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Incidence and predictors of virological failure among HIV infected children and adolescents receiving second-line antiretroviral therapy in Uganda, a retrospective study

BMC Infectious Diseases volume 24, Article number: 1057 (2024) Cite this article

Abstract

Background

In Uganda, 20% (19,073/94,579) of children and adolescents (0-19 years) living with HIV (CALHIV) were receiving second-line antiretroviral therapy (ART) by the end of March 2020. Data on incidence and predictors of virological failure among these CALHIV on second-line ART is limited. Lack of this information and limited access to HIV drug resistance testing prevents early identification of CALHIV at risk of virological failure on second-line ART. The aim of this study was to determine the incidence and predictors of virological failure among CALHIV on second-line ART in Uganda.

Methodology

This was a retrospective cohort study of all CALHIV aged 0-19 years who were switched to second-line ART regimen between June 2010 and June 2019 at the Baylor Uganda Centre of Excellence clinic. Data was analysed using STATA 14. Cumulative incidence curves were used to assess incidence of virological failure. Factors associated with virological failure were identified using sub-distributional hazard regression analysis for competing risks considering death, transfer out and loss to follow-up as competing risks.

Results

Of 1104 CALHIV, 53% were male. At switch to Protease Inhibitor (PI) based second-line ART, majority (47.7%) were aged 5 – 9 years,56.2% had no/mild immune suppression for age while 77% had viral load copies < 100,000 copies/mL. The incidence of virological failure on second-line ART regimen among CALHIV was 3.9 per 100 person-years (PY) with a 10-year cumulative incidence rate of 32%. Factors significantly associated with virological failure were age 10 – 19 years (HR 3.2, 95% 1.6 – 6.2, p < 0.01) and HIV viral load count > 100,000 copies/mL (HR 2.2, 95% CI 1.5 – 3.1), p < 0.01) prior to second-line ART switch.

Conclusion

Treatment outcomes for children and adolescents on second-line ART are favourable with one third of them developing virological failure at 10 years of follow up. Adolescent age group and high HIV viral load at the start of second-line ART were significantly associated with virological failure on second-line ART. There is need to determine optimal strategies to improve ART treatment outcomes among adolescents with high viral load counts at second-line ART switch.

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Background

Uganda has made progress in scaling up antiretroviral therapy (ART) with 69% (35652/51670) of the children below 15 years and 92% (58927/64051) of adolescents on ART by end of 2019 [1,2,3,4]. Despite this progress, favourable treatment outcomes among children and adolescents living with HIV (CALHIV) still lag behind those of adults [5] . The Uganda Population HIV Impact assessment 2016 -2017 showed lower viral load suppression among estimated HIV positive children (0-14 years) at 39.3%, and 42.5% for young adults (15- 24 years) compared to 59.6 % among adults aged 15 – 64 years [5]. This is way below the 3rd UNAIDS 95 target which is to achieve viral suppression in 95% of people living with HIV receiving ART. A similar picture of higher virological failure among children living with HIV (CLHIV) compared to adults has been documented in systematic reviews [6,7,8].

With children and adolescents failing on first-line ART and developing HIV drug resistant strains, more will need second-line ART [9,10,11,12,13]. In Uganda, 20% (19,073/94,579) CALHIV were receiving second-line ART by the end of March 2020 [14]. The development of HIV drug resistant strains is of public health concern due to limited access of genotypic resistance testing as well as third line ART [15,16,17,18]. At the time of the study, HIV drug resistance testing was being conducted only for those failing on a second-line ART regimen [19]. This prevents early identification of those children and adolescents with ART mutations likely to fail on second-line ART. Although studies have documented virological response of clients switched to second-line ART regimen, most of these studies did not target children, had a short follow up period, utilised one viral load test therefore did not ascertain confirmed virological failure (two consecutively high viral load tests) [20,21,22,23,24,25]. Boerma et al’s study to determine treatment outcomes for Ugandan children on second-line ART did not ascertain the incidence of virological failure among these children and was limited by a small sample size, utilisation of 1 high viral load count to determine virological failure and a short follow up period of 24 months [24].

