What this study adds: This study adds to limited real-world evidence on the challenges to rollout of paediatric formulations that can inform opportunities to strengthen HIV services for children living with HIV in resource-limited settings.

Children aged 0 to 14 years account for approximately 5% of all people living with HIV worldwide, with the majority (88%) residing in sub-Saharan Africa.¹ Despite progress in access to effective antiretroviral therapy (ART) across the globe, children living with HIV (CLHIV) continue to have marked disparities in access to life-saving and optimal paediatric ART and in reaching viral load suppression (VLS). In 2021, of the estimated 1.68 million CLHIV aged 0 to 14 years, only 52% received ART¹ compared to 76% of adults living with HIV, both below the 95% global target of treatment coverage.² The VLS rate among CLHIV is also suboptimal. A meta-analysis of studies among CLHIV from low- and middle-income countries found a VLS rate within 12 months of ART initiation of only 72.7%.³

With an estimated HIV prevalence in 2021 of 12.4% among people aged 15 years to 49 years,⁴ Mozambique is currently one of the top 10 countries with the highest HIV prevalence worldwide.⁵ CLHIV constitute 6% of all people living with HIV in the country. In 2022, the Mozambique Ministry of Health (MoH) reported that only 73% of CLHIV received ART, of which 71% were virally suppressed, far below the 95% global target.⁶

Dolutegravir (DTG) is an integrase strand transfer inhibitor recommended as first-line ART for children and adults in combination with a backbone of two nucleoside reverse transcriptase inhibitors (NRTI).⁷ DTG-based ART is associated with better virologic outcomes than other antiretroviral drugs.^8,9 As demonstrated by clinical trials in adults and children, DTG-based regimens have faster VLS than protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI).^10,11,12,13

Following guidelines from 2018 on the use of DTG as first- and second-line treatment for CLHIV weighing ≥ 20 kg, in 2019, the World Health Organization (WHO) updated these guidelines⁷ recommending the use of paediatric DTG (pDTG) 10 mg dispersible tablets for younger children weighing < 20 kg. After revising its national guidelines, Mozambique introduced pDTG in June 2021, with its subsequent rollout in late February 2022.¹⁴

According to national guidelines, all Mozambican children initiating ART and switching to new antiretroviral (ARV) regimens, including pDTG-based regimens, should undertake the first VL monitoring 6 months after ART initiation and at every 12 months thereafter if the VL result is < 1000 copies/mL. Children with VL ≥ 1000 copies/mL, should repeat VL 3 months after three enhanced counselling sessions.¹⁵ Prior national guidelines dated from 15 October 2020 recommended that children switch to or initiate ART with Abacavir (ABC) or Zidovudine (AZT)/Lamivudine (3TC)+Lopinavir/Ritonavir (LPV/r) regimen. After pDTG national rollout in February 2022, all children from 4 weeks of age and weighing < 20 kg (3 kg – 19.9 kg) regardless their ART regimen or VL result, were recommended to switch to or initiate ART with ABC/3TC+pDTG and then switch to ABC/3TC+ DTG 50 mg when they reached 20 kg.¹⁶

There is limited real-world evidence of pDTG national rollout targeting CLHIV in resource-limited settings. This study aims to describe programme rollout, including the transition rate to and new initiation of pDTG, VLS rates post-pDTG and factors associated with VLS among Mozambican CLHIV.

This is one of the few studies providing real-world evidence of pDTG national rollout, including post-transition virological outcomes in a sample of Mozambican children younger than 9 years. Most eligible children transitioned or initiated pDTG per national guidelines, and after ≥ 5 months post transition, slightly over three-quarters of children were virally suppressed. However, our study also identified challenges during the national rollout of this new ARV formulation. These included switches off pDTG after starting, VL monitoring gaps pre and post transition to pDTG, and incomplete documentation of ARV regimens and weight to determine drug eligibility. We also observed that some potentially eligible children did not switch to pDTG. A greater understanding of these challenges presents opportunities for strengthening health systems, primarily those in sub-Saharan Africa.

We found that most children initiated pDTG immediately after the formulation was made available at site level in March 2022, which aligns with the release of national pDTG guidelines. As expected, most eligible children who switched to pDTG were ART experienced. This is consistent with results from the rollout of the DTG 50 mg in the same 16 study sites, finding that about 96% of children who transitioned to DTG 50 mg were ART-experienced.²⁰ In our study, children of younger ages were more likely to initiate ART with pDTG than older children.

Overall, 15% of potentially eligible children < 9 years (n = 207) did not switch to pDTG after the national pDTG rollout. Of this group, 124 (59.9%) children had an unknown weight, but were all on DTG 50 mg and were more likely to be older, with a median age of 7.8 years (IQR: 6.6–8.3). If we assume this group was ≥ 20 kg based on their older age, and thus not eligible for pDTG and on the appropriate DTG formulation, we can estimate the rate of pDTG transition among potentially eligible children is between 85% and 93%. However, we also found that almost a quarter (n = 48) of children weighing < 20 kg did not transition to pDTG. Concerns about pDTG supply and an overstock of LPV/r may have also delayed transition among some ART-experienced children until late June 2022 – August 2022 and is likely to explain these findings. Also, we cannot ignore issues of the stock management system at sub-national levels that may potentially result in stockouts of ARVs, reinforcing the need for adequate forecasting and availability of ARVs during a national rollout.²¹

We found that 16% of children who initiated pDTG had one or more ARV switches during follow-up. In most children, these switches involved changes from pDTG to DTG 50 mg, representing the appropriate transition from the lower formulation based on weight. Providers also started a small proportion of children above 20 kg on the 10 mg formulation, which may have been in response to an actual or expected stockout of DTG 50 mg, and changed the child back when there were higher stock levels. Finally, providers may have responded in different ways to weight fluctuations. One might have postponed immediately changing a child’s treatment once they reached a certain weight, while another might have switched a child on and off a drug in response to fluctuating weight.

