More than half of European children infected with HIV through mother-to-child transmission show signs of metabolic abnormalities, including body fat changes and elevated blood lipid levels that could raise the risk of cardiovascular disease, researchers reported this week at the Eighteenth International AIDS Conference in Vienna.
A related study described at the same session found that children with HIV had about a 4% prevalence of cardiomyopathy, or heart muscle disease. Cardiomyopathy was associated with high mortality, but use of antiretroviral therapy (ART) lowered the risk.
Naufil Alam, from University College London Institute of Child Health, and colleagues looked at the likelihood of various types of metabolic problems among children in three European countries.
It is well recognised that HIV-positive adults are at risk of body shape changes and metabolic abnormalities associated with elevated cardiovascular disease risk, though there remains disagreement about whether this is attributable to chronic HIV infection, antiretroviral drugs or some combination of factors.
The prevalence and risk factors for metabolic changes amongst children with HIV, however, have not been extensively studied. The researchers noted that this is an issue of growing importance as treatment becomes more widely available worldwide and children infected at birth survive and remain on ART longer.
The investigators looked at participants in the European Paediatric HIV Lipodystrophy Study, comprising 389 children and adolescents age 2 to 18 years seen at multiple sites in Belgium, Italy, and Poland. Males and females were well balanced, the median age was 12 years, 69% were white and 27% were black; 7% had hepatitis C co-infection.
This will be a prospective study, but the findings presented at the conference were from a cross-sectional or one-time analysis of data collected at enrolment.
The analysis included two types of abnormalities, body fat changes (lipodystrophy) and metabolic changes. Metabolic changes included elevated cholesterol, elevated triglycerides and glucose intolerance.
At study entry, only 8% of the children had advanced HIV disease or AIDS (CDC categories B or C), but nearly 60% had fallen into one of these categories in the past. One-quarter currently had moderate or severe immune suppression.
All children were currently on ART, started at an average age of approximately four years with a median duration of eight years. Almost everyone had used nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), nearly 70% had used nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs) and about 80% had used protease inhibitors. Yet despite universal treatment, almost 40% still had detectable HIV viral load.
The researchers found that the prevalence of metabolic problems was high overall. About 14% of study participants had only blood lipid or glucose abnormalities, 25% had only body fat changes and 16% had both. One-third had blood abnormalities, either alone or with body shape changes. In total, 57% had at least one aspect of lipodystrophy syndrome
A statistical analysis adjusting for age and duration of ART showed that white race/ethnicity and current use of ritonavir (Norvir) predicted metabolic abnormalities, whilst current use of atazanavir (Reyataz) – a protease inhibitor with less effect on blood lipids – was protective. Having a viral load above 50 copies/ml was associated with reduced risk of elevated cholesterol, but doubled the risk of elevated triglycerides.
The researchers concluded that children taking ritonavir, including as a booster for other protease inhibitors, "may warrant increased surveillance", whilst atazanavir appears to confer better metabolic status.
They added that further study of lipodystrophy syndrome in children is warranted because metabolic abnormalities during childhood and adolescence "may be important in the early stages of development of cardiovascular disease".
In the second study, Kunjal Patel from Harvard School of Public Health and colleagues assessed predictors of cardiac dysfunction amongst children and adolescents with perinatal HIV infection.
In contrast with the previous study assessing metabolic changes that increase the risk of cardiovascular disease, including atherosclerosis (build-up of plaque that can eventually block arteries and cause a heart attack or stroke), this analysis looked at cardiomyopathy, or damage to the heart muscle.
In particular, the researchers focused on left ventricular dysfunction and enlargement as indicated by an echocardiogram, a method of heart imaging using ultrasound. This condition was recognised in HIV-infected children early in the epidemic and was added as a qualifying CDC category B diagnosis in 1994, according to Patel. Various studies have found prevalence rates ranging from 17 to 39%.
Explanations proposed over the years have included direct infection of cardiac muscle cells by HIV, inflammation triggered by viral replication in the heart, and drug-related mitochondrial toxicity (damage to energy-producing structures within cells) caused by older NRTIs such as ddC (discontinued), ddI (Videx) and d4T (Zerit).
Noting that earlier studies of cardiomyopathy amongst children with HIV were conducted prior to the advent of effective combination ART, the researchers aimed to determine the impact of HIV treatment on development of cardiac dysfunction, defined as a new diagnosis of cardiomyopathy or starting one of two drugs for the condition, digoxin or dobutamine.
The analysis included 3107 participants in ACTG/IMPAACT Study 219/219c, a US cohort study of long-term highly active ART (defined as at least two antiretroviral drugs from at least two classes) in children with perinatal HIV infection enrolled at more than 80 US sites between 1993 and 2007.
About 40% of participating children were under five years of age and about 80% were born before 1982. More than half were black and nearly 30% were Hispanic. Just under one-third had advanced CDC category C disease at study entry. A total of 136 cases of cardiac dysfunction were identified at baseline, a prevalence of 4.2%.
By the end of follow-up, 102 new cases of cardiac dysfunction were diagnosed, a rate of 5.7 per 1000 person-years. The median age at the time of diagnosis was about ten years. Mortality amongst children who developed cardiomyopathy was high, at 37%.
In a multivariate statistical analysis, factors significantly linked to cardiac dysfunction included earlier birth cohort, CDC category C disease, and low baseline CD4 cell percentage. Use of ddC nearly doubled the risk.
On the whole, however, use of combination ART was associated with a 60% decrease in the risk of developing cardiac dysfunction compared with suboptimal regimens such as NRTI monotherapy or drugs from only a single class.
The researchers concluded that whilst combination ART "is highly effective in reducing the incidence of cardiac dysfunction among HIV-infected children", certain factors predicted worse outcomes including older age at ART initiation, poor immune status, and prior ddC use.
Although the investigators went into the study looking for a link between ART use and increased cardiac dysfunction, these findings support those of SMART and other recent studies which found, contrary to expectations, that not being on treatment conferred a greater risk.
Patel suggested that inflammation may play a role in cardiomyopathy, as it does in cardiovascular disease. By reducing viral replication and the resulting inflammation, this benefit may outweigh any potential mitochondrial toxicity associated with NRTIs in the regimen.
Wrapping up the session on paediatric ART complications, moderator Professor Diana Gibb of the UK Medical Research Council emphasised the importance of continuing to follow perinatally infected children as they reach adulthood, rather than letting them get lost in typical adult HIV cohorts, in order to see if life-long HIV infection leads to unique outcomes.
View and read Naufil Alam's slides and abstract on the official conference website.
View and read Kunjal Patel's slides and abstract on the official conference website.
Alam N et al. Risk factors for metabolic abnormality in a European cohort of HIV-infected children and adolescents. Eighteenth International AIDS Conference, Vienna, abstract MOAB0404, 2010.
Patel K et al. Predictors of cardiac dysfunction among children and adolescents perinatally-infected with HIV-1. Eighteenth International AIDS Conference, Vienna, abstract MOAB0405, 2010.