Indian J Pediatr (December 2012) 79(12):16251633 DOI 10.

1007/s12098-012-0903-9

SYMPOSIUM ON PEDIATRIC HIV/AIDS

Antiretroviral Therapy in Children: Recent Advances

Rakesh Lodha & Mamta Manglani

Received: 13 June 2012 / Accepted: 4 October 2012 / Published online: 27 November 2012 # Dr. K C Chaudhuri Foundation 2012

Abstract Availability and successful use of various antiretroviral drugs has transformed HIV/AIDS from an incurable to a treatable chronic condition. The antiretroviral therapy can successfully suppress viral replication and preserve the immune system for many years. The implementation of antiretroviral therapy program in resource limited settings using the public health approach of the World Health Organization has had a dramatic impact on the lives of millions of HIV infected individuals. Antiretroviral therapy (ART) in children has many challenges: use of appropriate formulations, regular need for modification of doses as the child grows, adherence issues, etc. To reduce the high morbidity and mortality in HIV infected children, it is currently recommended that all HIV infected children less than 24 mo should receive ART; in older children the indications are based on clinical and/or immunological criteria. Highly active antiretroviral therapy regimens include at least 3 antiretroviral drugs. The first line therapy recommended for children is a combination of two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor. Infants who have had exposure to nevirapine should receive a combination of two nucleoside reverse transcriptase inhibitors and a protease inhibitor; the protease inhibitor of choice is ritonavir boosted lopinavir. The success of therapy is dependent on >95 % adherence. The second line regimen, used when the first line therapy fails, is based on a protease inhibitor. The ongoing research

focuses on simplification of regimen, discovery of more potent drugs, availability of more pediatric formulations, treatment of drug resistant strains etc. The optimal indications for initiation of therapy in children, are also being studied. Keywords Antiretroviral therapy . Children . HIV/AIDS . Recent advances

Introduction The HIV/AIDS epidemic is now nearly three decades old. Despite the advances in science in understanding the infection and extensive efforts in finding therapies, the infection remains incurable. The identification of HIV as the causative agent of AIDS in 1985 and the immediate unfolding of its complete genome paved the way for the development of selective inhibitors [1]. Six years after the identification of AIDS, the first antiretroviral drug, Zidovudine, was approved for use for HIV infection in 1987, by the USFDA. Within the next 6 y, other drugs were discovered. In 1992, the USFDA approved combination antiretroviral therapy. While single drug therapy led to improvement in the clinical and immunological status of patients, the effects were not sustained due to rapid development of resistance. The short life-cycle of HIV and high error rate in conversion of RNA to DNA (reverse transcription) causes the virus to mutate very rapidly, resulting in a high genetic variability of HIV; this leads to development and selection of drug resistant mutants. This problem persisted even with use of 2 drugs necessitating the use of at least 3 drugs for treatment of HIV infection. Highly active antiretroviral therapy (HAART), which includes 3 to 4 drugs in combination, has been highly beneficial to HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.

R. Lodha Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India M. Manglani (*) Department of Pediatrics, Division of Hematology-Oncology, Pediatric Centre of Excellence for HIV Care, LTM Medical College & General Hospital, Sion, Mumbai 400 022, India e-mail: mmanglani@hotmail.com

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Availability of antiretroviral therapy has transformed the HIV infection from a uniformly fatal condition to a chronic infection, and today, children with HIV infection can lead a near normal life. The currently available therapy does not eradicate the virus and cure the child; it only suppresses the virus replication for extended periods of time. When it is provided on a large scale, AIDS wards in hospitals are emptied, people living with HIV/AIDS return to their families and jobs, and AIDS-related morbidity and mortality fall dramatically [2]. Since antiretroviral therapy was introduced in 1996, these benefits were limited almost exclusively to industrialized countries, which had only 5 % of the global burden of HIV/AIDS. Major efforts by the governments, World Health Organization (WHO), public agencies and pharmaceutical industry have led to extension of benefits of antiretroviral therapy to the resource limited settings where >90 % of HIV-infected individuals live. The use of public health approach by the WHO has accelerated the provision of therapy to the individuals living in these settings [3]. In this approach, standardized simplified treatment protocols and decentralized service delivery enable treatment to be delivered to large numbers of HIV-infected adults and children through the public and private sector. Simplified tools and approaches to clinical decision-making, centred on the four Ss when to start drug treatment; substitute for toxicity; switch after treatment failure; and stop - enable lower level health-care workers to deliver care. Simple limited formularies have driven large-scale production of fixed-dose combinations for first-line treatment for adults and lowered prices. Similarly, for children, dispersible kid tablets with fixed dose combinations have been produced, enabling very young children to effectively receive antiretroviral therapy.

