Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes

Overall vertical transmission of HCV, transmission net of clearance, and timing of transmission

Background: It is widely accepted that the risk of HCV vertical transmission (VT) is 5-6% in mono-infected women, and that 25-40% of HCV infection clears spontaneously within 5 years. However, there is no consensus on how VT rates should be estimated, and there is a lack of information on VT rates “net” of clearance. // Methods: We re-analysed data on 1749 children in 3 prospective cohorts to obtain coherent estimates of overall VT rate and VT rates “net” of clearance at different ages. Clearance rates were used to impute the proportion of uninfected children who had been infected and then cleared before testing negative. The proportion of transmission early in utero, late in utero and at delivery was estimated from data on the proportion of HCV RNA positive within three days of birth, and differences between elective caesarean and non-elective caesarean deliveries. // Findings: Overall VT rates were 7.2% (95% credible interval 5.6-8.9) in mothers who were HIV negative and 12.1% (8.6-16.8) in HIV-co-infected women. The corresponding rates net of clearance at 5 years were 2.4% (1.1-4.1) and 4.1% (1.7-7.3). We estimated that 24.8% (12.1-40.8) of infections occur early in utero, 66.0% (42.5-83.3) later in utero, and 9.3% (0.5-30.6) during delivery. // Conclusion: Overall VT rates are about 24% higher than previously assumed, but the risk of infection persisting beyond age 5 years is about 38% lower. The results can inform design of trials of to prevent or treat pediatric HCV infection, and strategies to manage children exposed in utero

Spontaneous Clearance Of Vertically Acquired Hepatitis C Infection: Implications For Testing And Treatment

BACKGROUND: Current guidelines recommend that infants born to women with hepatitis C (HCV) viremia are screened for HCV antibody at age 18 months, and if positive, referred for RNA testing at 3 years to confirm chronic infection. This policy is based in part on analyses suggesting 25%-40% of vertically acquired HCV infections clear spontaneously within 4-5 years. METHODS: Data on 179 infants with HCV RNA and/or anti-HCV evidence of vertically acquired infection in three prospective European cohorts were investigated. Ages at clearance of infection were estimated taking account of interval censoring and delayed entry. We also investigated clearance in initially HCV RNA negative infants in whom RNA was not detectable until after 6 weeks. RESULTS: Clearance rates are initially high then decline slowly. Apparently, many infections clear before they can be confirmed. An estimated 65.9% (50.1-81.6) of confirmed infections cleared by 5 years, at a median 12.4 (7.1-18.9) months. If treatment began at age 6 months, 18 months or 3 years, at least 59.0% (42.0-76.9), 39.7% (17.9-65.9), and 20.9% (4.6-44.8) of those treated would clear without treatment. In seven (6.6%) confirmed infections, RNA was not detectable until after 6 weeks, and in 2 (1.9%) not until after 6 months. However, all such cases subsequently cleared. CONCLUSIONS: Most confirmed infection clears by age 3 years. Treatment before age 3, if it was available, would avoid loss to follow-up, but would result in substantial over-treatment

It ain't what you do, it's the way that you do it: The pitfalls of using routine data to measure early infant HIV diagnosis in HIV-exposed infants.

BACKGROUND: Early infant HIV diagnosis (EID) is critical to ensuring timely diagnosis of HIV-exposed infants, and treatment in those found to be infected. However estimates of coverage vary considerably, depending on data sources used. We used 4 methods to estimate coverage among a historical cohort of HIV-exposed infants in rural South Africa, between 2010-2016. METHODS: We estimated the proportion of infants ever tested (methods 1-3) and tested by 7 weeks of age (1-4) as follows: (1) infants born to women identified as HIV-positive in demographic surveillance were linked to those with ≥1 EID result in routine laboratory surveillance; (2) the number of infants with ≥1 EID result in laboratory surveillance divided by the estimated number of HIV-exposed infants, calculated as total live births multiplied by antenatal HIV seroprevalence; (3) the number of infants with ≥1 EID result in routine laboratory surveillance, divided by the number of HIV-exposed infants as estimated by the district health service; (4) from documentation in infants' Road-to-Health-booklets. RESULTS: The proportion ever tested was 43%, 88% and 138% for methods 1-3, and by 7 weeks of age was 25%, 49%, 86% and 46% for methods 1-4 respectively. CONCLUSIONS: The four methods, applied to a range of routine data sources, resulted in estimates varying considerably, and the true coverage of EID remains unclear. Our findings highlight the importance of developing unique patient identifiers, improving training of healthcare providers using reporting systems, and ensuring the accuracy of healthcare records, to ensure the best possible health outcomes for HIV-exposed infants

