Growing Up with Perinatal HIV Infection: Time for a HAART to Heart
Article Outline
Abbreviations: HAART, Highly active anti-retroviral therapy, HIV, Human immunodeficiency virus, NNRTI, Non-nucleoside reverse transcriptase inhibitor, NRTI, Nucleoside reverse transcriptase inhibitor, PCP, Pnemocystis pnemonia, PI, Protease inhibitor agent, VAT, Visceral adipose tissue
Early in the human immunodeficiency virus (HIV) epidemic, infants first came to attention severely ill with Pneumocystis pneumonia (PCP), and often they died. The infants who survived their acquired immunodeficiency syndrome-defining PCP and the infants and children who had HIV infection diagnosed before severe illness occurred faced bleak prospects for health and survival from this untreatable and often fatal infection. Physicians, nurses, social workers, and others on the front lines provided compassionate and supportive care to children and their mothers, who struggled with their own HIV infection, usually amid problems of poverty, substance abuse, mental illness, and discrimination. With specific therapy lacking, providers focused on preventing infections and encouraging parents to maximize high-calorie, high-fat intake in infected children in an effort to stave off growth failure and malnutrition. Physicians tirelessly evaluated and treated (and learned from) the ravages that HIV infection would wreak on the hearts, brains, lungs, and kidneys of these children and on the members of their family, all too often robbing the lives of their mothers and siblings. We witnessed countless examples of courage and determination in children and their families in this era, but had a shared understanding of the likely prospect of worsening illness and early death. We focused on making the best of the present—keeping families together, offering symptomatic and compassionate care—and demanding research to improve HIV care, but with the sober recognition that these children would likely not reach adulthood.
See related article, p 491
The arrival first of zidovudine and eventually of other anti-retroviral agents brought new hope. Adults infected with HIV who were given zidovudine lived longer than those who did not.1 Combinations of drugs seemed to offer even greater benefit. As is often the case, the study and use of these new drugs came later to children infected with HIV. But the improvement of conditions like HIV encephalopathy in children who were given zidovudine was, at times, breathtaking. By the 1990s, protease inhibitor agents (PIs) became available, and the use of highly active anti-retroviral therapy (HAART) demonstrated substantial benefits in morbidity and mortality in infected adults and children alike.2 Devastating conditions like PCP dramatically decreased.3 These benefits came with great effort: drugs were dosed several times per day, often had complicated food restrictions, produced unpleasant adverse effects, and would only be effective with nearly perfect adherence. Care teams and families (in many cases, of now orphaned children in kinship care, foster, or adoptive families) now had the daunting challenge of daily management of complicated medication regimens to reap the promised health benefits.
Since the advent of HAART, the complexity and tolerability of available medication options has improved dramatically, although somewhat less for children than adults. The use of potent, effective HAART has transformed HIV infection from a progressive, fatal illness to a chronic, manageable disease. Perinatally infected children—most of whom are now adolescents or young adults—and their families have undergone the joyous, but difficult, task of changing from a mindset of avoiding illness and death to increasing expectations of a long and healthy life. At clinic visits, we now speak about educational goals and career plans. We talk about their dreams for spouses and children of their own. And we increasingly discuss healthy lifestyle choices and means to promote long-term health, and what the potential impact of HIV infection and its treatment might be. However, we are substantially hampered by the uncertainty of how lifelong HIV infection and its lifesaving treatment might modify the prognosis of this perinatal cohort entering adulthood for the first time.
In this issue of The Journal, Miller et al4 explore cardiovascular risk factors in children infected perinatally with HIV and compare their profiles with those of population-based control subjects by using data from the National Health and Nutrition Examination Surveys (NHANES). Compared with NHANES control subjects, children infected perinatally with HIV were more likely to have higher triglyceride, higher low-density lipoprotein (trend), and lower high-density lipoprotein levels. As a group, children infected perinatally with HIV appear to be at higher risk for all these factors associated with cardiovascular disease. The authors point out that increased risk of myocardial infarction in adults infected with HIV already has been demonstrated.5 So, concern seems plausible, and it raises the question of the reasons behind increased risk. Is it HIV infection, its treatment, or something else?