Classes of Drugs Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits: Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription. These drugs are incorporated into the newly synthesized viral DNA strand as a faulty nucleotide leading to a chemical reaction resulting in DNA chain termination. This group includes drugs like zidovudine, lamivudine, stavudine, didanosine, zalcitabine and abacavir. The newer agents include tenofovir and emtricitabine. Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase directly by binding to the enzyme and interfering with its function. The commonly used NNRTIs are nevirapine and efavirenz. The other drugs in this class are delaviridine and etravirine. Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for the final assembly of new virions. The drugs in this class are saquinavir, indinavir, lopinavir, ritonavir, lopinavir/ritonavir, nelfinavir. The newer agents include atazanavir, fosamprenavir, tipranavir and darunavir. Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of the several targets. Maraviroc and enfuvirtide are the two currently available agents in this class. Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. Raltegravir became the first integrase inhibitor to receive USFDA approval in October 2007. Elvitegravir is another integrase inhibitor. Few other drugs in this class are being tested - S/ GSK1349572, MK-0536. Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polypeptides into the mature capsid protein (p24). Because these viral particles have a defective core, the virions released consist mainly of non-infectious particles. CCR5 receptor antagonists are antiretroviral drugs which do not target the virus directly; they bind to the CCR5 receptor on the surface of the T-cell and block viral attachment to the cell. Most strains of HIV attach to T-cells using the CCR5 receptor.

Goals of Antiretroviral Therapy In the absence of a cure of HIV infection, following are the goals of therapy [4]: 1. Clinical goals: Prolongation of life, normal growth and development, and improvement in quality of life. 2. Immunologic goals: Immune reconstitution that is both quantitative and qualitative (pathogen-specific immune response). 3. Virologic goals: Maximum possible suppression of viral replication (undetectable viral load) for as long as possible; this may halt disease progression and prevent or delay progression. 4. Therapeutic goals: Therapy should have rational sequencing of drugs in a fashion that achieves clinical, virologic, and immunologic goals while maintaining treatment options, limiting drug toxicity and facilitating adherence.

Challenges in Antiretroviral Therapy in Children Children have a much faster disease progression compared to adults and have various developmental considerations that

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affect the treatment decisions. In addition, there are challenges posed by the growth of children which necessitates change in the doses of medications with time. The issue of appropriate formulations is of paramount importance. Initially, syrups were used for individual drugs; however, the total volume to be administered for 3 drugs was quite unmanageable in most children. The availability of various Fixed Dose Combinations (FDCs) has revolutionized the treatment of HIV infected children. This combined with development of guidelines for the weight-band based dosing have simplified the therapy to allow a rapid scale up of antiretroviral therapy for HIV infected children in resource limited settings. To the extent possible, regimens should be simplified with respect to the number of pills or volume of liquid prescribed, as well as frequency of therapy, and chosen to minimize drug interactions and side effects. When feasible, once-daily regimens could be prescribed as several studies in adults have demonstrated better adherence in once-daily compared with twice-daily ARV regimens [5].

& & & & &

such data are available) with the regimen, preferably in children as well as adults; The extent of pediatric experience with the particular drug or regimen; Incidence and types of short- and long-term drug toxicity with the regimen, with special attention to toxicity reported in children; Availability and acceptability of formulations appropriate for pediatric use, including palatability, ease of preparation (e.g., powders), volume of syrups, pill size and number; Dosing frequency and, food and fluid requirements; and Potential for drug interactions with other medications.

Current Guidelines The currently available drugs and regimens do not offer cure; they do, however, allow prolonged suppression of viral replication which is important for recovery of and preservation of immune system. In addition, a potent regimen will also prevent development of drug resistance and therefore treatment failure. The fact that the drugs do not cure warrants lifelong therapy with unfailing adherence. The indications for initiation of therapy in children are developed weighing the benefits of initiation of therapy and potential risks. It is now recommended that all infants and children below 2 y of age should be initiated on ART irrespective of the CD4 counts and/or clinical stage. This is based on evidence that early diagnosis of HIV and early initiation of ART reduced early infant mortality by 76 % and HIV progression by 75 % [6]. Table 1 compares the recommendations of WHO, PENTA and US [79]. In India, the treatment guidelines for HIV infected children in the national program are the same as that of the WHO.

