Development and validation of decision rules to guide frequency of monitoring CD4 cell count in HIV-1 infection before starting antiretroviral therapy

Abstract

Background: Although CD4 cell count monitoring is used to decide when to start antiretroviral therapy in patients with HIV-1 infection, there are no evidence-based recommendations regarding its optimal frequency. It is common practice to monitor every 3 to 6 months, often coupled with viral load monitoring. We developed rules to guide frequency of CD4 cell count monitoring in HIV infection before starting antiretroviral therapy, which we validated retrospectively in patients from the Swiss HIV Cohort Study.

Methodology/principal findings: We built up two prediction rules ("Snap-shot rule" for a single sample and "Track-shot rule" for multiple determinations) based on a systematic review of published longitudinal analyses of CD4 cell count trajectories. We applied the rules in 2608 untreated patients to classify their 18 061 CD4 counts as either justifiable or superfluous, according to their prior ≥5% or <5% chance of meeting predetermined thresholds for starting treatment. The percentage of measurements that both rules falsely deemed superfluous never exceeded 5%. Superfluous CD4 determinations represented 4%, 11%, and 39% of all actual determinations for treatment thresholds of 500, 350, and 200×10(6)/L, respectively. The Track-shot rule was only marginally superior to the Snap-shot rule. Both rules lose usefulness for CD4 counts coming near to treatment threshold.

Conclusions/significance: Frequent CD4 count monitoring of patients with CD4 counts well above the threshold for initiating therapy is unlikely to identify patients who require therapy. It appears sufficient to measure CD4 cell count 1 year after a count >650 for a threshold of 200, >900 for 350, or >1150 for 500×10(6)/L, respectively. When CD4 counts fall below these limits, increased monitoring frequency becomes advisable. These rules offer guidance for efficient CD4 monitoring, particularly in resource-limited settings.

Figure 1. Illustration of CD4 monitoring decision rules.

The Snap-shot rule (left) uses a single observation Y_obs (square root transformed) of the biomarker at time t_obs. The Track-shot Rule (right) uses Y_obs plus one or more previous observations Y₋₁, Y₋₂ etc. available at times t₋₁, t₋₂ etc. The suitable time for next measurement, t_next, is when the predicted value has some minimal probability P to reach the decision limit for antiretroviral therapy Y_ART. Appropriate standard normal deviates z_P are used to weight the within-subject and between-subject dispersions, σ_e and σ_b respectively, according to the level chosen for P. The relevant prediction therefore depends on a worst-case scenario (Y_wst) rather than average population prediction (Y_pred). This illustration is schematic, as it is variances that are actually summed, not standard deviations.

Figure 2. Variogram for the Snap-shot rule.

The Snap-shot rule is applied to an initial CD4 cell count of 750×10⁶/L, observed at time = 0. It shows the lowest value that a subsequent measurement can be expected to reach with a probability of 5% (dashed line) or 10% (dotted line). The continuous line indicates the CD4 trajectory predicted for an average patient. The average curve will take 7.3 years to reach the 200×10⁶/L threshold (horizontal line); however, biological variability makes this outcome possible within 2 years for one patient in 20, and at 3 years for one patient in 10.

Figure 3. Nomograms for the Snap-shot rule.

These nomograms show the time to wait before the next CD4 count determination as a function of the actual observation, at two decision thresholds to start antiretroviral therapy, with varying probabilities of observing a value at this threshold. The 50% lines correspond to average population predictions. The arrows illustrate the rule applied to an intial count of 1000×10⁶/L, giving about 1.7 years to reach a count of 350×10⁶/L with a 5% chance, and about 3.4 years to reach a count of 200×10⁶/L.

Figure 4. CD4 cell count data from an illustrative patient.

The Snap-shot rule is applied to the first determination (closed circle) done 1.8 year after positive serology (discovered at time = 0), and indicates to repeat the test at 3.2 years (dashed arrow), when the CD4 count has 5% chance to reach 200 cells/µL. The second value actually measured at 3 years is thus declared superfluous and discarded (open circle). The rule is reapplied to the third value actually measured at 3.6 years, and designates the 3 next determinations as superfluous. The last 6 values fall below the threshold to question necessity. The treatment is actually initiated 7 years after HIV detection, once CD4 counts reach the threshold of 200 cells/µL. The lines indicate the average population slope. The Track-shot rule would give fairly similar results, except that it would indicate the 8th measurement as superfluous (dotted arrow and grey circle).