Human immunodeficiency virus (HIV) is a retrovirus which declines immune system, leaving the victim exposed to the possibility of being attacked by life threatening opportunistic infections, neurological disorders or unusual malignancies. Acquired Immune Deficiency Syndrome (AIDS) refers only to the last stage of HIV infection and is one of the major global public health.

Globally, an estimated 36.7 (34.0–39.8) million people were living with HIV (PLHIV) in 2015, and the coverage of antiretroviral therapy reached 46% [43–50%] at the end of 2015. In Asia, treatment coverage more than doubled, from 19% [17–22%] in 2010 to 41% [35–47%] in 2015. The gains in treatment are largely responsible for a 26% decline in AIDS-related deaths globally since 2010, from an estimated 1.5 million [1.3 million–1.7 million] in 2010 to 1.1 million [940 000 –1.3 million] in 2015[1]. In 2016 there were estimated 2.1 million [1.7 million–2.6 million] children (<15 years) living with HIV (CLHIV) who continue to experience persistent treatment gaps. HIV treatment coverage for children [43% (30-54%)] is far less than coverage for adults [54% (40-65%)] in 2016. In the same year, around 76% [60–88%] of pregnant women living with HIV had access to antiretroviral treatment to prevent mother to child transmission of HIV. New HIV infections among children declined by 47% since 2010, from 300 000 [230 000–370 000] in 2010 to 160 000 [100 000–220 000] in 2016[2].

The 2015 HIV Estimates confirm that HIV epidemic is overall declining in India. There is persistently increasing trend in treatment coverage with a constant decreasing trends in HIV prevalence, new HIV infections, AIDS related deaths in adults as well as in children at the national level. The adult HIV prevalence has continued its steady decline from an estimated peak of 0.38% in 2001-03 to 0.26% in 2015. Similar decreasing trend in prevalence is noticed among males and females. In the year 2015 prevalence was estimated at 0.30% among males and at 0.22% among females. The total number of PLHIV in India is estimated 2.12 million (1.71 million-2.65 million) in 2015, including 0.139 million children. Children (< 15 years) account for 6.54%, while two fifth (40.5%) of total HIV infections are among females. India is estimated to have around 86 (56 – 129) thousand new HIV infections in 2015, showing 66% decline in new infections since the year 2000. Children (<15 years) accounted for 12% (10.4 thousand) of total new infections. AIDS Related Deaths started declining in 2007, since then till 2015 the annual number of AIDS related deaths has declined by 54%. In 2015 an estimated 67.6 (46.4 –106.0) thousand people died of AIDS-related causes in the country, out of which 11% (7.5 thousand) were children. This decline is consistent with the rapid expansion of access to ART in the country. It is estimated with the expansion of free ART services, the treatment cumulatively saved the lives of around 0.45 million people till 2014[3].

Infants and children are dependent on adults for timely and correct treatment with ARV drugs. Children must be directly observed to swallow the medicine (sometime they spit it out or keep in the cheeks). Children differ from adults in that they have high rates of viral replication, very high HIV-1/2 viral load, high rates of CD4+ cell destruction, viral mutation, faster rate of disease progression and good immunologic response to Highly Active Antiretroviral Therapy (HAART). Antiretroviral drugs (ARVs) suppress viral replication and thus prevent mutant forms from developing. But if ARVs are not taken/taken in lower than recommended doses, then incomplete suppression occurs which leads to more replication, more opportunity for mutations and more chances that resistant virus will emerge and treatment failure occurs.

Studies [4,5,6,7,8,9] have shown that small increases in adherence can result in significant improvements in outcomes like physical growth, improvement in health status, decrease in morbidity and mortality, improvement in immunologic status of children and increased life expectancy. Studies in younger cohorts are essential to understand better the full spectrum of treatment responses in the developing world.

The present study was undertaken with following objectives:

1. To study the socio-demographic profile and baseline characteristics of HIV positive children at the time of ART initiation.
2. To determine the adherence to ART drugs and its outcome over time.