There is hence paucity of data on the incidence and predictors of virological failure among children and adolescents on second-line ART in Uganda. Determining how long it takes for CALHIV on second-line ART to develop virological failure will help guide Country ART programs plan for those with virological failure in need of 3rd line ART. Additionally, it is imperative that we understand the determinants of treatment success among CALHIV on second-line ART. Lack of this information and the limited access to HIV drug resistance testing prevents early identification of those CALHIV at risk of virological failure on second-line who would benefit from intensified remedial strategies and hence reduce the number of CALHIV failing on second-line ART in need of third line ART which is expensive with limited accessibility. The aim of this study was to determine the incidence and predictors of virological failure among HIV infected children and adolescents aged 0 to 19 years switched to second-line antiretroviral therapy in Uganda.

Methods

Study design, setting and study population

We conducted a retrospective cohort study of CALHIV (aged 0-19 years) who were switched to second-line Protease Inhibitor (PI) based ART regimen between June 2010 and June 2019 at the Baylor College of Medicine Children’s Foundation Uganda Clinical Centre of Excellence (Baylor Uganda COE), Kampala, Uganda. Baylor Uganda COE serves as the paediatric infectious diseases’ clinic at the Mulago National referral Hospital in Uganda. The clinic provides free comprehensive HIV care and treatment services to about 9000 clients, half of whom are CALHIV. The clinic was among the first to provide second-line ART in Uganda. At the time of the study, all CALHIV at the study site were being switched to a protease Inhibitor based regimen (Lopinavir/Ritonavir and Atazanavir/Ritonavir) as their second-line ART treatment according to the national ART guidelines. This was combined with nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (AZT), stavudine (d4t), abacavir (ABC), tenofovir disoproxil fumarate (TDF), lamivudine (3TC). During the study time, Dolutegravir based ART regimen was not available in the country as a first- or second-line ART regimen.

Clients attend the Baylor Uganda COE clinic at least once in three months and clinical data is captured using an electronic medical record (EMR) system. Data in the electronic database enabled availability of client level data at 10 years of follow up. Viral load monitoring for CALHIV is conducted every 6 months utilising plasma and Dry Blot Spot blood collection methods. CALHIV with viral loads >1000 copies/mL, undergo intensive adherence counselling once a month for three months, after which a viral load test is repeated. Clients with two consecutively high viral loads >1000 copies/mL are considered virological failures and are switched to the appropriate second-line ART regimen. Clients on second-line ART are considered for HIV drug resistance testing if they have a detectable viral load above 1000 copies/mL.

Second-line ART was defined as the second ART regimen following a switch (i.e. two drugs changed) from the first-line after virological failure.

Inclusion and exclusion criteria

The study included all CALHIV who were switched to second-line Protease Inhibitor based ART regimen between June 2010 and June 2019 at Baylor Uganda COE. CALHIV who had substitutions in their first-line ART regimen i.e. one drug changed were excluded to enable assessment of each backbone drug separately.

Data collection

We electronically extracted routine patient level data from the clinic EMR. A data tool was used to extract information on the specified variables.

Study variables and definitions

Independent variables and definitions

The baseline data variables extracted from the clinic records at initiation of second-line ART included age, sex, weight, WHO clinical stage, CD4 count, second-line ART regimen, Body Mass Index (BMI) for age z-scores, viral load. Baseline WHO clinical stage and CD4 count were measured on or at a date closest to the second-line ART initiation date within a window of six months prior and one month after second-line ART. Weights and heights were those taken within one month prior to or after second-line ART initiation. BMI for age z-scores was computed using the WHO child growth standards macro [26]. We utilized WHO’s criteria for immunosuppression based on CD4 count and age group i.e. moderate and severe immunosuppression respectively for each age group were expressed as; absolute CD4 counts of 750–1499 cells/mm3 (26-33%) and <750 cells/mm3 (<26%) for children <1 year, 500–999 cells/mm3 (22-29%) and <500 cells/mm3 (<22%) for children 1–<6 years of age and 200–499 cells/mm3 (14-25%) and <200 cells/mm3 (<14%) for children ≥ 6 years [27].

