Antiretroviral Therapy

Antiretroviral therapy (ART)
ART helps in improving and restoring the immune system functioning and decreasing the mortality and morbidity associated with HIV infection. ART does not cure HIV infection and requires very close adherence in order to be effective and prevent emergence of resistance and thus patient has to be prepared for life long treatment in order to optimally control the virus replication.

Treatment of pediatric HIV infection has evolved since antiretroviral therapy began in the late 1980s. Currently, highly active combination regimens including at least three drugs are recommended.

Goals of pediatric ART

The aims of treatment with antiretroviral (ARV) drugs in HIV-infected children are to achieve and sustain full HIV RNA viral load (VL) suppression and minimize short and long-term ARV drug toxicity.

Duration of ART

HIV infection cannot be eradicated by the antiretroviral drugs that are currently available. Proviral DNA persists in sanctuary sites such as the CNS and testis, making lifelong treatment necessary.

When to start antiretroviral therapy

Decisions about when to start therapy, what drugs to choose in antiretroviral-naïve children, and how to treat antiretroviral experienced children remain complex, and should be made in consultation with a specialist in pediatric and adolescent HIV infection.

Treatment with ART depends on clinical condition, immune status of the child and HIV viral load. Antiretroviral drug-resistant virus can develop in both multidrug experienced children and children who received initial regimens containing one or two drugs that incompletely suppressed viral replication. Additionally, drug resistance may be seen in antiretroviral-naïve children who have become infected with HIV despite maternal/infant antiretroviral prophylaxis. Thus, decisions about when to start therapy and what drugs to choose in antiretroviral-naïve children and on how to best treat antiretroviral-experienced children remain complex.

Although implementing ART is complex, a number of guidelines are available to help practitioners’ select effective regimens for particular patients. The decision to start ART depends on clinical, immunological and socioeconomic conditions. There are US guidelines, Penta guidelines, (World Health Organization) WHO guidelines and NACO (National AIDS Control Organization) guidelines that help in determining treatment protocols. There guidelines are regularly updated as and when newer research on treatment protocols and newer ARVs are available. The clinician treating HIV infected children should thus be aware of the latest treatment guideline. A comparison of when to start ART as per PENTA guidelines, WHO guidelines and US guidelines are depicted in Table 2.

Table 2: 

Comparison of current PENTA, WHO and US treatment thresholds

Before antiretroviral therapy is started, it is essential that parents, care-givers and patients are counseled regarding the importance of adherence to the prescribed treatment regimen. The goal of therapy should ensure normal growth and development, avoiding opportunistic infections and organ dysfunctions due to HIV and maintaining as healthy and normal life style as possible. Antiretroviral therapy is never an emergency and potential problems should be identified and resolved prior to starting therapy.

WHO guidelines 2013:

 The major shift in the 2013 WHO guidelines for antiretroviral therapy (ART) in children from previous recommendations is that it should be initiated in all children infected with HIV below five years of age, regardless of WHO clinical stage or CD4 cell count. Also recommended is that ART should be initiated in all HIV-infected children five years of age and older with CD4 cell count =500 cells/mm3, regardless of WHO clinical stage. But again, these recommendations are conditional because of the lack of evidence, however, this approach is expected to provide a high coverage of pediatric ART.

Which antiretroviral therapy regimens -

Aggressive treatment with at least three drugs is recommended. Dual NRTI remains the back bone of any regimen in combination with either a protease inhibitor or an NNRTI. Stavudine is no longer recommended. All PIs should be ritonavir boosted. The preferred NRTI combinations are Abacavir (ABC_ and lamivudine (3TC) for children who are HLA-B *5701 negative, and zidovudine (ZDV) and 3TC for children who are HLA-B *5701positive. The preferred NNRTI is nevirapine (NVP) for children aged less than 3 years, and efavirenz (EFV) for older children. With approval of tenofovir (TDF) for use in children above 2 years of age by US FDA, the choice of first line NRTI backbone for children above 10 years would be TDF + 3TC (or emtricitabine (FTC) with an NNRTI. In children above 5 years, ART now being recommended in those with CD4 count less than 500 cells/cumm as compared to previous guidelines of <350 cells/cumm, more children will be eligible for ART earlier. However, currently no evidence from randomized controlled trials to suggest that a strategy of initiating ART when the CD4 count is above 350 cells/µl (versus deferring initiation to around 350 cells/µl) results in benefit to the HIV infected child or adolescent and data from observational studies are inconsistent.The preferred PI is ritonavir-boosted lopinavir for young children. Alternative boosted PIs may be considered for older children, including fosamprenavir/r and darunavir/r, atazanavir/r which are licensed from age 6 years.

