Date Published: October 11, 2018
Publisher: Public Library of Science
Author(s): Gabriela Patten, Jonathan Bernheimer, Lee Fairlie, Helena Rabie, Shobna Sawry, Karl Technau, Brian Eley, Mary-Ann Davies, Justyna Dominika Kowalska.
In resource-limited settings holding regimens, such as lamivudine monotherapy (LM), are used to manage HIV-positive children failing combination antiretroviral therapy (cART) to mitigate the risk of drug resistance developing, whilst adherence barriers are addressed or when access to second- or third-line regimens is restricted. We aimed to investigate characteristics of children placed on LM and their outcomes.
We describe the characteristics of children (age <16 years at cART start) from 5 IeDEA-SA cohorts with a record of LM during their treatment history. Among those on LM for >90 days we describe their immunologic outcomes on LM and their immunologic and virologic outcomes after resuming cART.
We included 228 children in our study. At LM start their median age was 12.0 years (IQR 7.3–14.6), duration on cART was 3.6 years (IQR 2.0–5.9) and median CD4 count was 605.5 cells/μL (IQR 427–901). Whilst 110 (48%) had no prior protease inhibitor (PI)-exposure, of the 69 with recorded PI-exposure, 9 (13%) patients had documented resistance to all PIs. After 6 months on LM, 70% (94/135) experienced a drop in CD4, with a predicted average CD4 decline of 46.5 cells/μL (95% CI 37.7–55.4). Whilst on LM, 46% experienced a drop in CD4 to <500 cells/μL, 18 (8%) experienced WHO stage 3 or 4 events, and 3 children died. On resumption of cART the average gain in CD4 was 15.65 cells/uL per month and 66.6% (95% CI 59.3–73.7) achieved viral suppression (viral load <1000) at 6 months after resuming cART. Most patients experienced immune decline on LM. Its use should be avoided in those with low CD4 counts, but restricted use may be necessary when treatment options are limited. Managing children with virologic failure will continue to be challenging until more treatment options and better adherence strategies are available.
Treatment failure among HIV-positive children is a growing concern. In resource-limited settings, where access to second- or third-line combination antiretroviral therapy (cART) for HIV-positive children is frequently restricted, managing virologic failure is especially challenging. Children and adolescents face a number of adherence barriers, and drug formulations are often unpalatable with large pill burdens.[3–5] Switching children with virologic failure, who have suspected or proven poor adherence, to a new regimen runs the risk of increasing resistant mutations, thus limiting future treatment options. The South African national guidelines recommend holding strategies for those with ongoing adherence challenges.
The majority of children placed on LM experienced declines in CD4, 8% experienced WHO stage 3 or 4 events, and 3 children died. Those with higher CD4 count at LM start, lower nadir CD4 and older age experienced bigger absolute declines in CD4 count. Our composite outcome of immune decline (either a drop in CD4 below 500 cells/μL for those starting LM with CD4 above 500 cells/μL, or for those starting LM with CD4 count of 500 or below, a drop in CD4 of more than 10%) was experienced by roughly half of patients. Predictors of immune decline were lower nadir CD4 count, and having a history of treatment interruption. After resuming cART, the majority of patients achieved virologic suppression and some immune recovery. Adolescents and those on NNRTI-based cART were less likely to achieve virologic suppression on resumption of cART.
In conclusion, most patients experienced immune decline on LM, and its use should be avoided in those with low CD4 count. LM may be a useful strategy in the management of patients with virologic failure and poor adherence when treatment options are limited, but close clinical and immunological monitoring is required. Managing children with virologic failure will continue to be challenging until more treatment options and better adherence strategies are available.