The study is a Hospital based longitudinal study conducted in Antiretroviral Treatment (ART) Centres of two leading tertiary care hospitals in New Delhi; Kalawati Saran Children Hospital (KSCH) & Dr. Ram ManoharLohia Hospital (RML) on 171 children living with HIV of 18 months to less than 15 years and resident of Delhi, India. The study was carried out from November 2012 to December 2013. Enrolment of the cases was done from November 2012 to December 2012. Thereafter quarterly follow-up of all cases was done for next one year. Retrospective data at the point of initiation of ART were collected from the records.

Data was collected after obtaining approval from the institutional protocol and ethical committee. On consenting to participate in the study, a written consent was taken from their parents/primary caretaker if literate; otherwise left thumb impression in front of a witness was taken. For children greater than 7 years, assent was also taken. Confidentiality of enrolled children and their parents/primary caretaker was maintained.

Interview of primary caretaker was taken for children <10 years of age, while in children ≥ 10 years interview of children as well as primary caretaker was taken. Primary caretaker was defined as a person who has consistently assumed responsibility for the housing, health, or safety of the child. These individuals administered medication daily and bringing the child for clinic appointments.

A semi-structured interview schedule was designed, pretested and then used for data collection to study socio-demographic profile, immunological profile and adherence to HAART. Rate of adherence to ARV treatment was assessed using the pill count method, by the number of doses taken divided by the total number of doses prescribed during each visit. Adherence was classified as optimal (95%) and sub optimal (<95% adherence). Mean adherence was calculated for the study period which was used for statistical analysis.

Of 171 children who were enrolled in the study, there were 2 lost to follow up and 1 child transferred out from the respective ART centre at the end of the study, so 168 subjects completed the study and detailed analysis is done on these study subjects. Approximately two-third (67.8%) of study subjects were boys. 88.3% of study subjects were Hindu by religion followed by 7.6% of Muslims (Table 1). While majority (64%) of the study subjects had completed their primary immunization, 41 (21.7%) were partially immunized and 8 (4.2%) were not immunized (Figure 1). Around four fifth (79.9%) of the study subjects had HIV positive mother (Figure 2).

Table 1: Socio-demographic profile of the study subjects (N=171)

In the present study it was seen that at the beginning of HAART, 36 out of 168 (21.4%) children were ambulatory, 8 were bedridden, while the rest of the study subjects (73.8%) were in working functional status. With initiation of HAART almost all (98.8%) the study subjects moved to working functional status, only 2 study subjects, who were mentally retarded, were ambulatory and no child was bedridden at the end of the study. With the initiation of HAART the improvement in WHO clinical stage of study subjects was found to be statistically significant (p<0.01) (Figure 3 and Table 2).Majority of the study subjects were found to be adherent to the treatment given (89.3%) (Table 3).

Table 2: Distribution of study subjects according to WHO clinical stage (N=168)

Table 3:- Adherence of study subjects to ART

Losses to Follow Up were *2; **5; #3; †2 and 1 transferred out in the last month

There was statistical significant increase in CD4 percentage and CD4 count (p<0.001), since ART was started in these children (Table 4).

Table 4:- Immunological response of ART in study subjects (N=168)

With increase in adherence there is a statistical significant improvement in immunological status of study subjects (p<0.001) (Table 5).

Table 5- Association between adherence and immunological status of study subjects (N=168)

In the present study 67.7% of the study subjects were boys. There were more number of boys as compared to girls as reported in other Indian studies also[10,11,12,13,14,15]. 88.4% of the study subjects were Hindus, followed by Muslims (7.9%), Sikhs (2.6%), and Christians (1.1%). The results are comparable to the Census of India (2011)[16]; the percentage of Hindus, Muslims, Sikhs and Christians were 80.5%, 13.4%, 1.9% and 2.3%, respectively.

In almost 80% of the study subjects, mothers were HIV positive which is similar to an earlier study conducted in New Delhi [11]. Both parents were found to be HIV positive in nearly three fourth of the study subjects. A similar finding (74%) was seen in a study done in Surat[5], India while in Chennai[17], a relatively lower percentage of HIV infected parents was found (38%) indicating that mode of transmission may vary from place to place. Another study conducted by Okomo U, et al in West Africa [18], observed 10.8% HIV infected parents. In the present study, 64% of the study subjects had completed their primary immunization, 21.7% were partially immunized and 4.2% were not immunized. However in a study conducted in Karnataka [12] in 2007 only 45 % were completely immunized and more than 50% were either unimmunized or partially immunized. The immunization status of our study population is comparable to Coverage Evaluation Survey, 2009[19] where 61% children aged 12-23 months were fully immunized, 31.4% partially immunized and 7.6% were unimmunized.