What to start with

Response to ART in children
Within one month of starting effective ART in children, plasma HIV RNA viral load decreases substantially and the CD4 count starts to rise. Infants, who frequently start from a viral load of between 105-107 copies/mL, can take many months to become undetectable.

References

• Shah Ira. Management of Pediatric HIV Pediatric Oncall. Mumbai. 2005.
• Shah Ira. Adverse Effects of Antiretroviral Therapy in HIV-1 Infected Children. J Trop Pediatr. 2006 Aug;52(4):244-8
• Shah Ira. Lactic Acidosis in HIV Infected Children Due To Antiretroviral Therapy. Indian Pediatrics. Oct 2005; 42:1051-1052.
• Shah Ira, Dhabe H, Lala M, Katira B. Assessment of Adherence to Antiretroviral Therapy in HIV Infected Children – A Preliminary Indian Study. Pedicon 2007, Mumbai, January 2007.
• Shah Ira. Antiretroviral therapy (ART). In: Shah I, Shah NK, Manglani M (eds). IAP Textbook of Pediatric HIV. Mumbai, January 2007
• Shah Ira. Pediatric HIV in India – Current Issues. JK Science. 2006; 8: 183- 184
• Shah Ira, Katira B. Tuberculosis Co-Infection in HAART Naïve HIV Infected Children. Accepted for publication. Indian Journal of Pediatrics. 20-08-2008
• Mohanty S, Shah Ira. Use of Tenofovir and Abacavir for treatment of PML. Clinical Workshop on Pediatric HIV, Mumbai, 20th March 2008.
• Swaminathan S, Ramachandran G, Hemanth Kumar AK, Vasantha M, Soundararajan L, Kannabiran BP, Navaneethapandian PGD, Shah Ira, Karunaianandham R, Sikhamani R. Factors influencing plasma nevirapine levels: a study in HIV-infected children on generic antiretroviral treatment in India. J Antimicrob Chemother. Advance Access published March 9, 2011
• Shah Ira, Swaminathan S, Ramachandran G, Hemanth Kumar AK, Goray A, Chaddha U, Tayal S, Lala M. Nevirapine and efavirenz blood concentrations and effect of concomitant use of rifampicin in HIV infected children on antiretroviral therapy. Indian Pediatr. Accepted for publication 26 November 2010 (Ref.No. IP/2010/276)
• Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR, 1994;43:1-10.
• Hirsch MS, Burn-Vezinet F, Clotet B et al. Antiretroviral Drug Resistance testing in adults infected with Human Immunodeficiency Virus Type-1: 2003 Recommendations of an International AIDS Society – USA Panel. Clin Infect Dis 2003;37:113-28.
• PENTA Steering Committee. PENTA 2009 guidelines for the use of antiretroviral therapy in pediatric HIV-1 infection. HIV Medicine. 2009; 10: 591–613
• World Health Organization. Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Executive summary of recommendations. Preliminary version for program planning. WHO. Geneva. August 2010.
• Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. August 16, 2010; pp 1-219. Available at http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf.
• Gibb D. ARVs and children – part 1. Classification: mode of action of ART drugs and ART regimens. Available from Tr@inforPedHIV 2011
• Welch S. ARV's and children part 2. When to start ARV treatment and which regime to choose. Available from Tr@inforPedHIV 2011
• WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection : recommendations for a public health approach, June 2013. Available at URL: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf. Accessed on 25th October 2013r a public health approach, June 2013. Available at URL: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf. Accessed on 25th October 2013