Review of Tenofovir Use in HIV-Infected Children
Review of Tenofovir Use in HIV-Infected Children
In 2001, TDF was approved by the US Food and Drug Administration (FDA) as a once-daily 300 mg tablet for the treatment of HIV infection in persons ≥18 years of age. In March 2010, it was approved for use in adolescents aged 12–17 years, and for children aged 2 years and above in January 2012. The study by Della Negra et al documented safety of TDF when used in treatment experienced adolescents ages 12–18 years. Similarly, another study by Seaz-Llorens X demonstrated safety and tolerability of TDF in children aged 2≤16 years consistent with adults. The World Health Organization technical update review of available pediatric data concludes that toxicities are similar to those seen in adults and supports rolling out of TDF in treatment programs for children. The 2014 Department of Health and Human Services guidelines have different levels of recommendation for the use of TDF in children based on Tanner stage. In the 2013 World Health Organization guidelines, TDF is recommended as part of the first line ARV regimen as recommended for HIV-infected children from 10 years of age to adolescents which is aligned with recommendations for adults, while for children ages 3 to <10 years, zidovudine or abacavir is preferred over TDF.
TDF is available as an oral powder (40 mg per scoop) and tablets (150, 200, 250 and 300 mg). The dose by body weight band starts at age 2 years and weight >10 kg, based on the recommended pediatric dose of 8 mg/kg/dose once daily (Table 2). For FDCs, Truvada (emtricitabine/TDF) is FDA-approved for use in adolescents aged ≥12 years and who weigh ≥35 kg. Atripla (emtricitabine/TDF/efavirenz) is FDA-approved for use in adolescents aged ≥12 years and who weigh ≥40 kg. TDF/emtricitabine/rilpivirine (Complera) and TDF/emtricitabine/elvitegravir/cobicistat (Stribild) are not yet approved for patients aged <18 years.
A meta-analysis of 17 studies in adults showed that TDF use was associated with a small but statistically significant loss of renal function. The risk of acute renal injury associated with TDF-containing regimens was 0.7% (95% CI: 0.2–1.2); which was higher than non-TDF regimens. Of note, treatment with TDF plus boosted PIs was associated with a greater decline in renal function over 48 weeks compared with TDF plus NNRTI-based regimens. However, the risks of chronic kidney failure was not significantly increased when compared to control. According to the summary of postmarketing surveillance adverse drug reaction reported in the first 4 years of TDF used in 10,343 adults, renal failure was observed in 0.3%.
The Department of Health and Human Services guidelines recommend assessment of renal function prior to TDF initiation and regular monitoring of estimated creatinine clearance thereafter. However, the need and cost-effectiveness for routine creatinine monitoring in resource-limited settings is still controversial. In a 4-year prospective cohort study of 3316 HIV-infected African adults who received TDF in the Development of AntiRetroviral Therapy in Africa trial rarely identified any individuals with significant changes in the estimated glomerular filtration rate (eGFR). The cumulative incidence of eGFR < 30 mL/min/1.73 m was 2.8% and chronic kidney disease was 5.0%. Routine biochemistry testing did not improve patient outcomes compared with clinical monitoring alone. Therefore, the best approach for monitoring for renal toxicity in resource limited settings deserves further evaluation.
