HIV-Infected Children Facing New Challenges : Patients experience drug resistance, complications of therapy, and issues related to mental health.

BOSTON — The increased survival among HIV-infected children seen with effective prevention of perinatal transmission and the widespread adoption of highly active antiretroviral therapy has been accompanied by the emergence of a new generation of clinical, public health, and social challenges.

The median age of more than 3,500 infected children followed at U.S. clinical trial sites is now 15 years, and some patients are in their early 20s. The median age at death—9 years in 1994—had risen to 18 years by 2006, said Dr. Lynne Mofenson, chief of the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

Although mortality has decreased, it remains 30 times higher for HIV-infected children than for uninfected children. There also has been a shift in causes of death, with fewer children dying from AIDS-related opportunistic infections and central nervous system disease and more succumbing to end-stage AIDS with multiple organ failure, or to sepsis or renal failure, Dr. Mofenson said at the 15th Conference on Retroviruses and Opportunistic Infections.

Aside from the disease itself, these young patients and their caregivers today face multiple challenges including drug resistance, complications of therapy, and issues related to adherence and mental health, Dr. Mofenson said.

Several studies have found an increase in primary drug resistance among newly infected infants.

For instance, data from New York State showed a 58% increase in resistance between 1998 and 2002, reaching 19%. This was primarily accounted for by mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (J. Acquir. Immune Defic. Syndr. 2006;42:614–9).

Another series found resistance among 24% of infected children, with 10% being resistant to at least two classes of antiretroviral drugs, Dr. Mofenson said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Multidrug resistance is a particular problem for older children who were treated with monotherapy or dual therapy before triple therapy became the standard of care. Few choices remain for these children, particularly because many drugs available for adult patients have no pediatric formulations or dosing guidelines. "Without additional drugs, some HIV-infected children will run out of treatment options at a very early age," Dr. Mofenson said.

Investigations by the Pediatric Spectrum of Disease Project found that in 2001, 44% of children had already received two or more highly active antiretroviral treatment (HAART) regimens, and 3% had received five or more regimens. "This is only going to increase over time," she said.

These children increasingly face potentially severe complications of long-term therapy, particularly during puberty when as-yet unidentified physiologic changes appear to result in the development of hypercholesterolemia, which has been reported in up to 67% of children on therapy, and lipodystrophy, which has been reported in up to 47%.

Additionally, in one series, hyperinsulinemia was found in 60% of children, although insulin resistance was uncommon, she said.

Risk factors that have been identified for the development of these metabolic abnormalities include duration of antiretroviral therapy and the use of protease inhibitors and nucleoside reverse transcriptase inhibitors, particularly ritonavir, Dr. Mofenson said.

These findings further raise concerns about the potential for long-term cardiac complications. In one study from England, carotid intima thickness was significantly greater among 83 HIV-infected children, compared with a control group of 59 healthy children (Circulation 2005;112:103–9).

In that study, preatherosclerotic changes were particularly pronounced among patients treated with protease inhibitors. There may be roles for both HIV infection itself and intermittent antiretroviral therapy in the development of cardiovascular complications, she said.

Another area that is becoming important in pediatric HIV is mental health. "These children are born into families with multiple stresses including drug use and poverty," Dr. Mofenson said.

In one series of more than 300 children, the prevalence of attention-deficit/hyperactivity disorder was 24%, sixfold higher than in the general population of children, she said. Additionally, 29% had an anxiety disorder, which is a fourfold increase compared with healthy children, and 25% had clinical depression, which is a sevenfold increase.

"Finally, there is the overall challenge of HIV in adolescence," she said.

Many adolescents do not know they are infected, either because their perinatal infection has not been disclosed to them or they are at risk but have not been tested. And adherence to complex, lifelong therapy can present many difficulties, particularly in young patients who may appear well.

Infected adolescents also increasingly represent a high-risk population for HIV transmission. It has been estimated that 40%-60% of infected adolescents engage in unprotected sex, and there are high rates of substance abuse and smoking as well, she said.

Another disturbing finding that is emerging involves discrepancies in the use of HAART between children who were perinatally infected and those who were infected through risky sex.

"And of course HIV infection is a worldwide public health challenge that disproportionately affects children living in the poorest parts of the world. Infected children in high-resource settings such as the United States represent only 1% of the 2.3 million infected children worldwide," Dr. Mofenson commented.