Dependent variable and definition

The primary outcome was virological failure defined as a viral load count>1000 copies/mL on two consecutive viral load measurements taken 6 months after initiation of second-line ART, following adherence support of at least 3 months duration between the two viral loads [28]. Other secondary outcomes measured included mortality, transfer out or loss to follow-up. A study participant was considered lost to follow-up if s/he had not had a clinic visit for more than 90 days after the last scheduled clinic appointment date.

Data analysis

Patient characteristics at second-line ART initiation were described using summary statistics (proportions). We computed overall incidence rates for second-line ART failure per 100 person-years (PY), and by age and gender. Kaplan-Meier estimates for 10-year failure probability was calculated overall. Time to second-line ART failure was computed from the date of second-line ART initiation. We conducted competing risk analysis for treatment outcomes and participants were right censored at the earliest of either loss to follow-up, death, transfer out, or database closure date (31 march 2020). We examined risk factors for second-line ART failure using univariable and multivariable Cox proportional hazard regression models. We used a stepwise regression method to select the most parsimonious model. The criteria for a variable to enter and to stay in the model were p ≤ 0.15 and p ≤ 0.05, respectively.

Results

Characteristics of study participants

A total of 4,892 CALHIV received HIV care and treatment services at Baylor Uganda COE between June 2010 and June 2019. Of these 23% (1116/4892) had been switched to second-line during this period. Twelve of 1116 had substitutions within their first -line ART and were excluded from the study, therefore 1104 CALHIV were included in the study. Fifty-three percent male and 47.7% were aged 5 – 9 years. Majority of the children had no/mild immunosuppression (56.2%), viral loads <100,000 at second-line ART initiation (77%). The most common second-line ART was Abacavir based ART (64.6%). Ninety percent (997/1104) were active in care, 3% (30/1104) had died, 2% (18/1104) were lost to follow up while 5% (59/1104) had been transferred out at the database closure time.

The median duration on first-line ART prior to second-line ART switch was 5.1 years (IQR 2.9-7.2) while the median duration of follow-up on second-line ART was 3.0 years (IQR 1.4-4.6) with total follow up time of 3660 person-years. Of the 1104 CALHIV 13% (143/1104) developed virological failure on second-line ART. Of the CALHIV that failed second-line ART, 90% (128/143) were active in care, 4% (6/143) had died, 1% (2/143) were lost to follow up and 5% (7/59) had been transferred.

Table 1 summarises characteristics of study participants while the secondary outcomes are summarised in Table 2.

Table 1 Characteristics of study participants HIV infected children and adolescents at the start of second line-ART at Baylor Uganda COE
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Table 2 Secondary outcomes of HIV infected children and adolescents switched to second-line ART at Baylor Uganda COE
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Incidence of virological failure on second-line ART regimen

The overall incidence rate of virological failure on second-line ART among CALHIV was 3.9 per 100 person-years (IQR 3.3 – 4.6). Adolescents aged 10 – 14 years had the highest incidence rate of virological failure at 5.7 per 100 person-years (95% CI 4.5 – 7.4) followed by those aged 5-9 years [2.9(95% CI: 1.6-4.8) per 100 PY], 15-19 year . olds [3.0(95%CI: 1.4-6.8)] and the under-five years [2.9(95% CI: 1.6-4.8)]. There was no difference in incidence rates of virological failure between males [4.0(95%CI: 3.1-5.1)] and females [3.8(95%CI: 3.3-4.6)]. The estimated 3- year probability of virological failure on second-line ART was 12% while the 10-year probability of virological failure was 32% (95%CI: 2.4%-4.2%). The 10-year cumulative incidence of second-line ART failure is shown in Fig. 1.