At the end of one year follow-up, the improvement in the functional status of majority of the study subjects is likely to be due to successful response to HAART. At the point of ART initiation, nearly two-third (66.2%) of the study subjects had moderate to severe disease (WHO clinical stage III & IV). Similar to the present study a number of researchers[5,6,20,21,22] have also reported a significant proportion of children to be suffering from moderate or severe form of disease (31% - 76%) before ART initiation. In the present study there was significant improvement in the clinical staging of children following ART, similarly reported by Patel A et al[5], Kabue MM et al[6]. These benefits should be well documented and disseminated among positive persons and other stakeholders to encourage them to utilize services for antiretroviral treatment.

Majority of the study subjects had optimal adherence to HAART, which can be attributed to the adherence counseling session given to the study subjects/caretakers at each visit. Clinical improvement rapidly apparent to caretakers, may also motivate them to adhere to the treatment. Adherence to treatment was good and comparable to that reported in other Indian and International studies (range 73% to 97%) conducted in various regions of Africa[4,14,23,24,25,26,27,28,29,30], India[31] and Thailand[32]. One of the reasons for good adherence could be free ART treatment under National Aids Control Programme. Good provider-patient/caretaker relationships with open communication may also contribute to higher adherence. It was also stated that health care service providers should also be trained enough to take in-depth interviews, counseling and motivation of caretaker/patient for good preparation regarding ART before initiation of ART.

The immunologic efficacy in our cohort was comparable to that in paediatric cohorts from other studies conducted in different parts of the world,[5,8,9,20,31,33,34,35] showing improvement in CD4 count with ART. Similar results were reported in a study by M. Bhattacharya[31] (Delhi, 2011) where the rise in CD4 count after ART initiation was more marked in the high adherence group, with the difference being statistically significant after 6 months of ART initiation. Many other studies also have reported benefits of ART with respect to both clinical and immunologic progression of disease in HIV-infected children [5,9]. Adherence to ART is important determinant of immunological improvement and treatment outcomeand in children is strongly linked to the availability of treatment support.

It is critical to focus on maximizing paediatric ART adherence to ensure the effectiveness of ARV regimens and to improve their living status. In view of the serious implications of non-adherence from a medical and public health perspective, there is a critical need for targeted intervention strategies to increase the level of adherence to cent percent. For better adherence, more tools need to be used to counsel caregivers about the advantages and benefits of high level of drug adherence. Monitoring and evaluation of adherence strategies are important components of any ART program and can be useful in determining rates and identifying the key factors that influence adherence and thus they should also be emphasized and strengthened. In this study adherence was measured by pill counting, the observed immunological responses were objective evidence of the levels of adherence to medications within the cohort. Improvements in CD4 values can be used as a proxy for ART efficacy as is commonly done in this setting to see the response of ART.

LIMITATIONS

• Since the study was carried out in Kalawati Saran Children Hospital and Dr. Ram ManoharLohia Hospital on a small sample, the result may not be extrapolated to other settings or to other areas.
• Another potential confounder was that the entire cohort taken in this study was already on ART, which might affect adherence outcome of the study subjects.
• This study used pill counts method to measure adherence which is also relatively easy to perform and objective; however, participants may manipulate pills and appear to be more adherent.

From the observations made during the course of the study, there are few recommendations which may address the problem of HIV and adherence to ART. Our findings from a tertiary care ART centre (one of them being paediatriccentre of excellence) shows a good response to HAART even when started at advanced stage of HIV infection. The majority of children demonstrated satisfactory clinical and immunological response to antiretroviral treatment. Expansion of these services is recommended at various levels of health sectors.

Adherence to ART is importnt determinant of immunological improvement and treatment outcome and in children is strongly linked to the availability of treatment support. It is critical to focus on maximizing paediatric ART adherence to ensure the effectiveness of ARV regimens and to minimize the possible emergence of drug resistance. Besides counseling we may also need another strategy to address the level of adherence as pill remaining after a month can be manipulated. Monitoring and evaluation of adherence strategies are important components of any ART program and should be strengthened for identifying the key factors that influence adherence.

