Immunological response to combination antiretroviral therapy
By 12 months after starting cART, 59% of individuals had experienced an immunological response, with the greatest responses in those aged less than 2, 2–5 and 6–12 years (72, 82 and 78%, respectively). Immunological responses were lower and similar across the adult groups (Table 2 and Fig. 1b). After adjustment (Fig. 2b), those aged 6–12, 13–17 and 18–29 years were more likely to experience a response compared with those aged 30–39 years. Among older adults, immunological responses were generally similar across age groups, although those aged 60 years or older were 7% less likely to experience a response [0.93 (0.87–0.98)]. Other predictors of an improved initial immunological response were later years of starting cART, lower precART CD4 cell counts, higher precART viral load, no prior AIDS diagnosis, European origin and receipt of one proteas inhibitor (1PI) + ritonavir (RTV) + 2NRTI or 1NNRTI + 2NRTI regimens (data not shown).
There were marked differences over time in the pattern of CD4 change (Fig. 3), particularly among those aged 12 years or younger. Among very young children, mean CD4 cell counts increased rapidly in the first 6 months after starting cART but decreased thereafter, reflecting the physiological decline in CD4 cell count during early childhood. Sustained CD4 increases were seen in those aged 2–5 and 5–12 years, whereas increases were more gradual, but still maintained, in those aged at least 13 years. Age trends were similar when the proportion of individuals with a CD4 cell count of more than 200 cells/μl at 12 months was considered, with the percentage achieving this level decreasing with increased age.
Occurrence of new AIDS events, death and treatment discontinuation
The proportion of patients who experienced a new AIDS event or death by 12 months is shown in Table 2. In a multivariable model, comparable outcomes were seen across the age groups, with the exception of those aged 55–59 [1.19 (1.05–1.34)] and 60 years or older [1.34 (1.19–1.51)] years, who had poorer outcomes than those aged 30–39 years. After adjusting for the latest CD4 cell count as a time-updated covariate, the risk of AIDS remained higher in those aged 55–59 and 60 years or older [55–59 years: 1.18 (1.05–1.34); 60 years or older 1.32 (1.17–1.48)]. Similar trends by age were found when considering the time to the first new AIDS event only.
Changing or discontinuing one or more antiretroviral drug in the cART regimen in the first 12 months of cART was common (Table 2). In multivariable analysis, those aged 6–12 years were 40% less likely to switch or discontinue any antiretroviral drug compared with those aged 30–39 years [0.60 (0.50–0.72)]; in contrast, those aged 18–29 and 60 years or older were more likely to make a treatment switch [1.06 (1.03–1.09) and 1.07 (1.01–1.14), respectively]. However, complete treatment discontinuation for at least 2 weeks was rare (Table 2). Compared with those aged 30–39 years when starting cART, higher treatment discontinuation rates were observed among those aged 13–17 years [1.31 (0.99–1.73)] and 18–29 years [1.11 (1.06–1.17)], whereas lower discontinuation rates were observed among those aged 6–12 [0.81 (0.59–1.12)], 40–49 [0.83 (0.79–0.87)], 50–54 [0.71 (0.46–0.78)], 55–59 [0.74 (0.66–0.83)] and 60 years or older [0.73 (0.64–0.82)] years.
To our knowledge, this study reflects the first attempt to describe responses to cART across such a wide age span and with such a large sample size. This has enabled us to consider narrow age groups among children, adolescents and older patients to investigate in detail whether differences exist in the response to cART among these groups. Although responses to cART were reasonable across all age groups, age was a predictor of many of the outcomes considered, even after controlling for precART disease stage and other known confounders. These findings are of clinical importance, as they may permit treatment guidelines (particularly relating to the timing of initiation of HAART and frequency of subsequent patient monitoring) to be targeted to specific age groups. Furthermore, accurate information on the expected outcomes in each age group will allow clinicians to judge whether their own patients are responding better or worse than would be expected for someone of a particular age.
Despite having more advanced disease at treatment initiation (possibly due to later presentation for HIV care ), older people were more likely to demonstrate a good initial virological response to cART. Concerns about a greater potential for drug–drug interactions in older people, who may be receiving other concomitant medications, do not seem to lead to impaired virological responses. However, in line with previous studies [7,9,10,14,17–22], we observed a similar or slightly worse immune response among older individuals. These poorer responses, coupled with lower precART CD4 cell counts, suggest that older individuals are at greater risk of experiencing clinical events, a hypothesis that was confirmed in our study. Although it could be argued that our definition of an immunological response is likely to provide a relatively crude differentiation between those who have a good or poor response, more detailed measures of immune response were not available for most patients in this cohort. The fact that the increased risk of clinical events remained after adjustment for the latest CD4 cell count suggests that the functional impairment to the immune systems of older individuals may be more profound than expected, based on measurement of CD4 cell counts alone . Clinical events may not be limited to those traditionally considered to be associated with HIV, but may include a range of additional morbidities, many of which are associated with lower CD4 cell counts [29–31] and may occur more frequently in older individuals.