Fig. 1
figure 1

Kaplan Meier curve showing the probability of second-line ART failure

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Risk factors for virological failure among children and adolescents receiving second-line ART

At multivariate analysis, factors that were significantly associated with virological failure were age 10 – 19 years (HR 3.2, 95% 1.6 – 6.2, p < 0.01) compared to age band 5-9 years (HR 1.5, 95% CI 0.8-2.8), < 5 years (1) and HIV viral load count > 100,000 copies/mL prior to second-line ART switch (HR 2.2, 95% CI 1.5 – 3.1), p< 0.01 compared to < 1000 copies/mL. Gender, WHO clinical stage, level of immune suppression, BMI for age Z score and second-line ART regimen were not significantly associated with virological failure. Table 3 shows risk factors for virological failure among CALHIV receiving second-line ART at Baylor Uganda COE.

Table 3 Risk factors for virological failure among HIV infected children and adolescents receiving second-line ART at Baylor Uganda COE
Full size table

Discussion

The incidence of virological failure among HIV infected children and adolescents on second-line ART in this study was 3.9 per 100 person-years. This was lower than the pooled cumulative incidence reported in a multicentre analysis i.e. 8.2 per 100 PY with 6.2 per 100 PY for Sub Saharan Africa and 8.9 per 100 PY for Asian children [29]. It was also lower than that reported in a study of Asian CALHIV which was 7.25 per 100 person-years [23]. This difference in incidence rate can be partly attributed to the fact that in the cohort of Asian CALHIV, virological failure was defined as having at least 1 high viral load count > 1000 copies/mL while this study considered 2 high viral load counts > 1000 copies/mL.

A strength of this study was the long follow up period, close to 10 years. Over this period the estimated probability of second-line ART virological failure among CALHIV was 32% which indicates that majority of the CALHIV remain susceptible to a PI based regimen even up to 10 years. This could be due to low development of PI resistance mutations as reported in the previous studies [23, 30].

In this study, being an adolescent and a high viral load count above 100,000 copies/mL prior to second-line ART switch were significantly associated with virological failure. This finding of adolescence being significantly associated with virological failure on second-line ART has been reported in previous studies [23, 29, 31]. A higher cumulative incidence rate of virological failure observed in the adolescent age band 10 – 14 years in this study can be attributed to challenges of transitioning into adolescence that that have been reported in previous studies [32]. ART adherence challenges have been observed as children transition into adolescence and this contributes to the poor treatment outcomes in this age group [32]. ART fatigue, increased autonomy and refusal to take the medication were reported as challenges of adherence as children transition into adolescence [32]. Furthermore, high rates of non-adherence have been documented among adolescents with nearly half of the adolescents living with HIV reporting non adherence in the study by Kim MH et al [33]. The finding of high viral load levels prior to second-line ART switch being significantly associated with virological failure was also reported by Prasitsuebsai et al while lower viral load counts at switch were associated with viral load suppression in the study by Torsak Bunupuradah et al [23, 34]. The level of lopinavir concentrations has been shown to be a strong predictor of viremia among children and adolescents on second-line ART with lower drug concentrations being a predictor of high viremia [35, 36]. The finding of high viral load being associated with virological failure in this study could therefore be an indication of inadequate drug levels resulting from missed doses. We, however, did not include adherence levels in the analysis because measuring adherence in routine health care programs has been noted to be imprecise [37,38,39,40]. In such programs adherence assessment is usually overestimated and this underestimates its effect on virological failure [37,38,39,40].

The second-line ART regimen was found to be marginally significant in this study. However, zidovudine based second-line ART was more likely to be associated with virological failure. A higher rate of HIV drug resistance with zidovudine based ART regimen compared to tenofovir disoproxil fumarate based regimen has been reported by Prasitsuebsai, W., et al, Pierre, S [23, 41]. This might be because tenofovir disoproxil fumarate based regimens are more likely to be tolerated, have higher efficacy, lower level of toxicity compared to Zidovudine-based regimens [41].

Unlike the findings by Brian C. Zanoni et al this study did not find a significant association between gender and virological failure on second-line ART [20]. Brian C.Zanoni reported that females were significantly less likely to reach viral suppression after six months of second-line ART compared to males [20]. This was attributed to gender differences in mortality , baseline CD4 and baseline viral load seen in African pediatric HIV cohorts [42, 43]. Similar to findings by Prasitsuebsai et al, there was no significant association between virological failure and duration on first line ART, baseline WHO clinical staging at switch, as well as body mass index [23].