BOSTON — The increased survival among HIV-infected children seen with effective prevention of perinatal transmission and the widespread adoption of highly active antiretroviral therapy has been accompanied by the emergence of a new generation of clinical, public health, and social challenges.

The median age of more than 3,500 infected children followed at U.S. clinical trial sites is now 15 years, and some patients are in their early 20s. The median age at death—9 years in 1994—had risen to 18 years by 2006, said Dr. Lynne Mofenson, chief of the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

Although mortality has decreased, it remains 30 times higher for HIV-infected children than for uninfected children. There also has been a shift in causes of death, with fewer children dying from AIDS-related opportunistic infections and central nervous system disease and more succumbing to end-stage AIDS with multiple organ failure, or to sepsis or renal failure, Dr. Mofenson said at the 15th Conference on Retroviruses and Opportunistic Infections.

Aside from the disease itself, these young patients and their caregivers today face multiple challenges including drug resistance, complications of therapy, and issues related to adherence and mental health, Dr. Mofenson said.

Several studies have found an increase in primary drug resistance among newly infected infants.

For instance, data from New York State showed a 58% increase in resistance between 1998 and 2002, reaching 19%. This was primarily accounted for by mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (J. Acquir. Immune Defic. Syndr. 2006;42:614–9).

Another series found resistance among 24% of infected children, with 10% being resistant to at least two classes of antiretroviral drugs, Dr. Mofenson said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Multidrug resistance is a particular problem for older children who were treated with monotherapy or dual therapy before triple therapy became the standard of care. Few choices remain for these children, particularly because many drugs available for adult patients have no pediatric formulations or dosing guidelines. "Without additional drugs, some HIV-infected children will run out of treatment options at a very early age," Dr. Mofenson said.

Investigations by the Pediatric Spectrum of Disease Project found that in 2001, 44% of children had already received two or more highly active antiretroviral treatment (HAART) regimens, and 3% had received five or more regimens. "This is only going to increase over time," she said.

These children increasingly face potentially severe complications of long-term therapy, particularly during puberty when as-yet unidentified physiologic changes appear to result in the development of hypercholesterolemia, which has been reported in up to 67% of children on therapy, and lipodystrophy, which has been reported in up to 47%.

Additionally, in one series, hyperinsulinemia was found in 60% of children, although insulin resistance was uncommon, she said.

Risk factors that have been identified for the development of these metabolic abnormalities include duration of antiretroviral therapy and the use of protease inhibitors and nucleoside reverse transcriptase inhibitors, particularly ritonavir, Dr. Mofenson said.

These findings further raise concerns about the potential for long-term cardiac complications. In one study from England, carotid intima thickness was significantly greater among 83 HIV-infected children, compared with a control group of 59 healthy children (Circulation 2005;112:103–9).

In that study, preatherosclerotic changes were particularly pronounced among patients treated with protease inhibitors. There may be roles for both HIV infection itself and intermittent antiretroviral therapy in the development of cardiovascular complications, she said.

Another area that is becoming important in pediatric HIV is mental health. "These children are born into families with multiple stresses including drug use and poverty," Dr. Mofenson said.

In one series of more than 300 children, the prevalence of attention-deficit/hyperactivity disorder was 24%, sixfold higher than in the general population of children, she said. Additionally, 29% had an anxiety disorder, which is a fourfold increase compared with healthy children, and 25% had clinical depression, which is a sevenfold increase.

"Finally, there is the overall challenge of HIV in adolescence," she said.

Many adolescents do not know they are infected, either because their perinatal infection has not been disclosed to them or they are at risk but have not been tested. And adherence to complex, lifelong therapy can present many difficulties, particularly in young patients who may appear well.

Infected adolescents also increasingly represent a high-risk population for HIV transmission. It has been estimated that 40%-60% of infected adolescents engage in unprotected sex, and there are high rates of substance abuse and smoking as well, she said.

Another disturbing finding that is emerging involves discrepancies in the use of HAART between children who were perinatally infected and those who were infected through risky sex.

"And of course HIV infection is a worldwide public health challenge that disproportionately affects children living in the poorest parts of the world. Infected children in high-resource settings such as the United States represent only 1% of the 2.3 million infected children worldwide," Dr. Mofenson commented.