A summary of the renal effects of TDF from pediatric studies is shown in Table 3. Rates of significant decline in eGFR <60 mL/min/1.73 m are only 0.2–0.6%, similar to in adult reports. In a retrospective analysis of 159 children in the United Kingdom and Ireland who received TDF-containing regimens, the incidence of overall renal adverse events was 2.2 per 100 child years. Six children (3.7%) experienced serious nephrotoxicity; all but one had received TDF with didanosine and lopinavir/r. The report from United Kingdom has shown that increase serum creatinine associated with the use of TDF was reversible after treatment discontinuation. Data from the Pediatric AIDS Clinical Trials Group 219/219C showed that 22% of more than 2000 children in the cohort had a persistent renal abnormality (≥3 sequentially abnormal renal laboratory values; proteinuria or elevated serum creatinine, or decreased eGFR to <60 mL/min/1.73 m). Those who received TDF (10.7% of cases) had 2.3 times the risk of renal abnormalities compared to the comparison group. The Pediatric HIV/AIDS Cohort Study in the US reported cumulative prevalence of proteinuria of 22%, with annual prevalence of proteinuria ranged from 10.3 to 13.7%. TDF use longer than 3 years of exposure was an independent predictor. Reversible hypophosphatemia with the use of TDF occurred with an incidence of 4.5–10%, usually asymptomatic. In a randomized, open-label study among 97 HIV-infected children, 48 were randomized to a TDF-including regimen. None experienced significant renal toxicity during the first 48 weeks. With longer follow-up time for a median 104 weeks, 4 (4.5%) had to discontinue TDF due to proximal renal tubulopathy; 3 of 4 presented with hypophosphatemia. Fanconi syndrome and nephrogenic diabetes insipidus associated with the use of TDF have been reported in children as well as in adults. Nonetheless, all were case reports; the incidence of those renal conditions in prospective treatment cohort is rare.
In contrast an excellent renal safety profile has been reported from several cohorts. An Italian study in 26 children reported no evidence of impaired glomerular or tubular renal function throughout 60-months of follow-up. However, the sample size was small, there was no comparison group, and there were no other potential nephrotoxic ARTs (ie, indinavir, lopinavir/r and didanosine) used concomitantly. The randomized double-blinded placebo-controlled study in Brazil and Panama also found no statistically significant difference in change of serum creatinine and creatinine clearance in TDF versus placebo group during the 48-week follow-up. A study in 40 HIV-infected Thai children with 96-week follow-up also did not find any clinically significant decrease in eGFR overtime.
In clinical practice, TDF should be avoided in the presence of pre-existing renal disease if other ART options are available. HIV-infected children who receive TDF should be followed with caution for evidence of renal toxicity, especially when concomitantly used with drugs that increase TDF exposure such as didanosine or boosted PI. Although the data from over 4 to 5 years follow-up in Development of AntiRetroviral Therapy in Africa trial demonstrated small differences in eGFR changes when compared to other ARTs, laboratory monitoring that is readily available in most setting including serum creatinine, urine glucose and urine protein might be performed at 3- to 6-month intervals (the optimal frequency is undetermined), recognizing that the renal toxicities could develop with long-term use of TDF. For serum phosphate concentration that can vary from time to time, clinical observation for symptomatic hypophosphatemia might be applied instead of routine laboratory monitoring.
Low bone mineral density (BMD) in HIV-infected children and adolescents has been reported from several studies. Its etiology was described as multifactorial, including general risk factors such as smoking, less physical activity and vitamin D deficiency, and also HIV-related factors, such as HIV infection itself, chronic immune activation and the effects of antiretroviral treatment. Increased fracture risk has been reported in adults treated with TDF, with a yearly hazard ratio for osteoporotic fracture of 1.12 (95% CI: 1.03–1.21) compared to the control group. At present, no increase in clinical fracture risk related to TDF use in children has been documented, although it has been suggested that a high bone remodeling rate could disturb normal bone physiology.
The effect of TDF on bone might be different in children as compared to adults due to different stages of bone dynamics. A summary of the effects of TDF on bone mineral density from pediatric studies is shown in Table 4. In cross-sectional studies to assess bone mineral density among perinatally HIV-infected children and adolescents receiving ART, the reported prevalence rate of BMD z-score <-2 is in a range of 24–32%. Longitudinal assessment of BMD show that the median BMD z-scores usually decline from baseline in the first 6–12 months after initiation of ART and then remain stable thereafter. This is similar to reports from HIV-infected adults that the decrease in BMD was seen early during the first 48 weeks of therapy, and then stable up to 5 years of follow-up. The Gilead 321 study demonstrated a lower rate of BMD gain in TDF-treated children aged 12≤18 years at week 48 when compared to children in the placebo group; this difference was not seen among TDF-treated younger children aged 2≤12 years. Bone safety follow-up showed a modest decline from baseline in median spine and/or total body BMD z-scores through week 144 among children and adolescents who received TDF. Five out of 170 subjects had trauma-related bone fractures during follow-up period. In contrast, an Italian study reported that the change in BMD in treatment-experienced HIV-infected children with virologic suppression was not different from control after substitution of stavudine with TDF for 12 months. When they were followed upto 60 months, no significant change in BMD z-score from baseline was observed. This might be explained by the use of a relatively low dose of TDF and no concomitant use of boosted PIs.