Since the study utilised data that is routinely collected in a public health service setting the results obtained are more likely to be generalizable to routine health care of CALHIV. However, the study site being a Centre of Excellence for comprehensive HIV care in an urban setting could limit the generalisability of these findings to rural settings with less specialised care for CALHIV. Another limitation of the study was the use of retrospective data and hence the investigators had no control of the data quality including analysis of adherence as a predictor of virological failure among CALHIV on second-line ART.

Conclusion

Treatment outcomes for children and adolescents on second-line ART are favourable with one third of these children and adolescents developing virological failure at 10 years of follow up. Adolescent age group and high HIV viral load at the start of second-line ART were significantly associated with virological failure on second-line ART.

Recommendations

There is need to determine optimal strategies to improve ART treatment outcomes among adolescents with high viral load counts at second-line ART switch.

Availability of data and materials

All data supporting the findings of this study are available within the paper and its Supplementary Information.

Abbreviations

ART:

Antiretroviral Therapy

ARV:

Antiretroviral

BMI:

Body Mass Index

CLHIV:

Children Living with HIV

CALHIV:

Children and Adolescents Living with HIV

COE:

Centre of Excellence

CPHL :

Central Public Health Laboratory

HAZ:

Height for Age Z score

HIV:

Human Immunodeficiency Virus

NRTI:

Nucleoside Reverse Transcriptase Inhibitors

NNRTI:

Non-Nucleoside Reverse Transcriptase Inhibitors

UNAIDS:

United Nations for Acquired Immune Deficiency Syndrome

WAZ:

Weight for Age Z score

WHO:

World Health Organisation

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Acknowledgements

This project was conducted under the Afya Bora fellowship program. We are grateful to the Afya Bora consortium working group members, the Afya Bora consortium member institutions, the primary and site mentors for their support during this fellowship and on this project. We acknowledge staff at Baylor College of Medicine Children’s foundation Uganda that provide clinical care to children and adolescents living with HIV as well as the monitoring and evaluation officers that supported data abstraction and analysis.

Funding

The study reviewed routinely collected program data and hence had no additional funding.

Author information

Authors and Affiliations

  1. Uganda Protestant Medical Bureau, P.O. Box 4127, Kampala, Uganda

    Fiona Musiime-Mwase

  2. Infectious Diseases Institute, Makerere University College of Health Sciences, P.O. Box 22418, Kampala, Uganda

    Damalie Nakanjako & Esther M. Nasuuna

  3. Department of Medicine, College of Health Sciences, Makerere University, P.O. Box 7072, Kampala, Uganda

    Damalie Nakanjako & Nelson Sewankambo

  4. Baylor College of Medicine Children’s Foundation Uganda, P.O. Box 72052, Kampala, Uganda

    Jacqueline Balungi Kanywa, Ronald Oceng & Peter Elyanu

  5. Joint Clinical Research Centre, P.O. Box 10005, Kampala, Uganda

    Ronald Naitala

Authors
  1. Fiona Musiime-Mwase
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  4. Esther M. Nasuuna
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Contributions

FMM, PE, EN, DN, NKS conceptualized and designed the study. FMM, PE, RO, RN participated in data collection and analysis of the findings. FMM, PE, EN, JBK, ARK, DN, NKS drafted and edited the manuscript. All authors reviewed and gave approval of the final manuscript version to be published.

Corresponding author

Correspondence to Fiona Musiime-Mwase.

Ethics declarations

Ethics approval and consent to participate

The study was conducted as part of the outcome study at the Baylor Uganda COE which has ongoing approvals from the School of Medicine research and ethics committee, Makerere University College of Health Sciences (REC REF No: 2009-090) and Uganda National Council of Science and Technology (HS 649).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Musiime-Mwase, F., Nakanjako, D., Kanywa, J.B. et al. Incidence and predictors of virological failure among HIV infected children and adolescents receiving second-line antiretroviral therapy in Uganda, a retrospective study. BMC Infect Dis 24, 1057 (2024). https://doi.org/10.1186/s12879-024-09930-9

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BMC Infectious Diseases

ISSN: 1471-2334

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