After adjustment for potential confounders, children aged at least 6 years, adolescents and young adults were less likely to experience a virological response than older individuals, possibly reflecting the more disordered lifestyles that may be present among adolescents and younger adults, which, in turn, may have an impact on adherence . Impaired virological responses may lead to the emergence of drug-resistant virus, the consequences of which are particularly important for children and adolescents who will need to receive antiretroviral therapy for life and in whom preservation of treatment options is essential. Interestingly, we observed an improved CD4 response in children aged 6–12 years compared with adolescents and adults, despite the poorer virological responses in this group . The fact that older children and adolescents had poorer virological response but improved immunological response highlights the complex interplay between host (particularly thymic output) and virus.
We also found that children aged less than 6 years had a poorer initial virological response to treatment. Although this could be explained to some extent by the high precART viral loads in these children, formulation pharmacokinetics , the limited choice of antiretrovirals available for children over the study period, and adherence  may also play a role. Unfortunately, we were unable to include children aged less than 6 years in multivariable analyses; whereas CD4 cell counts in uninfected children fall towards adult values by mid-childhood [35–37] and have a similar prognostic value for short-term disease progression to adults from the age of 4 years , the high CD4 cell counts seen at birth mean that adjustment for the precART CD4 cell count may not adequately control for baseline immunological status among very young children. Although the CD4 percentage may be less variable than the CD4 cell count, the CD4 percentage may not always be recorded among adults. Further methodological studies are underway to identify appropriate statistical methods that can permit the inclusion of young children in the analyses while adjusting fully for baseline immunological status.
Infants initially had a rapid CD4 increase, although this diminished with time due to the natural decline in CD4 cell counts seen in young uninfected children. The risk of a new AIDS event or death after cART was high among these very young children, in contrast to their good immune response, highlighting the high mortality in infants infected when their immune system is immature . A relatively high proportion of children less than 2 years had an AIDS event before starting cART – these young children are likely to be ‘fast progressers’ and may appear to have a higher rate of clinical progression after starting cART than older children or adults.
Changes in cART regimen were commonly observed, particularly in adults. Treatment changes were less frequent in children, probably reflecting better tolerance of treatment and/or more limited drug options in this group. However, complete treatment discontinuation was rare at any age, although adolescents had twice the discontinuation rate of younger children and adults. The identification of ways in which therapy can be safely simplified and the development of specific interventions to improve adherence among adolescents may help minimize the emergence of resistance in this group.
Any comparisons of treatment outcomes by age are likely to be confounded by differences in sex and ethnicity [40,41]. Our associations between age and response to cART were independent of these factors. We found no evidence of any strong associations between sex and response to treatment, although those of non-European/unknown origin had better virological but poorer immunological responses to cART. The reasons for this are unknown, but geographical origin will capture a number of factors including HIV subtype, socioeconomic status and adherence. Unfortunately, we cannot comment on the role of any behavioural differences between individuals of different ages. Owing to the high colinearity with age group, we could not adjust for route of exposure to HIV. However, when the analyses were repeated after excluding homo/bisexual men and injection drug users (so removing some of the confounding effect of this factor), the results were unchanged.
Despite its large size and broad geographical representation, a number of limitations of our observational study must be acknowledged. Although every attempt has been made to adjust for known potential confounders, we cannot rule out the presence of unknown confounders and could not adjust for hepatitis B virus and hepatitis C virus status. We were not able to consider the development of toxicities, which may also differ by age group; information on toxicities has only recently begun to be collected by cohorts and has yet to be standardized, limiting any analyses that could be performed. Furthermore, as data are collected from a large number of participating cohorts, there is the potential for data collection methods to vary from cohort to cohort. However, the rigorous data quality assurance checks and the use of a unified data collection procedure should minimize any bias that might arise from this. Although we used a stringent definition of virological response requiring the use of an ultrasensitive assay, our results were robust to the choice of this endpoint. Owing to of our exclusion criteria, patients with missing precART CD4 cell counts and/or viral loads were excluded from this analysis; as many of these patients started cART in earlier calendar periods, we felt it was appropriate to exclude these patients so that the included patients were more representative of those currently starting cART. However, alternative methods (e.g. multiple imputation) could have been used which would have permitted the inclusion of these individuals in our analyses. Finally, we cannot rule out the possibility of a healthy survivor effect, particularly among the vertically infected children, as those who start cART at at least 6 years of age must have survived to this age in order to receive treatment at this time.
