Fig 1.
Schematic of viral recrudescence after ART-interruption.
(A) After ART-interruption, there is an initial delay when virus cannot grow, due to ‘washout’ of ART. Once viral replication is possible, there is a variable time until successful viral replication is initiated from the latent reservoir. The low initial level of replicating virus then increases until it reaches the detection threshold. Time to initiation refers to time until replicative infection commences, which is followed by a delay due to viral growth, and then by detection of plasma virus. (B) time-to-detection plotted as a ‘survival curve’. The initial shoulder occurs due to ART washout and viral growth, and is followed by an exponential decay in the proportion of patients with no detectable virus.
Fig 2.
Dynamics on recrudescence in nine patients enrolled in Panobinostat trial (reference [8]).
(A) The trajectory of viral load of individual patients after ART-interruption. Dashed line indicates threshold of detection (20 copies ml-1) (B) the ‘survival curve’ of patients without detectable virus. The frequency of recrudescence is equivalent to one initiation of viral replication occurring every 7.6 days. (C) growth rate of virus after detection is not significantly correlated with time to recrudescence (p = 0.9).
Table 1.
Summary of cohorts.
Fig 3.
Dynamics of recrudescence in 59 patients enrolled in the Pulse study (reference [15]).
(A) Trajectory of viral load in individual patients. Dashed line indicates threshold of detection (50 copies ml-1) (B) survival curve of time to detection (frequency of initiation of viral replication is once every 6.3 days). (C) Growth rate estimated from first two weeks of detectable virus. (D) Average viral load at detection for patients detected at different weeks. Dashed line indicates threshold of detection (50 copies ml-1)
Fig 4.
Time-to-detection of virus in cohorts 3 and 4.
(A) time-to-detection in cohort 3, of 18 patients undergoing interruption (reference [16]). The best-fit frequency of reactivation is once every 5.1 days. (B) time-to-detection in cohort 4, of 14 patients undergoing five interruptions, and monitored at days 4, 8, and 14 (reference [17]). The best-fit frequency over all interruptions is once every 7.2 days. (C) Time to recrudescence is not correlated with growth rate in cohort 3. (D) Higher reactivation rates in SIV than HIV. The estimated frequency of initiation of viral replication in SIV infected macaques treated with ART between 7 and 14 days post-infection (from reference [26]) is shown as solid line, and was found to be once every 1.7 days. The best-fit frequency of reactivation across the four HIV cohorts (a reactivation event every 6 days) is shown as a dashed line.
Fig 5.
Modelling of kinetics of time-to-detection:
A: Using the ratio of the number of copies of reactivation founder viruses to estimate rate of initiation of viral growth. The cumulative proportion of founders with different ratios (to the size of next largest founder) is shown. Solid line is ratios from the experimental data, dashed line is the theoretical distribution with the best fit frequency of rebound of once every 3.6 (CI 1.98–6.62) days. Ratios marked with an asterisk are where we could only estimate a minimum ratio (ie: there was no detected next founder virus). (B) Estimating the reduction in frequency of recrudescence (and reservoir size) from observed delay to detection of virus. For a ‘normal’ reservoir size, we find an average frequency of reactivation of once every 6 days (which also equates to an average delay to reactivation of 6 days). For patients with longer time-to-detection we can estimate the relative size of the reservoir compared to our cohort populations. Solid line shows the fold reduction in reservoir size that would be estimated simply comparing the observed time to detection with the estimated average of 6 days. Since reactivation does not always occur at the average time, the range expected for 95% of subjects is shown (shaded area). T1 and T2 are the delays for two patients that underwent allogeneic stem cell transplantation (reference [30]). T3 is the delay observed in the ‘Mississippi baby’ (reference [29]). (C) Difficulties using treatment interruption studies to measure changes in the reservoir. The number of patients required (y-axis) to have a 50% (dashed line), an 80% (solid line) or a 95% (dot-dash line) power to detect a given reduction in reservoir (x-axis) is shown, based on Log-rank test. This assumes a 100-day follow up after ART-interruption.