Published randomized clinical trials evaluating treatment strategies in infants and young children with HIV.

<p>ZDV, zidovudine; 3TC, lamivudine; NVP, nevirapine; LPV/r, lopinavir/ritonavir; NFV, nelfinavir; d4T, stavudine; CDC, Centers for Disease Control; DSMB, Data and Safety Monitoring Board.</p

HIV RNA at trial closure by monitoring strategy and line of regimen.

<p>HIV RNA at trial closure by monitoring strategy and line of regimen.</p

Reasons for not switching when first met immunological/clinical criteria for switch in patients receiving and not receiving CD4 monitoring.

*<p>based on a retrospective request for reasons why patients had not switched within 8 weeks of first meeting protocol switch criteria.</p>**<p>eg only presumptive diagnosis, responded to treatment for the clinical event, event judged related to recent period off ART, patient being monitored and doing well.</p

CD4 and VL at switch to second-line for first-line failure in patients not receiving CD4 or VL count monitoring (CDM).

*<p>p = 0.84 adjusted for whether whether enrolled in second-line studies (p<0.0001) and whether switched to second-line before or after 1 Jan 2007 (p = 0.15), sex (p = 0.45) and age at switch (p = 0.54). More participants switched for non-WHO 4 reasons later in the trial reflecting wider promotion of WHO 3 events as switch criteria in WHO 2006 guidelines<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057580#pone.0057580-World2" target="_blank">[9]</a>; see Results.</p>**<p>ROC area under the curve  =  0.90 (95% CI 0.83–0.98) in 117 patients enrolled in second-line studies, vs 0.93 (95% CI 0.86–0.99) in 64 patients not enrolled in second-line studies.</p>†<p>66/207 (32%) also had WHO 3 events in the month prior to switch (of which 37 were oral candida and 19 were weight loss >10%)</p>‡<p>retrospectively on stored plasma</p><p>Note: ROC  =  receiver operating characteristic, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057580#pone-0057580-g002" target="_blank">Figure 2</a>. Two switches 46 weeks after ART initiation: all others ≥52 weeks.</p

Clinical events triggering switch after 44 weeks on ART in patients monitored without CD4 cell counts (CDM).

<p>Note: SBI  =  severe bacterial infection; OHL = oral hairy leukoplakia; ERC = Endpoint Review Committee (blinded to randomised group). Data not shown for events with only 1 associated switch: visceral herpes simplex, HIV encephalopathy, recurrent pneumonia, weight loss+persistent fever, weight loss+oral candida+SBI, oral candida+OHL, pulmonary TB+SBI, HIV nephropathy, OHL). Additional new/recurrent WHO events which occurred during the first year on ART are included in the main trial report<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057580#pone.0057580-DART1" target="_blank">[4]</a>, but not here as switch to second-line for first-line failure only occurred after 1 year.</p

CD4 and VL at switch to second-line for first-line failure in patients receiving 12-weekly CD4 count monitoring, but no VL monitoring (LCM).

*<p>mostly CD4 declines to just over 100 cells/mm³</p>†<p>65/265 (25%) also had WHO 4 events at the time of switch (plus 1 of the 43 switching for other CD4 reasons)</p>**<p>CD4 <50 cells/mm³ on day of switch: did not have any previous CD4 <50 cells/mm³ or 2 previous CD4s <100 cells/mm³</p>‡<p>retrospectively on stored plasma</p>††<p>p = 0.95 in a multivariable logistic regression model for VL assayed (yes/no) adjusted for whether switched to second-line before or after 1 Jan 2007 (p = 0.12), whether or not joined second-line studies (p = 0.05), sex (p = 0.89) and age at switch (p = 0.61). More patients switched for other CD4 reasons later in the trial, reflecting wider promotion of other immunological criteria as switch criteria in WHO 2006 guidelines<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057580#pone.0057580-World2" target="_blank">[9]</a>; see Results.</p>‡‡<p>ROC area under the curve  =  0.62 (95% CI 0.45–0.79) in 115 patients enrolled in second-line studies, vs 0.78 (95% CI 0.58–0.99) in 72 patients not enrolled in second-line studies.</p><p>Note: ROC  =  receiver operating characteristic, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057580#pone-0057580-g002" target="_blank">Figure 2</a>. One switch 34 weeks after ART initiation: all others ≥48 weeks.</p

An illustrative representation of the mathematical model used to describe CD4 reconstitution.

<p>An illustrative representation of the mathematical model used to describe CD4 reconstitution.</p

Probability of viral suppression (HIV RNA<400 copies/ml) at trial closure.

<p>First-line and second-line ART columns show the absolute number (and denominator) of patients with viral suppression (HIV RNA<400 copies/ml). Estimates for both lines of ART are weighted averages accounting for variation in data completeness (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090772#s2" target="_blank">Methods</a>).</p><p>Baseline CD4 refers to CD4 at trial entry.</p><p>1. Multivariate logistic regression analysis, adjusting for all factors listed in Table and study site.</p><p>2. Per month.</p><p>P-value based on test for heterogeneity or test for trend, as appropriate.</p

Ability of a single CD4 at switch to second-line for first-line failure to predict VL.

<p>(a) in patients not receiving routine CD4 count monitoring (CDM: 20% >250 cells/mm3). (b) in patients receiving routine CD4 count monitoring (LCM: 2% >250 cells/mm3). Footnote 2 Receiver operator curves (ROC) show how the sensitivity and specificity of CD4 thresholds for predicting VL<400 copies/ml varies as CD4 increases from 1 to 788 (CDM) or 505 (LCM) cells/mm³. The straight line indicates performance no better than chance. The threshold with the greatest probability of correctly classifying each CD4 count according to whether it has VL<400 copies/ml or not is indicated with sensitivity (proportion with VL<400 c/ml who have CD4≥threshold), specificity (proportion with VL≥400 c/ml who have CD4 </p

VL and CD4 at switch to second-line for first-line failure in patients receiving and not receiving CD4 count monitoring.

<p>(a) in patients not receiving routine CD4 count monitoring (CDM: 20% >250 cells/mm3). (b) in patients receiving routine CD4 count monitoring (LCM: 2% >250 cells/mm3). Footnote 1 Points at >750000 and <400 have a small amount of ‘jitter’ added so that all observations are visible.</p