What to Start? (Table 2) Various professional bodies have issued recommendations for the antiretroviral therapy in HIV infected children based on the following considerations [79]: & Data demonstrating durable viral suppression, immunologic improvement, and clinical improvement (when

The Indian treatment guidelines under the national ART program by NACO, are based on the WHO 2010 guidelines [7]. In resource limited settings as well as in the national program, the national recommendations should be followed. This would maintain uniformity and facilitate inclusion of patients into the program with ease, in case of first line failure or unaffordability in the course of their treatment. Table 3 shows the recommended antiretroviral drug regimen for children as per NACO guidelines [10]. For children less than 2 y of age, the regimen is determined based on whether or not there was exposure to nevirapine. The WHO guidelines recommend a PI (lopinavir/ritonavir) based regimen for infants with prior exposure to nevirapine and a nevirapine based regimen for those who were not exposed to nevirapine [7]. However, evidence from recent trials suggests superiority of lopinavir/ritonavir based regimen over nevirapine based regimen in infants and young children irrespective of the nevirapine exposure; the treatment failure rate with nevirapine based regimen was approximately 40 % while that in PI based regimen was around 20 % [11, 12]. However, there are challenges in the use of lopinavir/ritonavir in young children. The liquid formulation requires a cold chain at central site of storage and is highly unpalatable and bitter. The drug is significantly more expensive than nevirapine. The pediatric solid formulation can be used only for children older than 10 y. In children older than 24 mo, NNRTI based regimen is recommended as the first line regimen; this is irrespective of the prior exposure to nevirapine. The PENPACT-1 study has compared the long-term immunologic, virologic and clinical outcomes in older children (median age 6.5 y) without prior exposure to nevirapine in perinatal period [13]. The study found similar efficacy in the two groups supporting the guidelines on use of NNRTI based first line therapy in older children. Use of NNRTIs as initial therapy preserves the PI class for future use and confers lower risk of dyslipidemia and fat maldistribution than use of some agents in the PI class. Additionally, for children taking solid formulations, NNRTI-based regimens generally have a lower pill burden than PI-based regimens. The major disadvantages of the current NNRTI

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Table 1 Comparison of recommendations of various organizations regarding the initiation of antiretroviral therapy in HIV infected children [79] Age 011 mo 1223 mo PENTA 2009 Treat all Treat if CDC Stage B or C/WHO Stage 3 or 4 Treat if CD4<25 % or<1000 cells/l Consider treatment if viral load >105 copies/mL Treat if CDC Stage B or C/WHO Stage 3 or 4 Treat if CD4<20 % or<500 cells/l Consider treatment if viral load >105 copies/mL Treat CDC Stage B or C/WHO Stage 3 or 4 Treat if CD4<350 cells/l Consider treatment if viral load >105 copies/mL US 2011 Treat all Treat if AIDS or significant HIV-related symptoms CD4 <25 %, regardless of symptoms or HIV RNA level Asymptomatic or mild symptoms and CD4 percentage 25 % and HIV RNA 105 copies/mL Consider treatment if Asymptomatic or mild symptoms and CD4 25 % and HIV RNA<105 copies/mL Treat if AIDS or significant HIV-related symptoms CD4 count 500 cells/l Asymptomatic or mild symptoms and CD4 count >500 cells/l and HIV RNA 105 copies/mL Consider treatment if Asymptomatic or mild symptoms and CD4 count >500 cells/l and HIV RNA <105 copies/mL WHO 2010 Treat all Treat all Treat if WHO Stage 3 or 4 Treat if CD4 <25 % or <750 cells/l No virological threshold Treat if WHO Stage 3 or 4 Treat if CD4 <25 % or <750 cells/l No virological threshold

2435 mo 3659 mo

>5y

Treat WHO Stage 3 or 4 Treat if CD4<350 cells/l

drugs approved for use in children are that a single viral mutation can confer high-level drug resistance, and cross resistance develops between nevirapine and efavirenz. Presently, nevirapine is initiated in half the dose for the first 14 d (Lead-in dosing) i.e. a single dose only. This is followed by dosing twice a day at 12 h interval, if no adverse event such as rash occurs. There have been attempts to simplify the initiation of therapy with nevirapine based

regimen. Mulenga et al. conducted a randomized controlled trial (RCT) to compare initiation of antiretroviral therapy with full-dose nevirapine (Triomune Baby or Junior in the morning and evening) vs dose escalation (half-dose nevirapine for 14 d [Triomune in the morning and stavudinelamivudine {Lamivir-S} in the evening], then full dose), in accordance with World Health Organization weight-band dosing tables [14]. The primary end point of the study was