Factors associated with higher risk of BMD loss in children treated with TDF were young age, prepubertal children and advanced World Health Organization stage. Increased level of bone turnover marker (morning osteocalcin) was reported, as well as change in serum calcium, serum phosphate, parathyroid hormone, vitamin D level and urinary calcium excretion, which implies that TFV stimulates bone reabsorption. Higher bone turnover in children as well as nutritional factors could possibly explain why TDF-related changes in BMD may be more obvious in children than in adults. For example, the Brazilian study reported low calcium and vitamin D intake in 72.9% and 91.5% of HIV-infected children, respectively.
In summary, the adverse impact of TDF on bone is well documented but its clinical significance remains controversial. More long-term studies are needed to see whether any clinically significant events occur. When TDF is prescribed for children, counseling on a balanced diet and age-appropriate exercise is warranted to minimize possible risks associated with low BMD.
Although the natural history of HIV infection is generally not influenced by HBV coinfection, there is an increased rate of antiretroviral-related hepatotoxicity, and immune-reconstitution hepatitis. A low rate of hepatitis B clearance resulting in chronic infection has been reported. Furthermore, in HIV-infected individuals with HBV infection, progression to liver cancer may occur at a younger age when compared to those with HBV infection alone. Treatment of HBV/HIV co-infected adults is aimed at suppressing HBV viral replication to undetectable levels, to reduce liver inflammation, and to stop or delay progression of hepatic fibrosis. Early introduction of ART is recommended in HBV/HIV co-infected patients regardless of immune status; an ARV regimen with TDF and lamivudine/emtricitabine as a backbone is advised for ARV naive patients with wild-type virus who have no contraindications to either drug. A retrospective Austrian cohort has reported that 91% of HBV/HIV-co–infected adults achieved complete HBV suppression despite high baseline viremia. TDF-containing cART led to high rates of hepatitis B "e" antigen seroconversion (50–57%) and hepatitis B surface antigen loss (25–29%) after 5 years of follow-up.
TDF is currently recommended for treatment of chronic hepatitis B infection in children 12 years of age and older; thus, initial choice of cART for co-infected children who are old enough to receive TDF is similar to adults. Regimens with both TDF and lamivudine/emtricitabine are advised; although there are no data that demonstrate better HBV outcomes with treatment of HBV infection in the immune tolerant phase. While cART containing lamivudine (or emtricitabine) without TDF is not recommended for adults with coinfection because of the emergence of HBV lamivudine resistance, such cART regimens are standard for infants and young children with coinfection. Most children with coinfection acquired both infections in infancy; however, lack of HBV screening in routine HIV care for children results in delayed diagnosis of HBV. Those children will likely have TDF incorporated into their cART regimen as they age, and, based on evidence from studies in co-infected adults with prior lamivudine exposure, this approach is expected to result in high rates of HBV suppression.
TDF is active against HBV, including virus with the lamivudine-selected tyrosine-methionine-aspartate-aspartate mutation. Combination HBV therapy with TDF and lamivudine has been reported as being linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HBV/HIV co-infected individuals than monotherapy. So far there has been no report of emergence of HBV resistance to TDF.
Specific Considerations for TDF use in HIV-infected Children and Adolescents
TDF Drug Approval Process
In 2001, TDF was approved by the US Food and Drug Administration (FDA) as a once-daily 300 mg tablet for the treatment of HIV infection in persons ≥18 years of age. In March 2010, it was approved for use in adolescents aged 12–17 years, and for children aged 2 years and above in January 2012. The study by Della Negra et al documented safety of TDF when used in treatment experienced adolescents ages 12–18 years. Similarly, another study by Seaz-Llorens X demonstrated safety and tolerability of TDF in children aged 2≤16 years consistent with adults. The World Health Organization technical update review of available pediatric data concludes that toxicities are similar to those seen in adults and supports rolling out of TDF in treatment programs for children. The 2014 Department of Health and Human Services guidelines have different levels of recommendation for the use of TDF in children based on Tanner stage. In the 2013 World Health Organization guidelines, TDF is recommended as part of the first line ARV regimen as recommended for HIV-infected children from 10 years of age to adolescents which is aligned with recommendations for adults, while for children ages 3 to <10 years, zidovudine or abacavir is preferred over TDF.
