numerous national HIV guidelines.9

However, actual implementation and widespread uptake have been slow outside the research studies.10,11 Even within research settings, those programs with high rates of loss to follow-up, or low rates of timely antiretroviral therapy (ART) initiation, do not demonstrate the same survival benefit as seen in clinical trials.11–13 Although CrAg screening programs have the potential to be life-saving, few studies have evaluated optimal rollout strategies and programmatic implementation to maximize survival among CrAg+ individuals. Despite recommendations in national HIV guidelines, there are no recommendations for how to effectively implement a new CrAg screening program in already overburdened, under-resourced HIV clinics.

Additionally, CrAg titer has been positively associated with development of meningitis and death.13 Specifically, those asymptomatic CrAg+ persons with a titer ≥1:160 are 9 times more likely to develop meningitis compared to those with a titer <1:160.13 Although national and international guidelines do not make recommendations regarding titer, customizing antifungal therapy according to CrAg titer, whereby more intensive therapy is given for those with high titers, is a potential treatment strategy worth exploring. However, prospective measurement of CrAg titer in real-time has not been performed or evaluated as part of CrAg screening programs.

We evaluated a CrAg screening program that implemented (1) clinic-wide educational sessions, (2) laboratory staff training, (3) a research nurse to identify a clinic point person responsible for CrAg screening, and (4) a system for ongoing review and feedback. We evaluated implementation and clinical outcomes of this CrAg screening program in 11 outpatient HIV clinics in Kampala. We also evaluated feasibility of performing and reporting CrAg titers in real-time, as a potential valuable strategy in future CrAg screening programs.

METHODS

Study Setting

Prospective CrAg screening occurred from December 2015 to January 2017 at 11 HIV clinics in Kampala, Uganda. Six were under the Kampala Capital City Authority, which operate in partnership with the Infectious Diseases Institute outreach program, providing care and treatment to more than 110,000 people living with HIV in Uganda, and 5 were within the city suburbs.

Study Design

This was a prospective cohort study of HIV-infected adults with a CD4 cell count ≤100 cells/µL. Implementation of the intervention was a phased roll out in which 2 clinics were enrolled every 2 months. Ethical approvals were obtained from the Joint Clinical Research Center (Kampala, Uganda), the University of Minnesota, and the Uganda National Council for Science and Technology.

Intervention

Two research nurse-counselors employed at 50% each were responsible for ensuring CrAg screening was performed successfully at 11 clinics. The interventions included:

  1. Education of health care workers—before initiation of CrAg screening, a 1-hour educational presentation was given on cryptococcal meningitis and CrAg screening to all clinic staff, including doctors, nurses, social workers, counselors, pharmacy, and laboratory staff. This was followed by more specific departmental trainings (30 minutes each) for clinicians, counselors, peer educators, pharmacy, and laboratory staff regarding their roles and expectations within each department. Trainings were delivered once during the study period by the research nurse who oversaw the CrAg screening program at the clinic, and the study coordinator.
  2. Laboratory staff training—Laboratory staff underwent additional training to become familiar with how to perform the CrAg test, perform CrAg titers, and document results. Laboratory staff were trained on how to incorporate CrAg results into existing CD4 registers, ensuring that each CD4 <100 cells/µL had a reflexive CrAg result, and reporting CrAg+ results as a critical laboratory result to the clinician in charge.
  3. In weeks 1 and 2 of the intervention, a point-person was identified among the clinic staff as the local CrAg screening champion. The main roles of the CrAg screening champion were to (1) receive CrAg+ results, (2) ensure CrAg+ patients returned to clinic (this sometimes required a phone call reminder), (3) inform the research nurse-counselors of symptomatic CrAg+ persons for appropriate referral, (4) prescribe fluconazole, (5) complete the national CrAg register for all CrAg+ patients, (6) oversee the laboratory, pharmacy, and peer educator roles, and (7) ensure CrAg+ persons start ART in a timely manner. These persons were not paid extra for this role.
  4. A laboratory CrAg screening champion was identified who was responsible for (1) receiving CrAg results from the central laboratory, (2) recording results in the clinic laboratory register, (3) identify those who had a CD4 <100 cells/µL but not received CrAg results, (4) communicate with peer educators about missing results, (5) inform clinicians of positive results, (6) run the point-of-care CrAg test as requested by the clinicians, (7) inform nurses of CrAg kit stock outs, and (8) train new laboratory staff about CrAg screening. These persons were typically laboratory assistants or technicians and were not paid extra for this role.
  5. A peer educator was responsible for (1) filing CrAg+ results, (2) calling patients who were not screened to return to clinic, (3) completing appointment log of CrAg+ persons, (4) contacting patients who missed their appointments, (5) accompanying unscreened patients to the laboratory and to the clinician, (6) accompanying CrAg+ patients to the pharmacy to ensure receipt of fluconazole. These persons were lay HIV-infected persons who were able to read and write. They were already involved in the clinic to carry out roles such as escorting patients, and identifying patient medical files.
  6. In weeks 4–6 of the intervention, the CrAg screening champion (appointed local clinic staff) ran the CrAg screening program, and the research nurse-counselor supervised activities.
  7. By week 8, the research nurse-counselor moved on to other clinics but was available for assistance, as needed.
  8. Monthly feedback was given to clinics regarding proportion screened and treated appropriately

