Long-Term Clinical, Virological and Immunological Outcomes Following Planned Treatment Interruption in HIV-Infected Children

R Freguja; A Bamford; M Zanchetta; P Del Bianco; C Giaquinto; L Harper; A Dalzini; TR Cressey; A Compagnucci; Y Saidi; Y Riault; D Ford; D Gibb; N Klein; A De Rossi

Disclosures

HIV Medicine. 2021;22(3):172-184. 

In This Article

Discussion

The PENTA 11 trial was undertaken in an era when treatment interruption was being advocated to spare patients from ART, also known as drug conservation.[3] There were also theoretical reasons why cessation of ART might allow host immune mechanisms to 'control' HIV-1 infection.[21] Interruption strategies were then shown to be detrimental in adults and are therefore not recommended in virologically controlled patients. PENTA 11 investigated the response to 48 weeks of CD4-guided PTI in HIV-1-infected children between 2004 and 2008.[8] The main trial showed that in children interrupting therapy, there were no differences in terms of mortality and clinical outcomes compared with those on continuous ART. Most children exhibited a drop in CD4 count within a month of treatment cessation, with some needing to restart ART because of low CD4. However, in most children, CD4 levels were maintained until ART was re-introduced at 48 weeks. CD4 nadir and age were important predictors of CD4 count following treatment cessation.[8]

In this long-term follow-up study, we show that at 5 years after the end of the trial, there were few clinical, virological or immunological differences between the two arms. Both arms had similar rates of undetectable plasma viraemia, HIV-1 DNA, cell-associated HIV-1 RNA and CD4 cell count. One consistent and persistent consequence of PTI was an increase in CD8 cells, which occurred within 8 weeks of ART cessation;[8] CD8 cells remained elevated during ART interruption and, although decreasing again following treatment re-initiation, were still elevated at 5 years, with the model predicting that they would remain elevated for many years and indeed may never return to the levels in the CT group. Increased CD8 count was an important driver of reduced CD4/CD8 in the PTI arm even after reintroduction of ART. In adults with low CD4/CD8 ratio, the CD8 memory compartment is particularly expanded.[19] In our children with low CD4/CD8 ratio both naïve and memory CD8 cells were expanded. Residual viral replication, outlined by the detection of intracellular HIV-1 RNA, may drive reduced CD4/CD8 ratio, with particular depletion of CD4 memory cells, target of HIV infection, as well as expansion of CD8 cells.

Our models suggest that by around 7 years, CD4/CD8 should be similar between the two arms, indicating that PTI does not appear to irreversibly influence the long-term CD4/CD8 ratio. Significant predictors of CD4/CD8 recovery in the PTI arm included trial baseline CD4/CD8 ratio, time since ART re-initiation and minimum CD4/CD8 ratio during PTI.

We previously reported that the initial fall in CD4 cell count in the first weeks off ART was due to decrease in both naïve and memory cells with accompanying increase in CD8 memory cells. CD4 count was subsequently maintained in most patients.[9] An interesting observation seen in this sub-study with longer follow-up was persisting lower CD4 memory cells in the PTI arm. This was despite maintenance of thymic output, as indicated by naïve CD4 cell recovery and TRECs. The approach used to identify naïve and memory T cells was sustained throughout the entire study. Whilst CD45RO memory cells can re-express CD45RA, and therefore potentially overestimate naïve T-cell subsets and underestimate memory cells, we found very low levels of this population, supporting our findings. Residual viral replication may only partially explain this observation. It may indicate a persistent redistribution of CD4 memory cells from circulation into lymphoid tissue. It may also indicate an ongoing requirement for maintaining memory cell involvement in controlling chronic infections, including HIV-1. Studies are required to observe future changes in memory cell dynamics as well as to fully understand the causes and consequences in children who have experienced treatment interruptions.

Although limited by small sample size and non-random selection of sub-study participants, overall our study shows that after PTI children had limited long-term clinical, virological or immunological consequences. This contrasts with most studies performed in adults.[22] The reasons for this observation remain to be fully determined but may be driven by the extensive capacity for children to maintain and indeed improve immune function through high rates of thymic output.

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