IAS: WHO clinical staging excluding many without symptoms from HIV treatment, despite need

In resource-poor settings where there is little or no access to laboratory facilities to do CD4 cell counts, the HIV/AIDS clinical staging system, devised by the World Health Organization (WHO), is often used to determine a patient’s need for antiretroviral therapy (ART); however, a recent study from South Africa has found that using WHO clinical staging alone could miss a lot of patients with CD4 cell counts below 200 cells/mm³.

“I’m very uncomfortable with using clinical staging only,” said Dr Glenda Gray, one of the study’s principal researchers from the Perinatal HIV Research Unit of the University of Witwatersrand, South Africa. She presented the study’s findings on behalf of Dr Neil Martinson at last week’s Third International AIDS Society Conference on HIV Treatment and Pathogenesis in Rio de Janeiro, Brazil.

WHO staging

The WHO clinical staging system for HIV/AIDS was designed for use in resource-limited settings where there is limited access to laboratory services. It emphasises the use of clinical parameters (symptoms, weight loss and different opportunistic infections) to guide clinical decision-making for the management of patients (see http://www.who.int/docstore/hiv/scaling/anex1.html and http://www.who.int/entity/hiv/pub/guidelines/clinicalstaging.pdf).

In the absence of CD4 cell testing, WHO recommends initiating ART for patients with stage III/IV disease and for those with stage II disease (mild symptoms) when the total lymphocyte count is under 1200.

However, some people with HIV experience substantial immunological deterioration without developing noticeable symptoms. Nonetheless, their weakened immune systems leave them vulnerable to life-threatening infections — which ART and cotrimoxazole prophylaxis might be able to prevent. Because CD4 cell counts are a direct reflection of the relative strength or weakness of the immune system, they are used in many countries, often together with WHO clinical staging, as the basis for making treatment decisions.

But the fact remains that CD4 cell count tests simply aren’t available to help decide which people with HIV need ART at the primary care level in many resource-limited settings. Thus, eligibility for antiretroviral treatment depends on accurate clinical staging by medical personnel, some of whom may be unfamiliar with HIV care.

So researchers in South Africa conducted a study at two primary healthcare facilities (one at an urban site in Soweto and the other at Tintswalo Hospital, a rural site in Limpopo Province) to see what proportion of patients with CD4 cell counts below 200 cells/mm³ would be classified as having WHO stage I or II disease (and thus ineligible for antiretroviral treatment despite advanced immunosuppression). Furthermore, they looked for factors that could help predict which patients with low CD4 cells might be assessed with WHO stage I or II HIV disease.

The cross-sectional, operational study involved 2000 HIV-positive adult patients attending the clinic, 1500 in Soweto and 500 in Limpopo. Both clinics offer comprehensive outpatient care, as part of a PEPFAR-funded wellness program, delivered by primary health care nurses supported by doctors.

At the first study visit, the patients were seen predominantly by nurses, who recorded the patient’s demographic information and assessed WHO staging. Participants also had CD4 cell counts measured within 90 days on either side of their first visit (when they were staged).

Results

The median CD4 cell count was 233 overall: 246 cells at the urban site, 203 at the rural site.

WHO staging varied substantially by site. Almost half (~47%) of the patients in the urban site were classified as stage I, compared to ~15% from the rural site; 16% vs. 23% were stage II: 35% vs. 55% were stage III and 2% vs. 7% were stage IV in the urban and rural sites respectively.

The median CD4 cell count by stages were:

• Stage I: 339 (Interquartile range: 199-525), 302 patients at the urban site; 413 (267-615), 78 patients at the rural site.
• Stage II: 194 (123-370.5), 123 patients at the urban site; 270 (134-420.5), 128 patients at the rural site.
• Stage III: 154 (67-279), 241 patients at the urban site; 147 (56-279), 285 patients at the rural site.
• Stage IV: 176 (30-450), 8 patients at the urban site, 105 (51-327), 33 patients at the rural site.

Overall, 23.9% of patients with stage I disease (25% urban, 14.5% rural) and 46.1% of patients with stage II disease (50.4% urban, 37.9% rural) had CD4 cell counts below 200 cells/mm³.

In a univariate analysis, there was a trend towards patients with lower CD4 cells from the urban site being classified as stage I or II. Dr Gray said that doctor supervision and staging of patients was more common in the rural site (and therefore possibly more accurate), though this was found not to be a predictor of misclassification in the multivariate analysis. However, CD4 cell counts and staging did appear to agree better as the nurses gained more experience.

However, one factor did seem to consistently predict this disagreement between CD4 cells and disease stage. Men were more likely to be staged as I or II but have CD4 cell counts <200 cells/mm³. This was significant in both the univariate and multivariate analysis.

Of the patients classified with stage III or IV disease, 59-62% had CD4 cells below 200 cells/mm³, 15-20% had CD4 cells between 200-350 cells/mm³, and 18-26% had CD4 cell counts above 350 cells/mm³.

Conclusions

“If ART were restricted to WHO clinical stages 3 and 4 exclusively, approximately one quarter of WHO stage 1 and half of WHO stage 2 patients would have been overlooked for ART,” said Dr Gray. “It appears that in our setting, CD4 count is an important adjunct to WHO clinical staging in determining eligibility for antiretroviral care.”