Laboratory Methods

CD4 testing was performed per routine clinical care; 6 clinics had CD4 tests run at a central laboratory, 2 clinics had CD4 testing performed at a local clinical laboratory, and 3 clinics had access to point-of-care CD4 testing (Alere Pima; Alere, Orlando, FL). Per our protocol, all CD4 results of ≤100 cells/µL reflexively had CrAg testing performed on remaining plasma using the CrAg lateral flow assay (Immy, Norman, OK), per the manufacturer's instructions. CrAg testing was performed in the same setting as CD4 testing. Thus, if CD4 testing was performed centrally, then CrAg testing was performed centrally. If CD4 performed as a point-of-care test in the clinic, CrAg testing was performed as a point-of-care in the same clinic. CrAg titers were performed by dilution as described by the manufacturer and reported in real-time. Initially only ART-naive persons were included in the study. ART status is routinely documented on laboratory CD4 request forms.

Clinical Assessment

Once a CrAg+ result was reported, this was considered a critical laboratory result. Patients were called and asked to return to clinic as soon as possible for clinical assessment; Although this should be standard of care, it typically is not performed in routine care because of the nature of under-resourced, overburdened HIV clinics. As a result, this was a task performed by the local CrAg screening champion. Per standard of care, the clinician evaluated the patient for signs and symptoms of meningitis. If they were symptomatic, or in the opinion of the physician there were concerns for meningitis, a lumbar puncture was offered for further evaluation. Although this is considered standard of care, the CrAg screening champion oversaw that these practices were fulfilled. If the patient was asymptomatic, they were considered for preemptive treatment. Contraindications to treatment included known pregnancy, liver disease, or abnormal liver tests.

Preemptive Treatment

Preemptive treatment was 800 mg of fluconazole daily for 2 weeks, followed by 400 mg of fluconazole daily for 8 weeks, per WHO and 2014 Ugandan national guidelines. Secondary prophylaxis of 200 mg daily for 6 months was prescribed per the discretion of the medical officer. Thus, regardless of CrAg titer results, all patients received standard of care therapy. For those on tuberculosis therapy including rifampin, fluconazole dose was recommended to be increased by 50% because of drug interactions.

Changes During the Study

In June 2016, we broadened our enrollment criteria to include those who were currently on ART, as we found a number of CrAg+ persons on ART who were not eligible for our study. This group on ART has not previously been studied, and it is unknown if CrAg screening is as beneficial in this population that is either failing ART or recently started ART.

In October 2016, one of the sites had a fluconazole shortage. As a result, they had 2 asymptomatic CrAg+ persons who were unable to be treated with clinic supplied fluconazole. We thought it unethical to perform a screening intervention where no treatment was available; thus ,we provided a small supply of fluconazole to provide to CrAg+ participants during stockouts.

Outcomes

Outcomes of interest included proportion of CrAg+ persons who received titers, proportion of CrAg+ eligible for treatment who received fluconazole treatment, time from CrAg screening to receipt of fluconazole, time from CD4 count to ART initiation, 6-month survival, and 6-month incidence of cryptococcal meningitis. Active tracing was performed for participants lost to follow-up, and if those lost were not found after active tracing, they were presumed dead.

Data Collection and Analysis

Laboratory data and data from clinical care were extracted from routinely collected chart data from the clinic and entered into a separate study database by the research nurse. Data on time of ART initiation, fluconazole dose and duration, symptoms of meningitis, and CD4 count were recorded. Vital status and incidence of meningitis at 6 months was collected. For demographic and clinical characteristics, median values were compared using Mann–Whitney U tests, and categorical characteristics were compared using Fisher exact test. P-values compared asymptomatic CrAg versus symptomatic CrAg groups. Analyses were conducted using SPSS software version 24.