Drug Formulation
TDF is available as an oral powder (40 mg per scoop) and tablets (150, 200, 250 and 300 mg). The dose by body weight band starts at age 2 years and weight >10 kg, based on the recommended pediatric dose of 8 mg/kg/dose once daily (Table 2). For FDCs, Truvada (emtricitabine/TDF) is FDA-approved for use in adolescents aged ≥12 years and who weigh ≥35 kg. Atripla (emtricitabine/TDF/efavirenz) is FDA-approved for use in adolescents aged ≥12 years and who weigh ≥40 kg. TDF/emtricitabine/rilpivirine (Complera) and TDF/emtricitabine/elvitegravir/cobicistat (Stribild) are not yet approved for patients aged <18 years.
TDF and Nephrotoxicity
A meta-analysis of 17 studies in adults showed that TDF use was associated with a small but statistically significant loss of renal function. The risk of acute renal injury associated with TDF-containing regimens was 0.7% (95% CI: 0.2–1.2); which was higher than non-TDF regimens. Of note, treatment with TDF plus boosted PIs was associated with a greater decline in renal function over 48 weeks compared with TDF plus NNRTI-based regimens. However, the risks of chronic kidney failure was not significantly increased when compared to control. According to the summary of postmarketing surveillance adverse drug reaction reported in the first 4 years of TDF used in 10,343 adults, renal failure was observed in 0.3%.
The Department of Health and Human Services guidelines recommend assessment of renal function prior to TDF initiation and regular monitoring of estimated creatinine clearance thereafter. However, the need and cost-effectiveness for routine creatinine monitoring in resource-limited settings is still controversial. In a 4-year prospective cohort study of 3316 HIV-infected African adults who received TDF in the Development of AntiRetroviral Therapy in Africa trial rarely identified any individuals with significant changes in the estimated glomerular filtration rate (eGFR). The cumulative incidence of eGFR < 30 mL/min/1.73 m was 2.8% and chronic kidney disease was 5.0%. Routine biochemistry testing did not improve patient outcomes compared with clinical monitoring alone. Therefore, the best approach for monitoring for renal toxicity in resource limited settings deserves further evaluation.
A summary of the renal effects of TDF from pediatric studies is shown in Table 3. Rates of significant decline in eGFR <60 mL/min/1.73 m are only 0.2–0.6%, similar to in adult reports. In a retrospective analysis of 159 children in the United Kingdom and Ireland who received TDF-containing regimens, the incidence of overall renal adverse events was 2.2 per 100 child years. Six children (3.7%) experienced serious nephrotoxicity; all but one had received TDF with didanosine and lopinavir/r. The report from United Kingdom has shown that increase serum creatinine associated with the use of TDF was reversible after treatment discontinuation. Data from the Pediatric AIDS Clinical Trials Group 219/219C showed that 22% of more than 2000 children in the cohort had a persistent renal abnormality (≥3 sequentially abnormal renal laboratory values; proteinuria or elevated serum creatinine, or decreased eGFR to <60 mL/min/1.73 m). Those who received TDF (10.7% of cases) had 2.3 times the risk of renal abnormalities compared to the comparison group. The Pediatric HIV/AIDS Cohort Study in the US reported cumulative prevalence of proteinuria of 22%, with annual prevalence of proteinuria ranged from 10.3 to 13.7%. TDF use longer than 3 years of exposure was an independent predictor. Reversible hypophosphatemia with the use of TDF occurred with an incidence of 4.5–10%, usually asymptomatic. In a randomized, open-label study among 97 HIV-infected children, 48 were randomized to a TDF-including regimen. None experienced significant renal toxicity during the first 48 weeks. With longer follow-up time for a median 104 weeks, 4 (4.5%) had to discontinue TDF due to proximal renal tubulopathy; 3 of 4 presented with hypophosphatemia. Fanconi syndrome and nephrogenic diabetes insipidus associated with the use of TDF have been reported in children as well as in adults. Nonetheless, all were case reports; the incidence of those renal conditions in prospective treatment cohort is rare.