Modelling the potential effectiveness of hepatitis C screening and treatment strategies during pregnancy in Egypt and Ukraine

BACKGROUND & AIMS: Hepatitis C (HCV) test and treat campaigns currently excludes pregnant women. Pregnancy offers a unique opportunity for HCV screening and to potentially initiate direct-acting-antiviral treatment. We explored HCV screening and treatment strategies in two lower middle-income countries with high HCV prevalence, Egypt and Ukraine. METHODS: Country-specific probabilistic decision models were developed to simulate a cohort of pregnant women. We compared five strategies: S0, targeted risk-based screening and deferred treatment (DT) to after pregnancy/breastfeeding; S1, WHO risk-based screening and DT; S2, WHO risk-based screening and targeted treatment (treat women with risk factors for HCV vertical transmission (VT)); S3, universal screening and targeted treatment during pregnancy; S4, universal screening and treatment. Maternal and infant HCV outcomes were projected. RESULTS: S0 resulted in the highest proportion of women undiagnosed:59% and 20% in Egypt and Ukraine, respectively, with 0% maternal cure by delivery and VT estimated at 6.5% and 7.9%, respectively. WHO risk-based screening and DT (S1) increased the proportion of women diagnosed with no change in maternal cure or VT. Universal screening and treatment during pregnancy (S4) resulted in the highest proportion of women diagnosed and cured by delivery (65% and 70% respectively), and lower levels of VT (3.4% and 3.6% respectively). CONCLUSIONS: This is one of the first models to explore HCV screening and treatment strategies in pregnancy, which will be critical in informing future care and policy as more safety/efficacy data emerge. Universal screening and treatment in pregnancy could potentially improve both maternal and infant outcomes. IMPACT AND IMPLICATIONS: In the context of two lower middle-income countries with high HCV burden (Egypt and Ukraine), we designed a decision analytic model to explore five different HCV testing and treatment strategies for pregnant women, with the assumption that treatment was safe and efficacious for use in pregnancy. Assuming DAAs in pregnancy reduced vertical transmission, model findings indicate optimal maternal and infant benefits with provision of universal (rather than risk-based targeted) screening and treatment during pregnancy: the proportion of women diagnosed and cured by delivery would be 65% in Egypt and 70% in Ukraine (versus 0% with standard of care), and the proportion of infants that would be infected at the age of 6 months would decrease from 6.5% to 3.4% in Egypt, and from 7.9% to 3.6% in Ukraine, compared to standard of care. While future trials are needed to assess safety and efficacy of DAA treatment in pregnancy and impact on VT, there is increasing recognition that the elimination of HCV cannot leave entire subpopulations of pregnant women and young children behind. Our findings will be critical in informing policymakers in improving screening and treatment recommendations for pregnant women

Evolution of CD4 T-Cell count with age in a cohort of young people growing up with perinatally acquired HIV