RESULTS

Between December 2015 and January 31, 2017, 1440 persons with a CD4 cell count ≤100 cells/µL were screened for CrAg. The median CD4 cell count of those screened was 40 (interquartile range [IQR]: 17–70) cells/µL. Of those screened, 193 (13.3%) were on ART, and 256 (18%) of CD4 and reflexive CrAg tests were performed as point-of-care.

Prevalence of CrAg positivity was 6.5% (94/1440) (Fig. 1). Demographic characteristics of those screened are summarized in Table 1. Of those CrAg+, 89% (84/94) had a CrAg titer performed in real time. Clinics with lower volume of screening were less likely to successfully perform the CrAg titer in real time. Of those CrAg+, 7 of 94 persons (7%) died or were lost to follow-up before returning to clinic for further evaluation; median CrAg titer was 1:80, and none of these 7 received ART.

FIGURE 1
FIGURE 1:
Consort diagram.
TABLE 1
TABLE 1:
Baseline Demographics

Plasma CrAg+ and Asymptomatic

Fifty-three (56%) of the CrAg+ persons were asymptomatic and eligible for treatment, 9 of whom were already on ART, and 11 of whom were concurrently taking rifampin (Table 1). Of those receiving ART at the time of CrAg screening, 8 of 9 had virologic failure and 1 started ART 1 day before CrAg screening. Median CD4 count was 20 cells/µL (IQR: 5–45), and median plasma CrAg titer was 1:40 (IQR: 1:20–1:160). One hundred percent of those asymptomatic CrAg+ persons who returned to clinic were prescribed fluconazole therapy at a median time of 14 days after CD4 testing (IQR: 7–27) (Table 2). On this same visit (median 14 days after CrAg screening), persons were assessed for symptoms. All initiated ART at a median time of 28 days after CrAg screening (IQR: 20–42). Six-month survival was 87% (46/53) (Table 2). Of those 7 who died, median time to death was 97 days (IQR: 70–152), median CrAg titer was 1:80, and median CD4 cell count was 16 cells/µL (Fig. 2). One died of cryptococcal meningitis, one with suspected/unconfirmed malaria (ie, febrile illness), and the other 5 of unknown causes at home. Five of 7 died after completing the 10-week recommended course of preemptive fluconazole therapy.

TABLE 2
TABLE 2:
Six-Month Outcomes for Asymptomatic and Symptomatic CRAG+ Persons
FIGURE 2
FIGURE 2:
Survival among asymptomatic and symptomatic CRAG+ persons. Median time from CD4 testing to death was 117 days (IQR: 71–160) in the asymptomatic CRAG+ group 9 days (IQR: 2–16) in the symptomatic CRAG+ group. For the 3 persons lost to follow-up in the symptomatic group, time until lost to follow-up was based on last contact with patient.

Two enrolled persons who received preemptive therapy developed cryptococcal meningitis during the follow-up period. One initiated ART and fluconazole on the same day and developed meningitis 44 days later and died; CD4 count was 16 cells/µL and CrAg titer was 1:2560. The second person had a CD4 count of 1 cell/µL and CrAg titer of 1:320. They developed cryptococcal meningitis 4 weeks after initiating fluconazole and 2 weeks after initiating ART, and they survived.

Plasma CrAg+ and Symptomatic for Meningitis

Of those 26 symptomatic, 23 reported headache, 11 fever, 10 neck pain, 5 photophobia, 4 stiff neck, 3 confusion, 3 behavioral changes, and 1 reported recent seizures. Only 1 person denied both headache and neck pain as well as having denied all symptoms, but the medical officer suspected meningitis based on physical examination. Of those 26 symptomatic, 19 consented to a lumbar puncture and 17 (89%) had confirmed cryptococcal meningitis either by cerebrospinal fluid (CSF) culture and/or CSF CrAg. Fifteen had CSF quantitative culture performed (median: 63,000 CFU/mL, IQR: 22,450–314,000 CFU/mL). All 17 were treated for cryptococcal meningitis with amphotericin and fluconazole. The median CD4 cell count for those found to have cryptococcal meningitis at the time of CrAg screening was 19 cells/µL (IQR: 9–43), and median plasma CrAg titer was 1:160 (IQR: 1:60–1:1280). Although there was a trend that CrAg titer was higher in symptomatic persons, this did not achieve statistical significance (P = 0.078) (Table 1). For those with confirmed meningitis, mortality was 35% (6/17) at 6 months despite amphotericin-based treatment. Median time from CD4 testing to death was 9 days in the symptomatic CrAg+ group as compared to 117 days in the asymptomatic CrAg-positive group (Log rank test P < 0.001) (Fig. 2). There was no statistically significant relationship between CrAg titer and mortality, or time to fluconazole and death. Those 2 with a negative lumbar puncture were started on fluconazole before lumbar puncture was performed.