We found a relatively low pre-pDTG suppression rate, 56.5%, among ART-experienced children who had VL data. The post-pDTG VLS rate increased to 75.1% among ART-experienced children and to 88.9% among newly initiated children. This is consistent with several prior studies in African settings providing evidence of favourable virologic outcomes after initiating DTG-based regimens.^22,23,24 In our study, older age and having a previously suppressed VL predicted VLS after pDTG-based regimen initiation. On the other hand, we found that almost one in four children who switched to pDTG-based regimen had unsuppressed VL after 5 months on this regimen.

According to the national guidelines, ARV regimens prior to switching included ABC/3TC or AZT/3TC backbones and, after the pDTG national rollout, the guidelines recommended a universal switch of children weighing < 20 kg to ABC/3TC+pDTG regimen. In our study, the majority of children (98.9%) maintained the same pre-switch NRTI backbone after switch, which could contribute to the poor viral suppression rate. The high rates of unsuppressed VL may also reflect a pre-existing resistance to the NRTI backbone that might decrease the effectiveness of DTG.²⁵ Given that in our study, 99% of children with unsuppressed VL were ART-experienced children, it is possible that cross-resistance between ABC and other NRTI drugs may partly explain the high proportion of unsuppressed patients after 5 months post switch to a ABC/3TC+pDTG regimen.²⁶ Evidence from other studies further emphasise this explanation, indicating that previous exposure to an ART, previous non-suppressed VL, no retention in care, ART duration of more than 24 months and malnutrition contributed to increased rates of virologic failure after a switch to a pDTG-based regimen.^27,28 Poor adherence is an important contributing factor for poor VLS and ART failure.²⁹ A study in Malawi among CLHIV under 20 kg who transitioned to a pDTG-based regimen found that almost half (47.2%) of studied children had poor adherence and it was linked to unsuppressed VL.³⁰

We observed that less than half of the children who switched to pDTG had a VL result. Of the 835 children on pDTG for ≥ 5 months, 541 (64.8%) did not have a VL performed, although this figure slightly underestimates VL coverage as we used a shorter duration than the 6-month cut-off per guidelines to increase the number of those contributing to this outcome given the short study period. This low rate is attributable in part to the study’s short follow-up, which was designed with an anticipated pDTG rollout date in January 2022. To collect a VL sample, a child would most likely need to start on pDTG by March 2022 or April 2022. Additionally, newly initiated children were more likely to have fewer months of follow-up, which explains significantly lower VL coverage rates among those just starting treatment (19% compared to 48% for ART-experienced children). However, some of the lower coverage could have been a result of implementation challenges precluding VL monitoring after ART initiation. Insufficient VL testing access has been reported in various HIV-prevalent settings.^31,32 Although at least yearly VL testing is recommended for HIV care and detection of virological failure,³³ high costs³⁴ and logistical complexities across the various stages of the VL cascade³⁵ have been reported in limited-resource settings. Logistical limitations from sample collection, processing and transport, and an extended time for result return can preclude effective VL monitoring.³⁶

Therefore, addressing these limitations and improving VL coverage and close VL monitoring is essential to monitor treatment failure. The issue of poor adherence is also worth noting.²⁹ Although we did not assess it, we recognise that this might have partly contributed to poor VLS observed in our study.³⁰ As such, implementing multidisciplinary strategies and patient-centred approaches to improve adherence are crucial to ensure treatment success. Lastly, addressing issues of the stock management system^37,38 while improving clinical records documentation^39,40 are additional strategies to strengthen service provision in the context of a new drug rollout.

There are limitations to this study originating primarily from its use of routine data sources. First, although the study team performed comprehensive data quality assurance activities, we can still not determine if missingness has a service-related justification or was a documentation gap. For instance, one in nine children had no follow-up regimen after switching to or initiating pDTG. Children starting pDTG towards the end of the study period may not have been scheduled to return yet, mainly if they were on a 3-month dispensation schedule and not expected to return until after the study endpoint. They may also have missed their scheduled pick-up visit or become lost to follow-up. Second, the broad study definition of children up to 9 years of age was intended to capture all those with pDTG weight eligibility of < 20 kg, but may have biased the findings towards overestimating eligible children and underestimating transition progress per guidelines. Finally, as noted above, the low VL coverage in our study was exacerbated by the limited VL results available due to the short study follow-up period.

Despite these limitations, our findings present some of the earliest data on real-world national transition to pDTG-based regimens among younger children. This study’s strengths include assessing the uptake of pDTG and comparing virological outcomes pre and post transition among a relatively large sample size of young children while documenting some implementation challenges during a national rollout of pDTG formulation.

We report on the rollout of the pDTG in a real-world and highly HIV-prevalent setting while comparing post-pDTG virological outcomes of more than a thousand younger children who initiated pDTG. Although most children switched to or initiated pDTG following the national guidelines, programmatic gaps remained. These gaps illuminate several opportunities for further strengthening the rollout of new treatment and formulations and HIV services for children, including more accurate drug forecasting, the need for increasing VL coverage and improved documentation of clinic records.