In summary, although we observed reasonable responses to cART across all age groups, virological responses were better in older individuals. However, immunological responses were poorer in this group, which, in combination with low precART values, may put this group at increased risk of HIV disease progression and other clinical events. Immunological responses were best in young children, although the extent to which this increased CD4 change translates into prolonged clinical benefit is less clear. Additionally, the possibility of a poorer virological response in young children may increase the risk of acquiring resistance mutations in this group.
Writing group for the study of age: Caroline A. Sabin (Project Leader), Colette J. Smith (Statistician), Antonella d'Arminio Monforte (ICONA), Manuel Battegay (SHCS), Clara Gabiano (ITLR), Luisa Galli (ITLR), Sibyl Geelen (ATHENA), Diana Gibb (CHIPS), Marguerite Guiguet (FHDH), Ali Judd (CHIPS), Catherine Leport (COPILOTE), François Dabis (AQUITAINE), Nikos Pantazis (AMACS), Kholoud Porter (CASCADE), Francois Raffi (COPILOTE), Claire Thorne (ECS), Carlo Torti (Italian Master Cohort), Sarah Walker (CASCADE), Josiane Warszawski (EPF), Uwe Wintergerst (KOMPNET), Genevieve Chene (Head, Bordeaux Regional Co-ordinating Center), Jens Lundgren (Head, Copenhagen Regional Co-ordinating Center).
COHERE Steering Committee: Executive Committee: Ian Weller (Chair, University College London), Dominique Costagliola (Vice-chair, FHDH), Bruno Ledergerber (Vice-chair, SHCS), Jens Lundgren (Head, Copenhagen Regional Co-ordinating Center), Genevieve Chene (Head, Bordeaux Regional Co-ordinating Center); Cohort representatives: Giota Touloumi (AMACS), Josiane Warszawski (ANRS CO1 EPF), Laurence Meyer (ANRS CO2 SEROCO), François Dabis (ANRS CO3 AQUITAINE), Murielle Mary Krause (ANRS CO4 FHDH), Cecile Goujard (ANRS CO6 PRIMO), Catherine Leport (ANRS CO8 COPILOTE), Frank de Wolf (ATHENA), Peter Reiss (ATHENA), Kholoud Porter (CASCADE), Maria Dorrucci (CASCADE), Caroline Sabin (UK CHIC), Diana Gibb (CHIPS), Julia Del Amo (Co-RIS), Niels Obel (Danish HIV Cohort), Claire Thorne (ECS), Amanda Mocroft (EuroSIDA), Ole Kirk (EuroSIDA), Schlomo Staszewski (Frankfurt), Santiago Perez-Hoyos (GEMES-Haemo), Jesus Almeda (HIV-MIP), Andrea Antinori (ICC), Antonella d'Arminio Monforte (ICONA, IMIT), Pier-Angelo Tovo (ITLR), Bernd Salzberger (KOMPNET), Gerd Fatkenheuer (KOMPNET), Jose Ramos (Madrid Cohort), Manuel Battegay (MoCHIV, Swiss HIV Cohort Study), Cristina Mussini (Modena Cohort), Pat Tookey (NSHPC), Jordi Casabona (PISCIS), Jose M. Miro (PISCIS), Antonella Castagna (San Raffaele), Stephane de Wit (St. Pierre Cohort), Carlo Torti (Italian Master Cohort), Ramon Teira (VACH), Myriam Garrido (VACH); European AIDS Treatment Group: Nikos Dedes; Project Leaders: Caroline Sabin, Andrew Phillips, Hansjakob Furrer, Ole Kirk, Matthias Egger, François Dabis, Marie-Louise Newell, Jonathan Sterne, Amalio Telenti.
All members of the writing group participated in discussions on the design of the study, the choice of statistical analyses and interpretation of the findings, and were involved in the preparation and review of the final manuscript for submission. In addition, Colette Smith and Caroline Sabin are responsible for performing all analyses; Colette Smith acts as guarantor for the analyses and has full access to the dataset.
The COHERE study group is funded by grants from the French Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), the Dutch HIV Monitoring Foundation and the Danish Augustinus Foundation. The study sponsors had no role in the design of the study, the collection, analysis and interpretation of data, the writing of the report or in the decision to submit the paper for publication.
No member of the Writing Group for this report has any financial or personal relationships with people or organizations that could inappropriately influence this work, although most members of the group have, at some stage in the past, received funding from a variety of pharmaceutical companies for research, travel grants, speaking engagements or consultancy fees.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
age; clinical outcome; combination antiretroviral therapy; HIV infection; immunological response; virological response