1. UNAIDS [Internet]. Global AIDS update: World Health Organization, Geneva, Switzerland. c2016 - [cited 2017 Sept 22]. Available from: http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf
2. UNAIDS [Internet]. Fact sheet. World Health Organization, Geneva, Switzerland. c2017 - [cited 2017 Sept 22]. Available from: http://www.unaids.org/sites/default/files/media_asset/UNAIDS FactSheet_en.pdf
3. NACO [Internet]. Ministry of Health and Family Welfare. Technical report India HIV Estimates Government of India, New Delhi. c2015 - [cited 2017 Sept 22]. Available from: http://www.naco.gov.in/sites/default/files/India%20HIV%20Estimations%202015.pdf
4. Mosha BLN, Bagenda DS, Mudiope PK, Mubiru MC, Butler LM, Fowler MG, et al. The long-term effectiveness of generic adult fixed-dose combination antiretroviral therapy for HIV-infected Ugandan children. Afri Health Sci 2012;11:249-58
5. Patel A, Trivedi SS, Chudasama RK, Patel PK. Effect of antiretroviral therapy on clinical and immunologic disease progression in HIV positive children:One-year follow-up study. J Family Community Med 2012;19:178-83
6. Kabue MM, Buck WC, Wanless SR, Cox CM, McCollum ED, Caviness AC, et al. Mortality and clinical outcomes in HIV-infected children on antiretroviral therapy in Malawi, Lesotho, and Swaziland. Pediatrics 2012;130:591-99
7. Ruhinda EN, Bajunirwe F, &Kiwanuka J (2012). Anaemia in HIV-infected children: severity, types and effect on response to HAART. BMC Pediatr 2012;12:170
8. Biressaw S, Abegaz WE, Abebe M, Taye WA, Belay M. Adherence to Antiretroviral Therapy and associated factors among HIV infected children in Ethiopia: unannounced home-based pill count versus caregivers’ report. BMC Pediatr 2013;13:132
9. Moore BC, Mbewe MM, Cantrell RA, Chintu N, Stringer EM, Chi BH, Stringer JSA. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA 2007;298:1888-99
10. Choudhary N, Gomber S, &Narang M. Clinico-immunological profile and outcome of antiretroviral therapy in HIV-positive children. Public Health Nutr 2012;15:1442-5
11. Arun S, Singh AK, Lodha R, Kabra SK. Disclosure of the HIV Infection Status in Children. Indian J Pediatr 2009;76:805-8
12. Pol RR, Shepur TA and Ratageri VH. Clinico-Laboratory Profile of Pediatric HIV in Karnataka. Indian J Pediatr 2007;74:1071-5
13. Sehgal R, Baveja UK, Chattopadhya D, Chandra J and Lal S. Pediatric HIV Infection. Indian J Pediatr 2005;72:925-30
14. Chapp-Jumbo AU, Onyire NB, Orji ML, Onwe OE, Ojukwu JU. Assessment of Rate of Adherence to Highly Active Antiretroviral Therapy (HAART) among HIV Infected Children Attending the Infectious Disease Clinic of Federal Teaching Hospital Abakaliki (FETHA), Ebonyi State, Nigeria. J Child AdolescBehav 2016;4:269
15. Zubayr B, Ibrahim M, Jumare J, Hassan-Hanga F, JGambo M, Dakum PS, et al. Adherence to Highly Active Antiretroviral Therapy among HIV-Infected Children in Kano, Nigeria. J Hum VirolRetrovirol 2015;2:00033
16. Ministry of home affairs [Internet]. Office of Registrar General and Census Commissioner, India. GOI. c2011- [cited 2017 October 24]. Available from: http://www.census2011.co.in/religion.php
17. Rajasekaran S, Jeyaseelan L, Raja K, Ravichandran N. Demographic & clinical profile of HIV infected children accessing care at Tambaram, Chennai , India. Indian J Med Res 2009;129:42-9
18. Okomo U, Togun T, Oko F, Peterson K, Townend J, Peterson I, et al. Treatment outcomes among HIV-1 and HIV-2 infected children initiating antiretroviral therapy in a concentrated low prevalence setting in West Africa. BMC Pediatr 2012;12:95