Table 2 Summary of the recommendations of various bodies for the antiretroviral therapy of HIV infected children Age 011 mos PENTA 2009a Nevirapine + lamivudine + abacavir (+zidovudine) or lopinavir/ritonavir + lamivudine + abacavir (+zidovudine) < 40 kg Efavirenz + lamivudine + abacavir or lopinavir/ritonavir + lamivudine + abacavir > 40 kg Efavirenz + (emtricitabine + tenofovir) or (lamivudine + abacavir) or lopinavir/ritonavir + (emtricitabine + tenofovir) or (lamivudine + abacavir) US 2011 (preferred regimen)b WHO 2010 Two NRTIs plus NVP; Infants exposed to nevirapine: Two NRTIs plus LPV/r Two NRTIs plus 1 NNRTI (NVP or EFV)

Two NRTIs plus LPV/r Two NRTIs plus LPV/r Two NRTIs plus EFV

13 y >3y

Two NRTIs plus LPV/r

>6y

Two NRTIs plus ATV plus low-dose RTV Two NRTIs plus EFV Two NRTIs plus LPV/r

HLA-B*5701 genetic testing should be performed before initiating abacavir-based therapy, and abacavir should not be given to a child who tests positive for HLA-B*5701 Preferred 2-NRTI Backbone Options for Use in Combination with Additional Drugs: ABC plus (3TC or FTC) (children age 3 mos); TDF plus (3TC or FTC) (adolescents age 12 y and Tanner Stage 4 or 5 only); ZDV plus (3TC or FTC)

Indian J Pediatr (December 2012) 79(12):16251633 Table 3 Regimens recommended in the national program of NACO for children above 2 y of age at enrolment National Pediatric ART Regimen Type of Regimen Regimen P I Regimen P I (a) Regimen P II Preferred First-line regimen First line regimen Regimen Remarks

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Zidovudine + Lamivudine + Nevirapine Preferred pediatric regimen for new patients Stavudine + Lamivudine + Nevirapine Zidovudine + Lamivudine + Efavirenz For children with Hb 9 g/dL Preferred for children on anti-tuberculosis treatment; Hb>9 g/dL and age>3 y and weight>10 kg For children on anti-tuberculosis treatment; Hb 9 g/dL and age>3 y and weight> 10 kg For patients not tolerating AZT or d4T on a NVP-based regimen For patients not tolerating AZT or d4T on a EFV-based regimen For patients not tolerating both NVP and EFV, and Hb>9 g/dL For patients not tolerating both NVP and EFV and Hb 9 g/dL

Regimen P II (a)

Stavudine + Lamivudine + Efavirenz

Regimen P III Regimen P III (a) Regimen P IV Regimen P IV (a)

Alternative First-line Abacavir + Lamivudine + Nevirapine regimen Abacavir + Lamivudine + Efavirenz Zidovudine+ Lamivudine + Lopinavir/ Ritonavir Stavudine + Lamivudine + Lopinavir/ Ritonavir

nevirapine-related clinical or laboratory grade 3 or 4 adverse events. Rash was observed to be more frequent in the full dose arm. This study provides evidence against use of full dose nevirapine for initiation. There are multiple options available for the NRTI backbone in first line regimen. Initially, the stavudine-lamivudine was the preferred NRTI combination for children as the FDC (with nevirapine) was available and the regimen was inexpensive, facilitating its use in resource limited settings. However, there have been concerns about the safety of the stavudine based regimen, particularly about the mitochondrial toxicity (lactic acidosis, lipodystrophy and dyslipidemias) [15] and neurologic side effects. Because of these concerns, the stavudine based regimens are no longer preferred. Currently, the zidovudine and lamivudine combination is preferred; pediatric FDC is now available for zidovudine and lamivudine. While there are concerns about zidovudine induced anemia with this regimen, it is reported in 5.4 to 12 % of children [16, 17] and in 16.2 % in adults in one study [18] and is generally well tolerated. The children who are started on zidovudine containing regimen have to be monitored for development of anemia in the initial period after starting ART. An increase in RDW and MCV is observed even without anemia and does not require any intervention; it may be useful for assessing adherence [19]. There are only a few studies comparing various NRTI combinations. In a randomized controlled trial in ART nave children, lamivudine + abacavir was found to be more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine + lamivudine or zidovudine + abacavir [20]. Abacavir is associated with serious hypersensitivity reaction; this is associated with HLA B*5701. In addition, abacavir formulations are more

