Reynolds S, Nakigozi G, Newell K, et al. Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda. AIDS 2009 Mar 27;23(6):697-700.
The high price and unavailability of viral load (VL) testing in resource-constrained areas led the World Health Organization (WHO) to develop immunologic criteria for defining failure of antiretroviral treatment (ART).(1) Using dried blood spots and simplified assays may make VL testing available in such settings;(2) however, studies have found that immunologic criteria may not predict virologic suppression.(3,4) Long-term evaluations of this method's ability to predict persons who need to change ART are needed, particularly as VL testing becomes more viable in resource-constrained regions.
To compare the WHO immunologic criteria for treatment failure against the "gold standard" approach of virologic monitoring
Rakai District, southwestern Uganda
Prospective cohort study
Patients of the Rakai Health Sciences Program (a mobile ART clinic) whose CD4 counts were <250 cells/µL or who had WHO stage IV disease (i.e., advanced HIV disease).
The sensitivity, specificity, positive and negative predictive value of immunologic criteria to predict virologic failure
Patients were seen weekly for the first month, bi-weekly for 2 months, and monthly thereafter. CD4 testing was done every 3 months for the first year on ART and then every 6 months. VL monitoring became routine for ART patients in November 2005. As per WHO guidelines, ART was changed if VL was >10,000 copies/mL.
First-line ART was two nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine or stavudine plus lamivudine) and nevirapine or efavirenz. Immunologic failure was examined for patients who had received ART for a minimum of 6 months and in the absence of any ongoing co-infection, was defined as 1) persistent CD4 cell count below 100 cells/mL; 2) a drop in CD4 cell count below baseline pretreatment levels; or 3) a drop in CD4 cell count of 50% from peak on treatment value. For criteria 2 and 3, the CD4 cell count also must have fallen to <200 cells/mL.
Three different virologic failure thresholds were used in the analysis: at least one RNA PCR result of >10,000 copies/mL during treatment follow-up; two or more RNA PCR results of >5,000 copies/mL; and two or more results of >400 copies/mL.
There were 1,133 patients included in the analysis. The follow-up period was 20.2 months (interquartile range [IQR]: 12.4-29.5 months). Ten participants (0.9%) were lost to follow-up after completing at least 6 months of monitoring, 6 (0.5%) transferred to another program, 11 (1.0%) stopped ART due to side effects, and 20 (1.8%) died.
The median baseline CD4 cell count was 153 cells/mL (IQR: 69-214) and 11 patients who had WHO stage IV disease. Eighty-nine percent (n=1,012) of patients experienced a rise in CD4 cell count in the first 6 months. Virologic failure, according to the three study definitions (i.e., thresholds of 10,000 copies/mL at one time point and 5,000 copies/mL or 400 copies/mL at two time points), occurred in 80 (7.1%), 36 (3.2%), and 112 (9.9%), participants, respectively. A total of 125 (11%) of the patients developed immunologic failure. Only 26 patients who met the lowest threshold for virologic failure also met the criteria for immunologic failure. A substantial proportion of patients (76.8%) only met the virologic criteria for treatment failure while 8.7% of patients developed immunologic failure but not virologic failure. The sensitivity and specificity of immunologic monitoring for predicting virologic failure (i.e., two viral load test results of >400 copies/mL) was 23% and 90%, respectively, with the positive and negative predictive value being 21% and 91%, respectively.
Immunologic criteria for ART failure poorly predicted virologic failure and would have resulted in persons changing therapy unnecessarily.
This was a high quality study. The cohort was representative of persons receiving ART in resource-constrained areas in terms of the study setting and clinical care provided. Absence of treatment failure at the start of the study was determined objectively, the follow-up time was acceptable, the measurement of the outcome was objective and determined a priori, and the proportion completing the study was acceptable.
The findings from this study are important because they show that the immunologic criteria currently used results in switching therapy unnecessarily in about 9% of patients followed for more than a year. This study confirmed the low sensitivity of immunologic criteria reported from other studies.(5,6) As the cost and practical barriers to VL testing are reduced, using VL to determine treatment failures is likely to better identify persons truly in need of a change in ART.
- World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: towards universal access. Recommendations for a public health approach; 2006:38-42.
- Waters L, Kambugu A, Tibenderana H, et al. Evaluation of filter paper transfer of whole-blood and plasma samples for quantifying HIV RNA in subjects on antiretroviral therapy in Uganda. J Acquir Immune Defic Syndr 2007;46:590-3.
- Moore DM, Mermin J, Awor A, Yip B, Hogg RS, Montaner JS. Performance of immunologic responses in predicting viral load suppression: implications for monitoring patients in resource limited settings. J Acquir Immune Defic Syndr 2006;43:436-9.
- Bisson GP, Gross R, Strom JB, et al. Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy. AIDS 2006;20:1613-19.
- Chaiwarith R, Wachirakaphan C, Kotarathititum W, Praparatanaphan J, Sirisanthana T, Supparatpinyo K. Sensitivity and specificity of using CD4+ measurement and clinical evaluation to determine antiretroviral treatment failure in Thailand. Int J Infect Dis 2007;11:413-16.
- Mee P, Fielding KL, Charalambous S, Churchyard GJ, Grant AD. Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS 2008;22:1971-7.