Balancing the Upside and Downside of Antiretroviral Therapy in Children

In the late 1980s part of my routine, as the director of a pediatric human immunodeficiency virus (HIV)/AIDS clinic, was to attend funerals of my patients, children who succumbed to this disease. Now I am attending their graduations from high school and some of my patients are going to college. This anecdotal observation about the dramatic impact of highly active antiretroviral treatment (HAART) on the outcome of HIV infection in children is substantiated by the results reported by Berk and colleagues¹ in this issue of JAMA, which demonstrate that decreased HIV progression and improved survival of infected children are associated with early and more advanced antiretroviral therapy (ART).

From the beginning, antiretroviral drugs were not as readily available to children as they were to adults. Some of the reasons included lack of appropriate formulations, poor palatability, limited or no pharmacokinetic data in children, and the smaller market. As a result, pediatricians selected treatment regimens based on individual patient characteristics and their knowledge based mostly on the adult literature. While this type of decision making was part of the art of medicine, it did not conform to the “cookbook” approach provided by guidelines. Thus, it is not surprising that the study by Brogly and colleagues,² also in this issue of JAMA, found that almost a quarter of the children who started ART after pediatric guidelines were published initiated therapy with regimens not recommended by these guidelines.

Unfortunately, it remains unclear when to initiate ART in children.³ Several studies suggest that very early HAART (before age 3 months) results not only in viral control but also in seroreversion and preservation of immune function.^{4 - 5} The data of Berk et al¹ showing improved outcomes with early treatment suggest that HAART could be considered for HIV-infected infants younger than 3 months, although these data are limited by small sample size. Issues associated with appropriate dosing for this population (related to rapid hepatic and renal maturational changes) and strategies to improve medication adherence need to be fully assessed before the decision to initiate therapy is made.

One puzzling finding in the study by Brogly et al² is the lack of association between adherence and the time to first regimen change (ie, treatment failure). Multiple adult and pediatric studies indicate that poor medication adherence leads to virological failure and increase in drug resistance.^{6 - 9} In addition, as HIV becomes a chronic disease and more adolescents struggle with complex treatments, adherence has become an even bigger issue.¹⁰ Several techniques, such as incentives, directly observed dosing, pill boxes, and beepers seem to be effective in promoting adherence and should be considered.^{11 - 14}

The studies by Brogly et al and Berk et al both show the benefits of ART in children but do not provide sufficient insight into the potential downside of such therapy. One such downside is the development of drug resistance. It is unfortunate that many children in resource-rich countries such as the United States were treated with only 1 or 2 drugs before the need for triple drug therapy was appreciated. While monotherapy has been shown to have a beneficial effect in symptomatic children, this effect is transitory because of the development of drug resistance.¹⁵ Thus, it is surprising to see that more than 1 in 6 (>15%) children in the study by Brogly et al were still receiving mono or dual therapy in 2003. Even the use of HAART in children is not always a recipe for success, and recent data suggest that the “standard” HAART is effective in only 50% of children.^{16 - 17} Some of the treatment failures were observed in compliant/adherent patients. Because the potency of HAART regimens depends on inhibition of viral reverse transcriptase, prior resistance to the reverse-transcriptase inhibitors may have contributed to these failures.

These observations are especially important with the current challenge to treat 3 million people with HIV by the end of 2005 (the World Health Organization “3 by 5” program).¹⁸ The grim reality is that some generic drugs, which were the inexpensive first line of ART in Africa and other countries, may have insufficient potency.¹⁹ A few medications that may have contributed to the development of drug resistance were even withdrawn from the World Health Organization–approved list.²⁰ Unfortunately, reports of such drug resistance are already appearing.²¹ It is critical that drug quality monitoring (eg, the US Food and Drug Administration Expedited Review Process), training of health care professionals in the use of tools to prevent the development of resistance (eg, directly observed therapy), and educating patients and their families about the importance of adherence will be the minimum requirements of any project that plans to expand ART use in resource-limited countries. Otherwise, drug resistance will rapidly become widespread and will eliminate any preliminary success.

Another downside of using HAART that is not addressed in the studies by Brogly et al and Berk et al are the adverse effects of HAART, ie, toxicity and long-term complications. While it is difficult to distinguish between these effects, several conditions such as mitochondrial dysfunction, fat maldistribution, hyperlipidemia, insulin resistance, hypersensitivity, and hematologic and bone changes are mainly caused by the drugs, while others such as behavioral and developmental problems are mainly the result of the long-term disease. There are probably many unknown issues that will appear as patients live longer and use more complex regimens. For example, how many children with hyperlipidemia (which in many cases is not treated due to lack of appropriate medications) will develop a myocardial infarction or stroke, and at what age?

Moreover, it was disappointing that the analysis by Brogly et al showed that only 50% of children born between 2000 and 2003 received zidovudine prophylaxis in the first 6 weeks of life.² Since 1994, when the Pediatric AIDS Clinical Trials Group protocol 076 showed that administration of zidovudine to pregnant mothers and their newborns substantially decreased HIV transmission, it has been difficult to establish that all pregnant women should be tested for HIV and if positive should receive zidovudine prophylaxis. Various political and societal pressures²² have prevented routine perinatal HIV testing with right of refusal (ie, “opt out”) and have forced pretest HIV counseling with specific written consent for an HIV antibody test (ie, “opt in”). The latter approach is associated with much lower rates of maternal HIV testing.²³ Thus, many HIV-positive mothers will not be offered zidovudine prophylaxis (as occurred in 50% of the patients in the study by Brogly et al). Several studies have shown that, once mothers are made aware of their HIV-positive status, they will rarely refuse zidovudine to prevent transmission.²⁴ Physicians need to be more vigilant in offering HIV testing to all pregnant women, including those who do not receive prenatal care.

While it is possible to celebrate the tremendous change in the outcomes of HIV-infected children treated with HAART, it is even more important to continue to prioritize research for the survivors who are now living with a chronic disease. The notion that the problem of HIV in children has been resolved is false—indeed, 15 000 to 20 000 perinatally-infected children and adolescents²⁵ still need answers to problems such as salvage therapy, long-term complications from the disease or from ART, neurodevelopmental complications, and the ongoing need for new and simplified treatments. It would be a mistake to reduce funding for clinical research on HIV-infected children living in the United States, because such research might not only help these children but also contribute to the care of HIV-infected children worldwide who are starting to benefit from ART and who, in the near future, undoubtedly will develop the same problems that US children are now experiencing.