The children we describe are the pioneering survivors among children with perinatal HIV in the US. Maternal use of ARVs during pregnancy and other interventions have made MTCT rare in the US, with fewer than 250 infants estimated to acquire perinatal HIV each year.18
Thus, the majority of children currently living with perinatal HIV in the U.S. were born prior to the implementation of effective interventions to prevent MTCT. These children have grown up during a period of expanding availability of ART and changing treatment guidelines. Many initially received single or dual NRTI therapy, now considered suboptimal therapy, which often results in incomplete suppression of viral replication and the selection of drug-resistant virus. As treatment options have expanded, many children have received multiple ART regimens.4
Other challenges these children have faced include a limited number of agents available in pediatric formulations and the difficulty in maintaining adherence to therapy.19
The children in this cohort benefited from these advances in therapy, surviving to late childhood or adolescence. Most received single or dual NRTI therapy until 1996 when the PIs ritonavir and nelfinavir became available. Although nevirapine use began in 1994, its use as a component of HAART was initially limited. Since 1997, most subjects have received HAART containing a PI, with a smaller proportion receiving an NNRTI or both a PI and an NNRTI. Since 2004, the fixed combination of lopinavir boosted with ritonavir has been the most commonly used PI. In 2008, 27% of subjects were receiving stavudine, a drug now recommended for use “only in special circumstances” by the US pediatric treatment guidelines.20
However, it was an “alternative” regimen in the 2006 guidelines 21
and most subjects were receiving it as part of a second ART regimen where stavudine is more likely to be used. In addition, stavudine toxicity is uncommon in children.14
Use of the newer classes of drugs, including fusion inhibitors, CCR5 antagonists, and integrase inhibitors, has been limited in children but is increasing recently. These children have had extensive ART experience, starting therapy at a median of 0.8 years of age and receiving a median of 11.4 years of therapy. Overall, they have been exposed to a median of seven different ARVs.
Despite these challenges, most of our subjects had virologic suppression (68%) and a normal CD4 percentage of ≥ 25% (78%) at study entry. This is noteworthy since 24% had previously experienced an AIDS-defining condition. Among 263 children studied in 2001 by the HIV Research network (HIVRN) cohort study, which included four sites across the United States, fewer children achieved virologic suppression (43%) and more had an AIDS diagnosis (30%) at a mean of 8.5 years of age. However, children in the HIVRN cohort were more likely to have a CD4% ≥ 25% (88%). 22
Likewise, among 205 infected children in a Northern California cohort born between 1988 and 2001, 40% had developed an AIDS diagnosis at a median of three years of age, compared to only 18% of those in our 1998–2002 birth cohort.23
However, the children in our study were older at entry, and children with a prior AIDS-defining condition are less likely to survive to an older age.
The outcomes of children in the different birth cohorts differed significantly. Children in the more recent birth cohorts had a higher CD4 percentage and a greater likelihood of virologic suppression at study entry. They initiated ART at an earlier age, were more likely to have received HAART as their initial regimen, and received fewer total ART regimens. Throughout their life, they maintained a significantly higher mean CD4% than the earlier birth cohorts (), and also had a higher nadir CD4%. All four birth cohorts demonstrate a modest fall in CD4% starting between 5 and 10 years of age. Children and adults who maintain viral suppression with HAART therapy continue to have an ongoing increase in their CD4+ T cells over at least 6 years of therapy.24,25
Thus, this fall in CD4% likely represents those subjects without viral suppression, who comprise one-third of subjects at entry. The improved immune and virologic status of later birth cohorts resulted in better clinical outcomes, with significantly fewer children developing AIDS (CDC Class C, p=0.004). A previous study found a similar rate of progression to AIDS (21%) among their latest birth cohort (1996–2001), which was significantly lower that of their earlier birth cohorts.23
The lower median peak viral loads observed in our earlier birth cohorts are likely because viral load testing was not generally available until 2000, when these subjects were older and already receiving ART, as reflected in their age at peak viral load and age at starting ART.
The important independent predictors of a higher CD4% at entry were a suppressed viral load at entry, a higher nadir CD4% prior to entry, and starting ART at a younger age, suggesting a benefit from starting ART at an earlier age and a higher CD4%. Several studies have shown that children initiating therapy with lower CD4 counts ultimately achieve CD4 counts that are lower than those who start therapy at higher CD4 values.5,6,26
In a large European study, predictors of the CD4 cell response to therapy included the baseline CD4 count, being treatment naive when starting HAART, and the CDC clinical classification.27
The long-term consequences of achieving lower, albeit normal, CD4% values is unclear, although several studies suggest a continued reduction in the risk of death and progression to AIDS with further increases in the CD4 count or percentage above normal values.28–30
Since the goal of therapy is to maximally restore and maintain immune function, initiating therapy at a higher nadir CD4% will result in higher overall CD4 values and fewer subjects with abnormally low CD4 values. This supports the current U.S. treatment guidelines for HIV-infected children which recommend initiating therapy at higher CD4 values than previously suggested.20
The association of a higher CD4% at entry with fewer ART regimens and a shorter total duration of ART suggests a lower frequency of ART-resistant virus in these subjects.
The independent predictors of a suppressed viral load at entry (≤400 copies/mL) were membership in a more recent birth cohort, male gender, receipt of HAART at entry, and receipt of fewer prior ART regimens. Subjects in earlier cohorts received more individual agents and regimens and commonly started therapy with a less potent regimen prior to receiving HAART, increasing the likelihood for development of drug-resistant virus. Multi-drug resistance could be one reason that 14% of subjects were not receiving HAART at entry. The association of gender with virologic response is of borderline significance but warrants further study in children. The CD4 cell response to ART is not related to gender in children 5
and there is little evidence of an effect of gender in the CD4 or virologic response in adults.31
Subjects in recent birth cohorts benefited from having HAART available for initial therapy as well as access to a greater number of ARV drugs. () It is expected that use of HAART, rather than a less potent regimen, will result in viral suppression. Both poor adherence to therapy and ARV drug resistance are likely to account for the association of virologic failure with a larger total number of regimens. We are currently collecting data on viral resistance testing which will clarify the impact of viral resistance on treatment failure.
A limitation of the study is that subjects whose families were willing to participate may not be representative of all children with perinatal HIV in the US. However, the study includes a large number of children from multiple sites. In addition, they were cared for by centers experienced in treating pediatric HIV and likely represent outcomes resulting from optimal care.
In conclusion, most children with perinatal HIV infection are achieving virologic suppression and normal CD4+ lymphocyte counts despite having extensive treatment experience. Children who started ART at a younger age and who had a higher nadir CD4% were more likely to achieve a higher CD4%. Likewise, viral suppression was more likely among children who were members of a recent birth cohort, who were receiving HAART, and had fewer prior ART regimens. Advances in ART for children over the past two decades have substantially improved the outcome for children with perinatally-acquired HIV infection surviving to adolescence and young adulthood.