Newer treatments for HIV in children

PURPOSE OF REVIEW: Several new antiretroviral agents have been introduced into pediatric and adult use. This review will summarize information about these new agents and other recent advances in the care of HIV-infected children. RECENT FINDINGS: New drugs like tenofovir, emtricitabine, and enfuvirtide are being rapidly introduced into antiretroviral treatments for adult patients. In addition, some well-established drugs are being modified to make them more convenient (specifically didanosine and stavudine). Unfortunately, pediatric data lag for these new agents, in some cases because of complicated pharmacokinetics in children. At the same time, critical information on how to use established drugs like nelfinavir and efavirenz in younger children is slowly becoming available. Although antiretroviral treatment in children has often been initiated at standard doses of milligrams per kilogram, and susceptibility to drug was presumed in individuals without a previous history of exposure, recent data show that some primary infections are caused by drug-resistant virus, and there is a tremendous variability in serum drug levels in children. Researchers and clinicians should consider the role of baseline antiretroviral susceptibility testing and therapeutic drug monitoring to identify the optimal treatment for each child. SUMMARY: New therapeutic options for children with HIV infection are becoming available as the pharmacokinetics and best strategies for use of newer drugs are studied.     

Clinical practice treatment of HIV infection in children

Perinatal transmission remains the main cause of HIV infection in the pediatric population. Treatment of HIV-infected children has become less of a problem in resource-rich countries with a remarkable decrease of perinatal infections, resulting in an effective prevention of mother-to-child transmission and antiretroviral treatment of HIV infection in pediatrics because of differences in drug pharmacokinetics, the lack of available licensed drugs, the use of different immunologic markers and age-related adherence issues. This review, for the general pediatrician, summarizes the most recent pediatric data and guidelines for treatment of HIV. Recommendations for when to initiate therapy are more aggressive in children than in adults, particularly in infants because disease progression in children is more rapid. The indications to start therapy differ by age and are based on international immunologic and clinical classification system for HIV infection. At present, combination regimens of at least three drugs are recommended. Moreover, therapies must also consider the potential complications in these children currently treated for a long time.     

Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children

The contemporary treatment of the child infected with human immunodeficiency virus (HIV) unavoidably requires combination therapy with antiretroviral agents and may include additional drugs for the prevention and treatment of opportunistic infections or other disease states. The current guidelines for the treatment of the HIV-infected child recommend that the same principles of treatment for adults should apply to children. However, the pharmacokinetic and pharmacodynamic characteristics of many agents and regimens used in adults have not been defined adequately in children, and large-scale clinical trials to establish safety and show efficacy have not been completed. Therefore, the clinician will be required to use agents with incomplete knowledge about their pharmacologic properties. The purpose of this article is to provide an overview of the pediatric pharmacologic principles, a review of the pharmacologic characteristics of selected antiretroviral agents in children, and a prospectus on the design of drug dosing regimens in children.     

Educational paper

Although cure rates for children with cancer are approximately 70%, improvements in cure rates have slowed in the past decade, likely due to our inability to further improve outcome using currently available drugs. Novel drug approaches are needed for children with difficult-to-treat malignancies, such as stage IV neuroblastoma, sarcomas, brain tumors, and relapsed leukemia. Several novel agents show promise for improving outcome in patients with either high risk or recurrent disease. For leukemia, inhibitors of cell cycle progression, such as clofarabine and nelarabine, have shown great promise in their ability to increase treatment efficacy in high-risk disease. Targeted agents such as tyrosine kinase inhibitors, DNA binding compounds (trabectedin), and monoclonal antibodies (GD2 inhibitors for neuroblastoma and anti-CD22 antibodies for pre-B acute lymphocytic leukemia (ALL)) also show promise for future treatment. Extensive reviews of each of these agents are presented elsewhere; this article provides an overview of molecular agents at different stages of FDA/EMA approval; those that are currently approved for use in children, currently approved for use in adults, as well as those that show promise in early clinical trial testing, or are supported by strong preclinical data.     

Empfehlungen zur antiretroviralen Therapie bei HIV-infizierten KindernVollständig überarbeitetes und aktualisiertes Konsensusstatement der Pädiatrischen Arbeitsgemeinschaft Aids (PAAD) und der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI)

In the era of effective antiretroviral combination therapy, the clinical presentation of HIV infection in childhood and adolescence has changed from a severe immunodeficiency with acute potentially fatal opportunistic infections to a chronic infection that can be treated quite successfully. However, the latest results of basic research and clinical studies on the current antiretroviral therapy regimens show, that eradication of HIV cannot be achieved, that there is an insufficient suppression of viral replication in many children and that long term side effects of the medication cannot be ruled out. While there is substantial evidence that new effective antiretroviral drugs will become available, it is uncertain whether the success of antiretroviral therapy can be maintained long term. Consequently there is a need for a new treatment approach. On this basis the Pädiatrische Arbeitsgemeinschaft AIDS (PAAD) consensus group has updated the recommendations regarding when to start, what regimen to start with and how to monitor antiretroviral therapy in childhood.     