BOSTON — The increased survival among HIV-infected children seen with effective prevention of perinatal transmission and the widespread adoption of highly active antiretroviral therapy has been accompanied by the emergence of a new generation of clinical, public health, and social challenges.

The median age of more than 3,500 infected children followed at U.S. clinical trial sites is now 15 years, and some patients are in their early 20s. The median age at death—9 years in 1994—had risen to 18 years by 2006, said Dr. Lynne Mofenson, chief of the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

Although mortality has decreased, it remains 30 times higher for HIV-infected children than for uninfected children. There also has been a shift in causes of death, with fewer children dying from AIDS-related opportunistic infections and central nervous system disease and more succumbing to end-stage AIDS with multiple organ failure, or to sepsis or renal failure, Dr. Mofenson said at the 15th Conference on Retroviruses and Opportunistic Infections.

Aside from the disease itself, these young patients and their caregivers today face multiple challenges including drug resistance, complications of therapy, and issues related to adherence and mental health, Dr. Mofenson said.

Several studies have found an increase in primary drug resistance among newly infected infants.

For instance, data from New York State showed a 58% increase in resistance between 1998 and 2002, reaching 19%. This was primarily accounted for by mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (J. Acquir. Immune Defic. Syndr. 2006;42:614–9).

Another series found resistance among 24% of infected children, with 10% being resistant to at least two classes of antiretroviral drugs, Dr. Mofenson said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Multidrug resistance is a particular problem for older children who were treated with monotherapy or dual therapy before triple therapy became the standard of care. Few choices remain for these children, particularly because many drugs available for adult patients have no pediatric formulations or dosing guidelines. "Without additional drugs, some HIV-infected children will run out of treatment options at a very early age," Dr. Mofenson said.

Investigations by the Pediatric Spectrum of Disease Project found that in 2001, 44% of children had already received two or more highly active antiretroviral treatment (HAART) regimens, and 3% had received five or more regimens. "This is only going to increase over time," she said.

These children increasingly face potentially severe complications of long-term therapy, particularly during puberty when as-yet unidentified physiologic changes appear to result in the development of hypercholesterolemia, which has been reported in up to 67% of children on therapy, and lipodystrophy, which has been reported in up to 47%.

Additionally, in one series, hyperinsulinemia was found in 60% of children, although insulin resistance was uncommon, she said.

Risk factors that have been identified for the development of these metabolic abnormalities include duration of antiretroviral therapy and the use of protease inhibitors and nucleoside reverse transcriptase inhibitors, particularly ritonavir, Dr. Mofenson said.

These findings further raise concerns about the potential for long-term cardiac complications. In one study from England, carotid intima thickness was significantly greater among 83 HIV-infected children, compared with a control group of 59 healthy children (Circulation 2005;112:103–9).

In that study, preatherosclerotic changes were particularly pronounced among patients treated with protease inhibitors. There may be roles for both HIV infection itself and intermittent antiretroviral therapy in the development of cardiovascular complications, she said.

Another area that is becoming important in pediatric HIV is mental health. "These children are born into families with multiple stresses including drug use and poverty," Dr. Mofenson said.

In one series of more than 300 children, the prevalence of attention-deficit/hyperactivity disorder was 24%, sixfold higher than in the general population of children, she said. Additionally, 29% had an anxiety disorder, which is a fourfold increase compared with healthy children, and 25% had clinical depression, which is a sevenfold increase.

"Finally, there is the overall challenge of HIV in adolescence," she said.

Many adolescents do not know they are infected, either because their perinatal infection has not been disclosed to them or they are at risk but have not been tested. And adherence to complex, lifelong therapy can present many difficulties, particularly in young patients who may appear well.

Infected adolescents also increasingly represent a high-risk population for HIV transmission. It has been estimated that 40%-60% of infected adolescents engage in unprotected sex, and there are high rates of substance abuse and smoking as well, she said.

Another disturbing finding that is emerging involves discrepancies in the use of HAART between children who were perinatally infected and those who were infected through risky sex.

"And of course HIV infection is a worldwide public health challenge that disproportionately affects children living in the poorest parts of the world. Infected children in high-resource settings such as the United States represent only 1% of the 2.3 million infected children worldwide," Dr. Mofenson commented.