Immunological and Virological Response to Initial Antiretroviral Therapy Among Older People Living With HIV in the Canadian Observational Cohort (CANOC)

A Zhabokritsky; L Szadkowski; AN Burchell; C Cooper; RS Hogg; M Hull; DV Kelly; M Klein; M Loutfy; A McClean; J Montaner; SL Walmsley


HIV Medicine. 2021;22(8):759-769. 

In This Article


In this large Canadian cohort of 12 489 participants, of whom 1993 (16%) were > 50 years old, older participants started ART at more advanced stages of HIV infection and had lower absolute CD4 recovery with treatment but better virological response. However, when pre-treatment CD4 count was taken into account, CD4 recovery was similar across ages, except in individuals over the age 60, who displayed a slightly lower CD4 recovery.

The effect of ageing on the adequacy of immunological response to ART has been assessed in a number of cohorts, yielding variable results. In 2004, a 3015 participant cohort in France found that age over 50, along with lower pre-treatment CD4 count and higher viral load were associated with significantly lower CD4 recovery despite adequate viral suppression.[9] The following year, a 293-participant Swiss cohort demonstrated that older age was predictive of incomplete CD4 recovery to < 500 cells/mL.[6] On the other hand, a 2004 prospective case–control study of 596 participants in Italy found no difference in CD4 recovery based on age (age > 50 vs. 20–35).[10] Furthermore, in a 2016 study out of Tanzania, older participants who initiated treatment earlier had better CD4 recovery trajectory, relative to those starting at lower CD4 counts,[20] suggesting that older adults are capable of immune reconstitution, but perhaps early treatment initiation is especially important in the ageing population. The seemingly contradictory findings in these studies might be a reflection of variable sample sizes, differences in pre-treatment CD4 counts and duration of HIV infection at the time of therapy initiation. Furthermore, heterogeneity among 'older' individuals, who were traditionally looked at as a single group over age 50, may have confounded the outcomes. Given our large sample size, we were able to compare immunological outcomes among older individuals. This revealed reduced CD4 recovery in individuals over age 60, but not in individuals in the 50–60 year age group. In light of this, sub-categorization of older PLWH may be warranted in future studies.

We did not find a difference in time to CD4 recovery ≥ 200 cells/μL across ages; however, older individuals had slower recovery to ≥ 500 cells/μL. Indeed, age had a graded effect on time to CD4 recovery ≥ 500 cells/μL, with individuals over the age of 60 having the slowest recovery trajectory and lowest likelihood of achieving CD4 count ≥ 500 cells/μL. Overall, this shows that older individuals initiate immune reconstitution in a similar manner to younger individuals, but subsequent CD4 recovery beyond ≥ 200 cells/μL is slower and less robust.

Pre-treatment CD4 count had a great impact on subsequent CD4 recovery in our study, irrespective of age. The START trial showed a clear benefit to immediate, rather than deferred, ART initiation across age groups and underscored the importance of early recognition of infection.[21] The benefit was most pronounced in the over-50 group, where immediate ART initiation resulted in greater reduction of cumulative adverse outcomes compared with younger individuals.[22] Although we observed a blunted immunological response in the oldest age group, there seems to be an important interaction between age and pre-treatment CD4 count in terms of CD4 recovery (Figure S1) and therefore early ART initiation at higher pre-treatment CD4 counts may overcome the challenges in CD4 recovery in older individuals. In terms of choice of ART regimen, there are emerging data showing improved immune reconstitution with INSTIs.[23,24] However, we did not find a difference in CD4 recovery according to initial ART regimen with the exception of marginally lower CD4 recovery to ≥ 500 cells/μL with NNRTI- relative to INSTI-based regimens. Overall, this suggests that treatment choice is less important than the timing of treatment initiation.

Older individuals were more likely to have a lower pre-treatment CD4 count and a higher viral load at the time of ART initiation; despite this, they were more likely to achieve viral suppression and less likely to have virological failure following ART initiation. It has been previously postulated that older individuals are more likely to adhere to therapy or have more favourable ART pharmacokinetics than their younger counterparts.[25,26] Overall, this demonstrates once again that older adults can have a robust and sustained virological response to ART.

Individuals with hepatitis C co-infection or history of IDU had worse outcomes in terms of both immunological and virological responses. When age and pre-treatment CD4 count were taken into account along with other variables, both of these factors were independently associated with lower absolute CD4 counts, lower likelihood of reaching a CD4 count of ≥ 200 and ≥ 500 cells/μL, lower likelihood of achieving virological suppression and greater likelihood of virological failure. Reduced adherence to treatment, socioeconomic factors in addition to sequestration of CD4 cells in the spleen among individuals with advanced liver disease may have contributed to this observation. Although women were more likely to achieve a CD4 count ≥ 500 cells/μL, they were less likely to reach virological suppression and more likely to have virological failure. Our findings highlight the ongoing need for tailored approaches for these priority populations, which may include strategies for clinical engagement and retention in care and potentially choice of ART regimen. INSTI-based regimens were associated with greater likelihood of achieving virological suppression, potentially resulting from improved tolerability, and may be of particular benefit for individuals at risk of poor virological response.

This study is an important addition to the current literature addressing ageing and HIV for several reasons. In this large, interprovincial Canadian cohort, we were able to capture over 12 000 participants, allowing us to compare outcomes across ages and also within older age groups (51–60 vs. > 60 years). Although the differences were modest, it does suggest that future studies may benefit from stratifying outcomes among older individuals living with HIV rather than treating them as a single group > 50 years old. Our analysis included responses to early initiation of modern ART regimens, including INSTIs, which are now the recommended agents for initial therapy. However, our study had some limitations. Duration of infection prior to treatment initiation was not accounted for beyond pre-treatment CD4 count and we were unable to assess treatment adherence, as treatment interruptions were not adequately captured in the database. Furthermore, documentation of race and risk factor was incomplete (data missing in nearly 30% and 20% of study participants, respectively); while missing data were not thought to be informative, future studies should consider multiple imputation of missing data. There were limitations to the collection of mortality data (participating clinic sites do not regularly link to death registries, potentially misclassifying death as lost to follow-up), although the use of cause-specific PH models mitigates the potential impact of this misclassification. Finally, although representative of our clinical population at the time of the study, women and individuals over the age of 60 made up a minority of the cohort. Despite this, the large study sample size was adequate to detect differences between age groups with regard to primary endpoints.

In conclusion, individuals > 60 years old had blunted CD4 recovery, despite excellent virological suppression and low likelihood of virological failure. CD4 count at the time of ART initiation had a great impact on absolute CD4 recovery across ages and ART classes, supporting recommendations for early ART initiation, especially in older adults. Success of this approach relies heavily on timely diagnosis of infection, which is often under-recognized in older individuals.