expensive than the other ones. Currently, in the national program abacavir containing regimens are only recommended as alternative drugs in case of toxicity as well as for 2nd line regimens in case of failure of first line drugs due to resistance of the virus. Tenofovir containing regimens are preferred in adults. In children, there is concern about adverse effects on bone mineralization and its use is currently restricted to children older than 12 y with hepatitis B co-infection.

Dosing of Various Antiretroviral Drugs The weight bands based dosing of the various antiretroviral drugs recommended in treatment of HIV infected children is available in the national guidelines published by NACO [10].

Drugs and Combinations not Recommended in Children for Initial Therapy Some drugs and drug combinations are not recommended for initial therapy in children because of inferior virologic response, potential serious safety concerns (including potentially overlapping toxicities), or pharmacologic antagonism [9]. These drugs and drug combinations are listed in Table 4.

Second Line ART Though many children can remain stable on first-line antiretroviral therapy for years, there may be indication to reassess

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Table 4 Regimens or Components that should never be used for antiretroviral therapy of HIV infected children [9] Rationale Antiretroviral regimens never recommended for children One ARV drug alone (monotherapy)

Two NRTIs alone (except initial therapy)

TDF plus ABC plus (3TC or FTC) as a triple-NRTI regimen

TDF plus ddI plus (3TC or FTC) as a triple-NRTI regimen

Rapid development of resistance Inferior antiviral activity compared with combination including 3 ARV drugs Rapid development of resistance Inferior antiviral activity compared with combination including 3 ARV drugs High rate of early viral failure when this triple-NRTI regimen used as initial therapy in treatment-naive adults High rate of early viral failure when this triple-NRTI regimen used as initial therapy in treatment-naive adults Potential additive hyperbilirubinemia Enhanced toxicity Similar resistance profile and no additive benefit Antagonistic effect on HIV Potential for teratogenicity

Antiretroviral components never recommended as part of an antiretroviral regimen for children ATV plus IDV Dual-NNRTI combinations Dual-NRTI combinations: 3TC plus FTC

d4T plus ZDV EFV in first trimester of pregnancy or for sexually active adolescent girls of childbearing potential when reliable contraception cannot be ensured NVP in adolescent girls with CD4 count >250 cells/mm3 or adolescent boys with CD4 count >400 Increased incidence of symptomatic cells/mm3 (including serious and potentially fatal) hepatic events in these patient groups Unboosted SQV, DRV, or TPV Poor oral bioavailablity Inferior virologic activity compared with other PIs

3TC Lamivudine; ABC Abacavir; ARV Antiretroviral; ATV Atazanavir; d4T Stavudine; ddI Didanosine; DRV Darunavir; EFV Efavirenz; FTC Emtricitabine; IDV Indinavir; NNRTI Non-nucleoside reverse transcriptase inhibitor; NRTI Nucleoside reverse transcriptase inhibitor; NVP Nevirapine; PI Protease inhibitor; SQV Saquinavir; TDF Tenofovir; TPV Tipranavir; ZDV Zidovudine

the treatment regimen with time. Treatment failure can be defined as suboptimal response or a lack of sustained response to therapy using clinical, immunologic and virologic criteria. The criteria for determining treatment failure vary in different guidelines [79]. The WHO guidelines as also our national NACO guidelines have defined treatment failure as: & & Clinical failure is defined as the appearance or reappearance of WHO clinical stage 3 or stage 4 events after at least 24 wk on ART in a treatment-adherent child. Immunological failure is defined as developing or returning to the following age-related immunological thresholds after at least 24 wk on ART, in a treatment-adherent child: CD4 count of <200 cells/mm3 or %CD4 <10 for a child 2 y to <5 y of age; CD4 count of <100 cells/mm3 for a child 5 y of age or older. Virological failure is recognized as a persistent VL above 5000 RNA copies/ml, after at least 24 wk on ART, in a treatment-adherent child.