Background: Recent studies have shown a decrease in CD4 count during adolescence in young people with perinatally acquired HIV (PHIV). We examine changes and predictors of CD4 over time in PHIV in the UK and compare to published CD4 data in the general population.// Methods: PHIV followed in the Collaborative HIV Paediatric Study who started antiretroviral therapy (ART) from 2000 onwards were included. Follow-up data from the UK Collaborative HIV Cohort Study were also used. Changes in CD4 count over time from age 10 to 20 years were analysed using mixed effects models. Potential predictors included demographics, age at ART start, nadir CD4 z-score (age-adjusted) in childhood and time-updated viral load.// Results: Of 1,258 PHIV included, 669 (53%) were female, median [IQR] age at ART initiation was 8.3 years [3.5, 12.1] and nadir CD4 z-score was -4.0 [-5.9, -2.5]. In multivariable analysis, mean CD4 count was higher in PHIV who started ART before age 10 and had a nadir CD4 z-score ≥-4 in childhood; these PHIV had a decline in CD4 count after age 10 which was comparable to the general population. Mean CD4 count was lower in PHIV who had started ART before age 10 and had a nadir CD4 z-score <-4 in childhood; for this group the decline in CD4 count after age 10 was steeper over time.// Conclusions: In children, as well as starting ART at an early age, optimising ART to maintain a higher CD4 z-score during childhood may be important to maximize immune reconstitution later in life

Overall vertical transmission of HCV, transmission net of clearance, and timing of transmission.

BACKGROUND: It is widely accepted that the risk of HCV vertical transmission (VT) is 5-6% in mono-infected women, and that 25-40% of HCV infection clears spontaneously within 5 years. However, there is no consensus on how VT rates should be estimated, and there is a lack of information on VT rates "net" of clearance. METHODS: We re-analysed data on 1749 children in 3 prospective cohorts to obtain coherent estimates of overall VT rate and VT rates "net" of clearance at different ages. Clearance rates were used to impute the proportion of uninfected children who had been infected and then cleared before testing negative. The proportion of transmission early in utero, late in utero and at delivery was estimated from data on the proportion of HCV RNA positive within three days of birth, and differences between elective caesarean and non-elective caesarean deliveries. FINDINGS: Overall VT rates were 7.2% (95% credible interval 5.6-8.9) in mothers who were HIV negative and 12.1% (8.6-16.8) in HIV-co-infected women. The corresponding rates net of clearance at 5 years were 2.4% (1.1-4.1) and 4.1% (1.7-7.3). We estimated that 24.8% (12.1-40.8) of infections occur early in utero, 66.0% (42.5-83.3) later in utero, and 9.3% (0.5-30.6) during delivery. CONCLUSION: Overall VT rates are about 24% higher than previously assumed, but the risk of infection persisting beyond age 5 years is about 38% lower. The results can inform design of trials of to prevent or treat pediatric HCV infection, and strategies to manage children exposed in utero

Spontaneous Clearance Of Vertically Acquired Hepatitis C Infection: Implications For Testing And Treatment.

BACKGROUND: Current guidelines recommend that infants born to women with hepatitis C (HCV) viremia are screened for HCV antibody at age 18 months, and if positive, referred for RNA testing at 3 years to confirm chronic infection. This policy is based in part on analyses suggesting 25%-40% of vertically acquired HCV infections clear spontaneously within 4-5 years. METHODS: Data on 179 infants with HCV RNA and/or anti-HCV evidence of vertically acquired infection in three prospective European cohorts were investigated. Ages at clearance of infection were estimated taking account of interval censoring and delayed entry. We also investigated clearance in initially HCV RNA negative infants in whom RNA was not detectable until after 6 weeks. RESULTS: Clearance rates are initially high then decline slowly. Apparently, many infections clear before they can be confirmed. An estimated 65.9% (50.1-81.6) of confirmed infections cleared by 5 years, at a median 12.4 (7.1-18.9) months. If treatment began at age 6 months, 18 months or 3 years, at least 59.0% (42.0-76.9), 39.7% (17.9-65.9), and 20.9% (4.6-44.8) of those treated would clear without treatment. In seven (6.6%) confirmed infections, RNA was not detectable until after 6 weeks, and in 2 (1.9%) not until after 6 months. However, all such cases subsequently cleared. CONCLUSIONS: Most confirmed infection clears by age 3 years. Treatment before age 3, if it was available, would avoid loss to follow-up, but would result in substantial over-treatment