The additional analysis by Miller et al demonstrates that use of HAART is associated with adverse lipid profiles and increased visceral adipose tissue (VAT; another cardiovascular risk factor), but the association differs by the type of anti-retroviral agent used. Use of PIs, the cornerstone of HAART for most children perinatally infected with HIV, was a significant independent risk factor for higher low-density lipoprotein and triglyceride levels and lower high-density lipoprotein levels, mirroring findings in adults. Nucleoside reverse transcriptase inhibitors (NRTIs), like zidovudine, were predictive of increased VAT. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), however, appeared to confer a beneficial effect, including higher high-density lipoprotein values and less VAT. In addition, older age, sex, race, ethnicity, and body mass index were associated with at least 1 cardiovascular risk factor, reminding us that the genetic-environmental background is important for cardiovascular risk in patients infected with HIV, as it is for people uninfected by HIV. Recommendations for low-fat, heart-healthy diets now replace earlier efforts to put weight on children combating HIV-related growth failure in the past.
This study enhances but does not fully inform our understanding of the cardiovascular future of perinatally infected children and youth. Ongoing intensive health surveillance of this population in the coming decades will be important, especially because the childhood predictors of adult cardiovascular health generally are not as conclusively defined as adult predictors. Investigation of alternative anti-retroviral agent choices and of cardiovascular interventions (eg, lifestyle changes, lipid-lowering therapies) in the context of aging perinatally infected people will be required. The PI atazanavir, for example, has been used increasingly in adults for its low rate of adverse lipid events compared with other PIs, but only recently has it been approved for children and made available in a pediatric formulation. Some caregivers have tried changing from a PI-based HAART regimen to a NNRTI-based HAART regimen for the potential of reducing cardiovascular risk factors6; however, enthusiasm for this approach may be dampened by concerns for resistance and teratogenicity in adolescents at higher risk of non-adherence and unintended pregnancy. Recent information about potential cardiotoxicity of the NRTI abacavir in adults raises questions about the effect abacavir may have on the hearts of children.7 In addition to cardiovascular health, the effects of long-term infection and treatment on bone health, neurocognitive health, and malignancy risk also need to be explored further.
The message for perinatally infected children for their families and their providers? Comprehensive care including effective HAART holds the potential for a full and long life, but work does not end there. Treatment, especially with certain anti-retroviral drugs, may increase some long-term health problems, such as cardiovascular disease, and it will be important to reduce modifiable risk factors to take advantage of comprehensive and preventive medical care and to be alert for new information about additional ways to further improve long-term health. Patients, families, and providers must work together to demand research that enhances the understanding of the effects of HAART on cardiovascular and other aspects of long-term health from infancy to adulthood and research that leads to the development of ever more potent and less toxic anti-retroviral therapies. The children who many thought would never survive continue to be pioneers in the first-ever journey of perinatal HIV infection into adulthood.
References
- The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex (A double-blind, placebo-controlled trial). N Engl J Med. 1987;317:185–191
- Pediatric AIDS Clinical Trials Group Protocol 219 Team (Effect of combination therapy including protease inhibitors on mortality among children and adolesecents infected with HIV-1). N Engl J Med. 2001;345:1522–1528
- Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA. 2006;296:292–300
- Risk factors for cardiovascular disease in human immunodeficiency virus-1 infected children. J Pediatr. 2008;153:491–497
- Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356:1723–1735
- . Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the First Pediatric Switch Study. Pediatrics. 2003;111:e275–e281
- DHHS Adults and Adolescents Antiretroviral Treatment Guidelines Panel's communication regarding abacavir. April 4, 2008. Available at: http://aidsinfo.nih.gov/contentfiles/ABCComm.pdf. Accessed May 1, 2008.
PII: S0022-3476(08)00479-4
doi:10.1016/j.jpeds.2008.05.049
© 2008 Mosby, Inc. All rights reserved.
Refers to article:
- Risk Factors for Cardiovascular Disease in Children Infected with Human Immunodeficiency Virus-1 , 09 June 2008