Of those symptomatic who declined lumbar puncture, 7 of 7 died. Five died of presumed cryptococcal meningitis and 2 of unknown cause. Median time to death of those who declined lumbar punctures was 16 days from CrAg screening, and none initiated ART. Only one was documented to have initiated fluconazole.

DISCUSSION

Our screening program with intensive education and training of all clinic staff resulted in 100% of asymptomatic CrAg+ who returned to clinic initiating fluconazole within 2 weeks of screening and ART initiation within 4 weeks of screening. This resulted in significantly improved survival and reduced incidence of meningitis compared to the symptomatic CrAg+ persons within our study and compared to asymptomatic CrAg+ persons in historical studies without screening.5 The program retained all asymptomatic CrAg+ persons who returned for CrAg results in care with none lost to follow-up. Notably 7 of 94 CrAg+ persons screened did not return for their results and were presumed dead. In total, 30% of CrAg+ (asymptomatic and symptomatic) identified on routine screening were dead or lost to follow-up at 6 months, even with preemptive therapy for those asymptomatic and standard amphotericin-based treatment for those with meningitis. Other CrAg screening studies have found a similar 25%–30% failure rate despite preemptive fluconazole for asymptomatic CrAg+ persons.2,13 One CrAg screening study in Tanzania and another from South Africa found only 50% survival among CrAg+ persons who received fluconazole.7,10 Although this is an improvement from 100% mortality found in CrAg+ persons who received ART but no antifungal therapy,5,7 further investigation into enhanced preemptive therapy for asymptomatic CrAg+ persons and immediate return to clinic for antifungal therapy is likely warranted.

Implementation of CrAg screening in HIV clinics remains challenging. The value of a screening program is undermined by lack of treatment for those who screen positive. Fluconazole stockouts are a reality on the ground, along with shortages of amphotericin, and no supply of flucytosine for those with meningitis. Our study used a clinic-wide system of education and training of existing health care workers in the operational aspects of CrAg screening and treatment. This is feasible, given that outside the 2 part-time research nurses who oversaw this study at 11 sites, no additional health care workers were employed. Existing health care workers who had similar duties at the clinic were given responsibilities in identifying at risk patients and navigating their care. Oversight from experts intermittently to give clinics feedback could be done remotely via phone or Skype on a monthly basis to answer questions and assist with management of more complicated patients. CrAg titer was feasible within our setting with additional training, should this become employed in the future for customized antifungal therapy. Given that CrAg titer was not predictive of meningitis or death, but other studies have drawn this conclusion, a larger, meta-analysis might be informative. Titers seem to be associated with symptoms and meningitis, but many of the screening studies are small, and therefore limited in their ability to draw firm conclusions.

The timing of deaths among CrAg+ persons may inform future interventions to improve outcomes in CrAg+ persons. Seven CrAg+ were dead or lost to follow-up before returning to clinic after CD4 count and CrAg testing. A positive CrAg result is a critical value, and CrAg+ patients need to return to clinic as soon as possible, as without antifungal therapy, they will die. This population with advanced AIDS ideally should be identified and linked to care earlier and may have benefited from immediate ART initiation and more targeted intensive follow-up. Second, of the 7 asymptomatic CrAg+ who died after initiating preemptive therapy, most died between 3 and 5 months after CrAg screening. Fluconazole preemptive therapy was 10 weeks, and any additional maintenance fluconazole of 200 mg daily was prescribed at the discretion of the medical officer. Both WHO and 2017 Ugandan HIV guidelines now recommend maintenance fluconazole therapy for 6 months. However, in reality, there are stockouts of fluconazole, even for initial preemptive therapy. Thus, practically, fluconazole maintenance is frequently not prescribed. The role of fluconazole maintenance therapy among this asymptomatic CrAg+ population has not been systematically studied. In the absence of clinical trials, large prospective studies are needed to assess outcomes with and without maintenance fluconazole, especially given the limited supply of fluconazole.