19. Ministry of Health and Family Welfare [Internet]. Universal Immunization Program, CES. c2009 - [cited 2017 Sept 22]. Available from: http://www.mohfw.nic.in/WriteReadData/l892s/Immunization_UIP.pdf
20. Sauvageot S, Deribew A, Amberbir A, Deribe K. Adherence to highly active antiretroviral therapy and its correlates among HIV infected pediatric patients in Ethiopia.BMC Pediatr 2008;8:53
21. Gebremedhin A, Gebremariam S, Haile F, Weldearegawi B, Decotelli C. Predictors of mortality among HIV infected children on anti-retroviral therapy in Mekelle Hospital, Northern Ethiopia: a retrospective cohort study. BMC Public Health 2013;13:1047
22. Shet A, Mehta S, Rajagopalan N, Dinakar C, Ramesh E, Samuel NM, et al. Anemia and growth failure among HIV-infected children in India: a retrospective analysis. BMC Pediatr 2009;9:37
23. Ugwu R, Eneh A. Factors influencing adherence to paediatric antiretroviral therapy in Portharcourt, South- South Nigeria. Pan Afr Med J 2013;16:30
24. Zegeye S. Antiretroviral Therapy Adherence Among Pediatric Patients Attending ART Clinics in Harar and Dire Dawa, Ethiopia. ISRN AIDS 2013;96:152-70
25. Haberer JE, Kiwanuka J, Nansera D, Ragland K, Mellins C, Bangsberg DR. Multiple Measures Reveal Antiretroviral Adherence Successes and Challenges in HIV-Infected Ugandan Children. PLoS ONE 2012;7:e36737
26. Haberer JE, Cook A, Walker AS, Ngambi M, Ferrier A, Mulenga V, et al. Excellent Adherence to Antiretrovirals in HIV+ Zambian Children Is Compromised by Disrupted Routine, HIV Nondisclosure, and Paradoxical Income Effects. PLoS ONE 2011;6:e18505
27. Davies MA, Boulle A, Fakir T, Nuttall J, Eley B. Adherence to antiretroviral therapy in young children in Cape Town, South Africa, measured by medication return and caregiver self-report: a prospective cohort study. BMC Pediatr 2008;8:34-45
28. Nabukeera BN, Kalyesubula I, Kekitiinwa A, Byakika TJ, Musoke P. Adherence to antiretroviral therapy in children attending Mulago Hospital, Kampala. Ann Trop Paediatr 2007;27:123-31
29. Eticha T, Berhane L. Caregiver-reported adherence to antiretroviral therapy among HIV infected children in Mekelle, Ethiopia. BMC Pediatr 2014;14:114-21
30. Akahara C, Nwolisa E, Odinaka K, Okolo S. Assessment of Antiretroviral Treatment Adherence among Children Attending Care at a Tertiary Hospital in Southeastern Nigeria. J Trop Med 2017;2017:1-4
31. Bhattacharya M, Dubey AP. Adherence to antiretroviral therapy and its correlates among HIV-Infected children at an HIV clinic in New Delhi. Ann of Trop Paediatr 2011;31:331-7
32. Puthanakit T, Oberdorfer A, Akarathum N, Kanjanavanit S, Wannarit P, Sirisanthana T. Efficacy of Highly Active Antiretroviral Therapy in HIV-Infected Children Participating in Thailand’s National Access to Antiretroviral Program. Clin Infect Dis 2005;41:100-7
33. Lodha R, Upadhyay A, Kapoor V, Kabra SK. Clinical Profile and Natural History of Children with HIV Infection. Indian J Pediatr 2006;73:201-4
34. Song R, Jelagat J, Dzombo D, Mwalimu M, Mandaliya K, Shikely K, et al. Efficacy of highly active antiretroviral therapy in HIV-1 infected children in Kenya. Pediatrics 2007;120:856–61
35. Beghin JC, Ruelle J, Goubau P, Krishna M, Hall L, Linden DV. Virological and Immunological Long-Term Outcome of Human Immunodeficiency Virus-1 Infected Children Treated before One Year and after Two Years of Age in a Resource-Limited Setting of South Africa. J AIDS Clin Res 2017;8:690