Kantor R, Diero L, Delong A, et al. Misclassification of first-line antiretroviral treatment failure based on immunological monitoring of HIV infection in resource-limited settings. Clin Infect Dis. 2009 Aug 1;49(3):454-62.
As antiretroviral therapy (ART) becomes more available in resource-limited settings, treatment failure and the need for second- and third-line ART will increase commensurately. It is estimated that between 5% and 20% of patients who begin ART will fail therapy within four years, despite good adherence and therapeutic drug levels.(1, 2) Second- and third line ART is expensive and complex, and switching from a first-line regimen should not be done prematurely. In upper- and middle-income settings, treatment failure is usually diagnosed when there is evidence of virologic failure; that is, when viral replication, as measured by plasma viral load increases. This technology however, is not widely available in sub-Saharan Africa, and other methods of diagnosing treatment failure are under consideration. One such method is monitoring for immunological failure, that is, using a decline in CD4 cells to diagnose treatment failure. According to World Health Organization (WHO) guidelines, a decreasing CD4 count is a surrogate marker for treatment failure and should trigger a switch in ART, particularly if the cell count is <200 cells/µL.(3)
To document the frequency with which treatment failure based on immunological criteria alone is misdiagnosed compared with virologic monitoring in a teaching hospital in Kenya
Retrospective cohort study
Adult patients attending Moi Teaching and Referral Hospital clinic in Eldoret, Kenya, from May 2006 to March 2007. Patients were eligible who 1) had been treated for more than six months with a WHO-recommended First-line ART regimen; 2) had adhered to ART (i.e., taking >50% of their medication per month before the study visit; and 3) had evidence of immunological failure (i.e., consecutive 25% decrease in CD4 cell count over six months).
All patients had viral load measures at two clinic visits approximately six months apart. The main outcome variable was misclassification of ART failure as defined by consecutive decreases of 25% in their CD4 cell count over six months but with a viral load of <400 copies/mL. The primary predictor variable was CD4 stratum at the second visit. The investigators also explored clinical predictors of misclassification using regression tree analysis.
Of the 149 patients who met the inclusion criteria (i.e., immunological failure), 86 (58%) had viral loads <400 copies/mL and were misclassified as failing ART. The proportion who were misclassified was highest where CD4 cell count was ≥350 cells/µL (22/26, 85%); even among the 29 patients with <100 cells/µL, 12 (41%) were misclassified. In multivariate modeling, variables associated with misclassification were higher CD4 cell count (odds ratio [OR], 2.13 per 100-cell increase; 95% confidence interval [CI]: 1.22-3.72) and a shorter duration of therapy (OR, 1.06 per month; 95% CI: 1.02-1.11). The model also suggested that smaller decreases in CD4 cell percentage were associated with misclassification (OR, 1.22 per 10% smaller decrease; 95% CI: 0.98-1.54). Regression tree analyses showed that patients were more likely to be misclassified if their CD4 cell counts were ≥268 cells/µL, ART was ≤19.5 months, and CD4 cell percent decrease was ≤14%.
The investigators concluded that immunological monitoring as a sole indicator of virologic failure frequently could lead to misclassification and potentially to premature switches from first- to second-line regimens, especially in patients with high CD4 counts, shorter durations of ART, and smaller changes in CD4 cell counts over six months.
Using the Newcastle-Ottawa scale, this proved to be a high-quality study with no loss to follow-up.
The implications of this study are that not using viral loads to monitor therapy can lead clinicians to erroneous conclusions and premature switches in therapy. This conclusion confirms the results of another study from South Africa, where Mee and colleagues(4) showed that WHO clinical and immunologic criteria poorly predict virologic failure after one year of treatment. With limited options for second-line therapy, it is important to keep patients on regimens that suppress viral replication for as long as possible.
- Calmy A, Ford N, Hirschel B, et al. HIV viral load monitoring in resource-limited regions: optional or necessary? Clin Infect Dis 2007;44:128-34.
- Kantor R. Impact of HIV-1 pol diversity on drug resistance and its clinical implications. Curr Opin Infect Dis 2006;19:594-606.
- World Health Organization (WHO). Antiretroviral therapy for HIV infection in adults and adolescents. Recommendation for a public health approach (2006 revision).
- 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.