Furthermore, 28% of CrAg+ persons were identified as symptomatic during routine screening. Most had confirmed cryptococcal meningitis, and 54% of the symptomatic CrAg+ population was dead or lost to follow-up at 6 months. This not only highlights the inadequacies in pursuit of lumbar punctures for cryptococcal meningitis diagnosis and treatment in our setting but also the value of such a screening program to identify persons with AIDS-related opportunistic infections. One might consider that with 7% CrAg+ not returning to clinic secondary to death or loss to follow-up, and an additional 28% symptomatic, raising the threshold for CrAg screening to CD4 ≤150 or 200 cells/µL may allow us to identify one-third of this critically ill population earlier. Studies in Ethiopia and Tanzania have used the CD4 <150 cells/µL threshold but still have observed high prevalence of symptomatic meningitis and death.2,7 The cost-effectiveness of such a policy would need to be evaluated on a national scale.

When screening for symptoms, asking about headache and neck pain identified 96% of symptomatic individuals. For future programs, simply asking for these 2 symptoms should be sufficient in classifying a person as symptomatic CrAg+.

Although CrAg titer seemed to be associated with severity of disease (ie, symptomatic CrAg+ persons were more likely to have higher titers, compared to asymptomatic CrAg+ persons), as seen in previous studies, this did not achieve statistical significance, likely because there was a 2-week delay between CrAg titer testing and return to clinic. Those with low titers who developed meningitis presumably had rapid progression of disease.14 Ensuring that CrAg-positive persons return to clinic urgently would likely reduce the proportion who return with symptoms of meningitis. Alternatively, rechecking CrAg titer at the time of return may also be informative if a customized treatment approach was implemented.

Areas of future research for CrAg screening and treatment programs include timing of preemptive fluconazole therapy in the context of immediate ART initiation, the role of fluconazole maintenance therapy, and enhanced preemptive therapy for those with high titers at high risk of meningitis and death. Immediate ART initiation is favored in this immunosuppressed population; however, there is a concern of unmasking cryptococcal immune reconstitution inflammatory syndrome if ART is initiated without first starting antifungal therapy.15 High mortality (approximately 70%) of those with cryptococcal immune reconstitution inflammatory syndrome must be weighed against the 93% of the population that is CrAg negative, that would likely benefit from test and treat strategies. Further implementation science studies to guide ministries of health and individual clinics are desperately needed to translate this life-saving intervention from clinical trials into routine care.

Limitations of our study include the lack of a control group to compare survival and incidence of meningitis. We also did not rigorously investigate adherence to fluconazole, so it is possible that poor adherence to fluconazole would minimize the effect of fluconazole on survival. Before the study, our goal was to have asymptomatic CrAg+ persons initiate fluconazole within 2 weeks and initiate ART within 4 weeks. This was based on the presumed time to perform the test, get results back in patient charts, contact patients, and have them return to clinic. Based on the high proportion who were symptomatic, and the 7 who died before returning for laboratory results, future CrAg screening programs should expedite the turn-around-time for CrAg test results, so that patients can be appropriately triaged for lumbar puncture, or preemptive treatment (Table 3). One could consider screening for symptomatic meningitis with questions of headache and neck pain over the phone, akin to the tuberculosis symptom screen, when CrAg test results are being communicated. If at time of presentation to clinic, a patient presents with headache and/or neck pain, one could consider a point-of-care CD4 or CrAg lateral flow assay, knowing that symptomatic CrAg+ persons have a 50% risk of death, at approximately 3 weeks. This delay between CrAg testing, laboratory results, patient return to clinic, and initiation of fluconazole and ART needs to be further reduced to improve patient outcomes. Improved access to WHO essential medicines of amphotericin and flucytosine across sub-Saharan Africa, where the burden of disease is greatest, is essential.16

TABLE 3
TABLE 3:
Recommendations for CRAG Screening Programs

Finally, our ability to identify more than 1400 people with CD4 ≤100 cells/µL in 11 HIV clinics in Kampala over a 13-month period speaks to the wide gap between the ambitious 90-90-90 goals proposed by the Joint United Nations Programme on HIV/AIDS, and current reality on the ground. Enhancing services to identify HIV-infected persons early and expeditiously initiate ART would diminish the need for CrAg screening and treatment programs for those with advanced HIV disease in the long term. Until this goal can be achieved, CrAg screening and treatment programs are a valuable investment to save lives, although require further refinement in optimal early detection and treatment strategies.

REFERENCES

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Keywords:

cryptococcal screening; cryptococcal meningitis; opportunistic infections

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