Old Problems for New Providers: Managing the Postpediatric HIV Generation

(See the Major Article by Jeannie Collins et al on pages 1105’12.) For the past few years, increasingly dire predictions have been made about the future of adolescents living with human immunodeficiency virus (HIV). HIV-associated mortality is increasing when it has decreased for other age groups, adherence to antiretroviral therapy (ART) is worse than in adults, and treatment failure and drug resistance are consequently increasing—all at a time when pediatricians are handing over a generation of these patients to their adult infectious diseases counterparts. In this issue of Clinical Infectious Diseases, Collins et al’s analysis of the United Kingdom and Ireland’s national HIV program’s patients as they transition out of pediatric care [1] gives us reason to hope that things may not be as bad as we fear, as well as data to show why some of these patients are still unlikely to reach the population-comparable life expectancies promised to adherent patients who acquired their infections as adults. The Collaborative HIV Paediatric Study (CHIPS) follows almost all perinatally HIV-infected children receiving care in the United Kingdom and Ireland. This report on the one-third (N = 644) who have moved on to adult HIV care is the largest published to date on adolescents with HIV at transfer from pediatric care. Almost all of the infections in their cohort were perinatally acquired (91%), and the numbers of those who were locally born have been exceeded by those born abroad (62%), primarily in African countries (85%). The overall immunologic and virologic characteristics at transfer were worse in earlier years, but substantially improved over time. Those with CD4 counts ≤350 cells/mm3 went from 67% in 2000–2002 to 32% in 2012–2014, with half of transferring patients having CD4 counts >500 cells/mm3 in the latter period. Viral suppression at a threshold of <50 copies/mL went from <20% up to 68% in the latter period for those on any ART. Despite these clear improvements in care outcomes, the ART regimen use and drug resistance observed in this cohort reflect the consequences of both earlier and current challenges to optimizing pediatric HIV care. While 26% were still on their first combination ART regimen, 44% were on a subsequent regimen, 6% were on a mono- or dual-ART regimen, and 13% had interrupted treatment—showing that almost three-fourths were already on second-line or on alternate regimens. While not surprising given the median 11 years of follow-up time in the cohort, it is important to recognize that by the time of transfer, perinatally infected young adults are generally highly treatment experienced. About half of those on any ART had an HIV genotype that was matched through the UK HIV Drug Resistance Database. Overall, 82% had resistance mutations to at least 1 drug class: 26% to 1 class, 44% to 2 classes, and 12% to 3 classes. Although availability of drug resistance testing was likely subject to bias, the proportion tested is similar to a US multicenter pediatric cohort study that reported 72% with high-level resistance to at least 1 drug class and 18% with triple-class resistance [2]. Similar to the findings in that cohort, the availability of integrase inhibitors now means that despite extensive resistance, the goal for salvage therapy in this population should still be undetectable viral load. Effective treatment of children is challenging, and major barriers include a small range of useable, potent antiretrovirals owing to lack of data, concerns for inadequate exposure, intolerance, and toxicities. Thus, treatment in the presence of ongoing viral replication is not uncommon in pediatric HIV care, leading to the risk of very early multiclass resistance. This is consistent with the finding in this report that those who were diagnosed and initiated on antiretrovirals earlier in life were more likely to have triple-class exposure. As children age into adolescence, other challenges emerge that are associated with normal development—impulsivity, sensation seeking, increased peer influence—which can lead to poor adherence. A real tension exists for their practitioners between wanting to prescribe effective treatment and a fear of “running out of options” for those with adherence problems. Adolescents with poor adherence may be put on extended drug holidays as a last resort or a compromise to get them to come to clinic, even though US data have shown that the resultant immunologic decline may be substantial and difficult to reverse [3]. Another situation is that providers may be unwilling to make changes to an outdated regimen that still seems to be working. It is as if adherence is so tenuous that the practitioner does not want to do anything to upset the current balance. While the potential for undertreating is real, so is the struggle to balance the psychosocial issues intrinsic to adolescence and limited available options for regimen sequencing [4]. Adult HIV providers may recall an earlier time when their patients had similar ART management problems due to suboptimal drug combinations and extensive multiclass resistance. Young adults with complex ART histories are now in need of the multidisciplinary team approach that helped address those issues in the past by constructing regimen sequencing strategies that took into account anticipated access to newer antiretrovirals combined with individualized adherence interventions. If we view the current situation of transitioning youth through the lens of the history of the HIV epidemic, these are old problems that we can overcome again. Changes to optimize regimens can begin prior to transfer. There are feasible management interventions that can lead to the immunologic and virologic improvements observed in the UK/Ireland cohort. A report on an antiretroviral stewardship program in an urban US referral hospital described a 5-year effort to objectively assess ART regimens by pediatric HIV clinical and medicines experts [5]. Half of the 106 patients they reviewed had an issue with their regimen, which included relying on older resistance data on which to base drug selection and the persistent use of stavudine. Some of the drug changes that were made led to increases in CD4 and reductions in viral load, side effects, and drug–drug interactions. Notably, preliminary posttransfer data from the CHIPS cohort showed that both CD4 and viral suppression levels increased after transfer to adult HIV care, which may have been related to developmental maturation of the patients leading to improved adherence or management interventions that the adult providers made [6]. These outcomes differ by setting and patient mix, as a Canadian study reported that CD4 fell after adolescent transfer [7]. The emerging message may be that better outcomes can be achieved for young adults when pediatric and adult providers work together, which has been observed in smaller cohorts [8, 9]. Collins et al show that the majority of their postpediatric patients who have grown up with HIV are now arriving in adult clinics with a high CD4 cell count and a suppressed viral load. However, there remains a socially complicated and difficult-to-manage subgroup of young adults who need more intensive efforts to construct optimal regimens and support adherence to help reverse the increasing trends in HIV-associated mortality [10, 11]. The next steps for similar cohorts around the world will be to document and report on outcomes after transition to adult care, so we can ensure that the hard work that went into keeping the pediatric HIV population alive throughout childhood is sustained, and young people with perinatally acquired HIV can thrive as adults. Disclaimer. The comments and views of the authors do not necessarily represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health. Potential conflicts of interest. Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.