Increasing antiretroviral drug access for children with HIV infection

Although there have been great gains in the prevention of pediatric HIV infection and provision of antiretroviral therapy for children with HIV infection in resource-rich countries, many barriers remain to scaling up HIV prevention and treatment for children in resource-limited areas of the world. Appropriate testing technologies need to be made more widely available to identify HIV infection in infants. Training of practitioners in the skills required to care for children with HIV infection is required to increase the number of children receiving antiretroviral therapy. Lack of availability of appropriate antiretroviral drug formulations that are easily usable and inexpensive is a major impediment to optimal care for children with HIV. The time and energy spent trying to develop liquid antiretroviral formulations might be better used in the manufacture of smaller pill sizes or crushable tablets, which are easier to dispense, transport, store, and administer to children.     

Principles of antiretroviral treatment of children and adolescents with human immunodeficiency virus infection

Human immunodeficiency virus (HIV) infection requires life-long therapy to attain durable suppression of HIV replication and prevent or reverse HIV-related symptoms or immune system dysfunction. Combination therapy with 3 or more antiretroviral medications is currently widely recommended for treatment of children and adolescents with HIV infection. While potent regimens can initially reduce virus load to below assay quantitation limits in the majority of persons with HIV infection, 30% to 80% of children will have regimen failure and return of detectable plasma virus within 1 year. Adherence to therapy is critical to regimen success. Optimal treatment requires careful use of potent combinations of drugs, with attention to adherence, palatability, toxicity, and pharmacokinetics. Practitioners with experience caring for children and adolescents with HIV infection should be involved.     

Pediatric aspects of HIV1-infection--an overview

Mother-to-child transmission of HIV1 is the main cause for pediatric HIV1-infection. Since 1995 in developed countries the rate of vertical HIV1 transmission was reduced from 40% to 1-2% by the combination of antiretroviral therapy of pregnant women, antiretroviral prophylaxis in the newborn and refraining from breast-feeding. Nowadays the main causes for HIV1-infection in children are 1) not offered (voluntary) HIV1-testing in early pregnancy (in spite of recommendation for prenatal care) and 2) missing knowledge about prophylactic interventions in HIV1-positive pregnant women and their HIV1-exposed newborn. Diagnosis and/or exclusion of HIV1-infection in HIV1-exposed and HIV1-positive infants is difficult, because maternal HIV1-antibodies pass the placenta and can persist in the child up to two years after birth. Since in 1996 the era of "highly active antiretroviral therapy (HAART)", the use of an antiretroviral three-drug-regimen, began, HIV1-infection in children changed from a fatal illness to a chronic disease with decreased mortality and improved qualitiy of life. The lack of drug approvement, absence of adequate drug formulation and of pharmacokinetic data for children make the treatment of HIV1-infection in children much more difficult than in adults. Treatment of children depends on clinical category, CD4 cell count, viral load and age of diagnosis. With the current state of knowledge (failure of treatment interruption studies in adults and pending ones in children) once HAART is started it must be carried on life-long. This implies great challenges in adherence to avoid development of resistance and in confrontation with long-term adverse effects of HIV1-therapy.     

Antiviral therapy of influenza

The prevention of influenza virus infections by the use of vaccines remains the most cost-effective and practical method of influenza virus control, but the use of antiviral prophylaxis and treatment in certain populations or high-risk individuals is also possible. Four antiviral drugs are currently licensed in the United States for the treatment and/or prevention of influenza virus infection in children. The M2 blockers, (amantadine and rimantadine) have been licensed for the prophylaxis and treatment of influenza in diverse high-risk populations, including children, for years. Advantages of these agents include the low cost, high oral bioavailability, and relative tolerability of one of these agents (rimantadine) in children. Disadvantages include efficacy against influenza A viruses only (not type B), the relative rapid development of resistance, and adverse effects associated with amantadine in particular (especially in the elderly and those with decreased renal function). Two agents in a new antiviral class, the neuraminidase inhibitors, have been licensed recently for the treatment and prophylaxis of influenza in the United States. Oseltamivir is licensed for the treatment of influenza in children older than 1 year and for the prophylaxis in children older than 13 years. This drug is safe and well-tolerated, and is available in capsules or a liquid suspension. Another neuraminidase inhibitor, zanamivir, is administered as an inhaled powder via a special inhaler device and is licensed for the treatment of influenza in children older than 7 years. Both neuraminidase inhibitors appear to be similarly effective and are not associated with the development of antiviral resistance. No direct comparisons of any of these antiviral agents has been performed; all result in clinical improvement approximately 1 to 2 days earlier in otherwise healthy children when therapy is initiated within 48 hours of onset of symptoms.