The causes of treatment failure, which include poor adherence, drug resistance, poor absorption of medications, inadequate dosing, and drug-drug interactions, should be assessed and addressed. The US and PENTA guidelines suggest that the choice of second-line and subsequent ART regimens should be informed by previous drug history and adherence, resistance testing, expert advice and suitable formulations available for the individual child [8, 9]. The WHO guidelines recommend the use of boosted PI component + two NRTI components. Table 5 summarizes the WHO recommended second line regimen.

Use of FDCs in Children Availability of pediatric FDCs has vastly improved the administration of the ART to children. In order to simplify the dosing of children of various weights, weight band dosing has been developed [7]. Currently, in India 3 drug pediatric FDCs

&

Indian J Pediatr (December 2012) 79(12):16251633 Table 5 Preferred second-line regimens

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Situation INFANTS AND CHILDREN <24 MO Not exposed to ARV Exposed to NNRTI Unknown ARV exposure CHILDREN Children 24 mo or more CONCOMITANT CONDITIONS Child or adolescent with severe anaemia Child or adolescent with TB Adolescent with hepatitis B

First-line regimen

Preferred second-line regimen

NVP+2 NRTIs LPV/r+2 NRTIs NVP+2 NRTIs NNRTI+2 NRTIs NVP+2 NRTIs no AZT EFV+2 NRTIs or 3 NRTIs TDF+3TC+NNRTI

LPV/r+2 NRTIsa NNRTI+2 NRTIsa LPV/r+2 NRTIsa Boosted PI+2 NRTIsa Boosted PI+2 NRTIsa Boosted PI+2 NRTIsa Boosted PI+2 NRTIsa

NRTIs other than those used in the first line regimen should be used

are available for 2 regimens: Stavudine + Lamivudine + Nevirapine and Zidovudine + Lamivudine + Nevirapine. In addition 2 drug pediatric FDCs are available for Stavudine + Lamivudine and Zidovudine + Lamivudine. And for second line regimen, combination of Abacavir and Lamivudine as FDC is also available.

Once Daily Dosing of ART Once-a-day dosing of antiretroviral drugs is feasible for some drugs in adults. In children, not all of these drugs have been found to be suitable for once a day dosing. The drugs which can be administered once a day in children include efavirenz, tenofovir (approved for use in children > 12 y and> 35 kgs by USFDA in March 2010), emtricitabine, abacavir (once daily dosing can be considered only in clinically stable patients with undetectable viral load and stable CD4 cell count), didanosine (enteric coated extended release capsules), lamivudine (once a day dosing of 300 mg only in adolescents), atazanavir, darunavir/ritonavir (once daily dosing only for children>12 y age). Following once a day regimen may be considered for use: didanosine + emtricitabine + efavirenz [21, 22].

Interruption of Therapy Patients who interrupt HAART without medical indications experience a rapid viral load (VL) rebound followed by depletion of CD4 lymphocytes [23, 24]. In contrast, during structured treatment interruptions (STI) of HAART, controlled increases in viral replication could promote the development of a specific immune response against HIV, which in turn could cause a delay in the rebound of viral load, with a greater delay with each interruption [25, 26]. This strategy may be useful

in reducing the chronic toxicity of antiretroviral drugs, decreasing treatment costs and improving patient quality of life. Studies performed in adult patients have reported variable results [2629]. Information available on STI of HAART in pediatric patients is limited. In a prospective multicenter study of aviremic pediatric patients on highly active antiretroviral therapy who underwent progressively longer antiretroviral treatment interruptions in cycles starting with 3 d, increasing by 2 d in length during each consecutive cycle, Borkowsky et al . observed increased HIV-specific immune responses and decreased HIV RNA in those children, who have had >10 cycles of antiretroviral discontinuations of increasing durations acting as autologous virus vaccinations [30]. Palacios et al. evaluated the viral, immune and clinical impact of a structured treatment interruption (STI) program of highly active antiretroviral therapy (HAART) in three cycles of 4 wk off/12 wk on therapy in a cohort of children with HIV infection under chronic viral control [31]. They observed that the STI of HAART in cycles of 4 wk off/12 wk on therapy in children with chronically undetectable VL could cause progressively lower viral rebounds followed by a decrease to undetectable levels, with a low risk of severe immunosuppression and without the occurrence of symptoms related to HIV. The study however had a sample size of only 4. In view of the limited evidence, this strategy is not recommended in children.

Use of Newer Agents in Children [9] There are several new agents that appear promising for use in adults that do not have sufficient pediatric pharmacokinetic (PK) and safety data to recommend their use as components of an initial therapeutic regimen in children. These agents include maraviroc (a CCR5 antagonist), raltegravir (an integrase

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Indian J Pediatr (December 2012) 79(12):16251633 4. Bartlett JG, Gallant JE. Medical management of HIV infection. Baltimore: Johns Hopkins Medicine Health Publishing Business Group;2004; pp 49. 5. Molina JM, Podsadecki TJ, Johnson MA, et al. A Lopinavir/ ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 wk. AIDS Res Hum Retrovir. 2007;23:150514. 6. Violari A, Cotton MF, Gibb DM, CHER Study team, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359:223344. 7. World Health Organization. Antiretroviral therapy of HIV infection in infants and children: towards universal access: recommendations for a public health approach - 2010 revision. Geneva 2010. 8. PENTA Steering Committee. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med. 2009;10:591613. 9. Panel on Antiretroviral Therapy and Medical Management of HIVInfected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. August 11, 2011; pp 1268.Available at http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf Accessed (September 5, 2011). 10. Guidelines for HIV care and treatment in Infants and Children. November 2006. published by IAP and NACO, available on www.nacoonline.org. 11. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. 2010;363:151020. 12. Palumbo P, Violari A, Lindsey L, et al. NVP- vs LPV/r-based ART among HIV + infants in resource-limited settings: the IMPAACT P1060 trial [abstract no.129LB]. 18th Conference on Retroviruses and Opportunistic Infections;2011 Feb 27-Mar 2; Boston (MA). 13. The PENPACT-1 (PENTA 9/PACTG 390) Study Team. Firstline antiretroviral therapy with a protease inhibitor versus nonnucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infect Dis. 2011;11:273 83. 14. Mulenga V, Cook A, Walker AS, et al. Strategies for nevirapine initiation in HIV-infected children taking pediatric fixed-dose combination baby pills in Zambia: a randomized controlled trial. Clin Infect Dis. 2010;51:10819. 15. World Health Organization. Rapid advice. Antiretroviral therapy for HIV infection in adults and adolescents. Geneva: WHO; 2009. 16. Kumarasamy N, Venkatesh KK, Cecelia AJ, et al. Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. AIDS Patient Care STDs. 2008;22:337 44. 17. Shah I. Adverse effects of antiretroviral therapy in HIV-1 infected children. J Trop Pediatr. 2006;52:2448. 18. Agarwal D, Chakravarty J, Chaube L, Rai M, Agrawal NR, Sundar S. High incidence of zidovudine induced anaemia in HIV infected patients in eastern India. Indian J Med Res. 2010;132:3869. 19. Romanelli F, Empey K, Pomeroy C. Macrocytosis as an indicator of medication (zidovudine) adherence in patients with HIV infection. AIDS Patient Care STDS. 2002;16:405 11. 20. Paediatric European Network for Treatment of AIDS (PENTA). Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 y in children. AIDS. 2007;21:94755. 21. McKinney Jr RE, Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and

inhibitor), tenofovir (in children age <12 y), etravirine and ripilvirine (both NNRTIs). Enfuvirtide, a fusion inhibitor, is approved for use in combination with other ARV drugs to treat children 6 y of age, with evidence of HIV replication despite ongoing ART (i.e., treatment-experienced children on nonsuppressive regimens). The drug has to be administered subcutaneously twice daily and is associated with a high incidence of local injection site reactions (98 %). Currently, data are insufficient to recommend use of enfuvirtide for initial therapy of children. Raltegravir, an integrase inhibitor, is being evaluated in treatment-experienced children; however, PK, safety, and efficacy data are not yet available and no pediatric formulation is commercially available. In June 2008, USFDA approved tipranavir boosted with ritonavir (protease inhibitors) for use in treatmentexperienced children age 218 y; however, current evidence is insufficient to consider use of the agent for initial therapy.

Future Directions While substantial progress has been achieved in scaling up of antiretroviral therapy for children, particularly in resource limited settings, challenges still remain. There is need for further simplification of regimen to improve the adherence. Newer drugs need to be developed to tackle the problem of drug resistance. Pharmacokinetic studies are required for establishing dosing guidelines for efavirenz in children less than 3 y of age. The role of newer classes of drugs like integrase inhibitors has to be defined. New strategies for effective antiretroviral therapy in HIVTB co-infected children need to be assessed.

Conflict of Interest None.

Role of Funding Source

None.

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