In contrast an excellent renal safety profile has been reported from several cohorts. An Italian study in 26 children reported no evidence of impaired glomerular or tubular renal function throughout 60-months of follow-up. However, the sample size was small, there was no comparison group, and there were no other potential nephrotoxic ARTs (ie, indinavir, lopinavir/r and didanosine) used concomitantly. The randomized double-blinded placebo-controlled study in Brazil and Panama also found no statistically significant difference in change of serum creatinine and creatinine clearance in TDF versus placebo group during the 48-week follow-up. A study in 40 HIV-infected Thai children with 96-week follow-up also did not find any clinically significant decrease in eGFR overtime.
In clinical practice, TDF should be avoided in the presence of pre-existing renal disease if other ART options are available. HIV-infected children who receive TDF should be followed with caution for evidence of renal toxicity, especially when concomitantly used with drugs that increase TDF exposure such as didanosine or boosted PI. Although the data from over 4 to 5 years follow-up in Development of AntiRetroviral Therapy in Africa trial demonstrated small differences in eGFR changes when compared to other ARTs, laboratory monitoring that is readily available in most setting including serum creatinine, urine glucose and urine protein might be performed at 3- to 6-month intervals (the optimal frequency is undetermined), recognizing that the renal toxicities could develop with long-term use of TDF. For serum phosphate concentration that can vary from time to time, clinical observation for symptomatic hypophosphatemia might be applied instead of routine laboratory monitoring.
TDF Effect on Bone Mineral Density
Low bone mineral density (BMD) in HIV-infected children and adolescents has been reported from several studies. Its etiology was described as multifactorial, including general risk factors such as smoking, less physical activity and vitamin D deficiency, and also HIV-related factors, such as HIV infection itself, chronic immune activation and the effects of antiretroviral treatment. Increased fracture risk has been reported in adults treated with TDF, with a yearly hazard ratio for osteoporotic fracture of 1.12 (95% CI: 1.03–1.21) compared to the control group. At present, no increase in clinical fracture risk related to TDF use in children has been documented, although it has been suggested that a high bone remodeling rate could disturb normal bone physiology.
The effect of TDF on bone might be different in children as compared to adults due to different stages of bone dynamics. A summary of the effects of TDF on bone mineral density from pediatric studies is shown in Table 4. In cross-sectional studies to assess bone mineral density among perinatally HIV-infected children and adolescents receiving ART, the reported prevalence rate of BMD z-score <-2 is in a range of 24–32%. Longitudinal assessment of BMD show that the median BMD z-scores usually decline from baseline in the first 6–12 months after initiation of ART and then remain stable thereafter. This is similar to reports from HIV-infected adults that the decrease in BMD was seen early during the first 48 weeks of therapy, and then stable up to 5 years of follow-up. The Gilead 321 study demonstrated a lower rate of BMD gain in TDF-treated children aged 12≤18 years at week 48 when compared to children in the placebo group; this difference was not seen among TDF-treated younger children aged 2≤12 years. Bone safety follow-up showed a modest decline from baseline in median spine and/or total body BMD z-scores through week 144 among children and adolescents who received TDF. Five out of 170 subjects had trauma-related bone fractures during follow-up period. In contrast, an Italian study reported that the change in BMD in treatment-experienced HIV-infected children with virologic suppression was not different from control after substitution of stavudine with TDF for 12 months. When they were followed upto 60 months, no significant change in BMD z-score from baseline was observed. This might be explained by the use of a relatively low dose of TDF and no concomitant use of boosted PIs.
Factors associated with higher risk of BMD loss in children treated with TDF were young age, prepubertal children and advanced World Health Organization stage. Increased level of bone turnover marker (morning osteocalcin) was reported, as well as change in serum calcium, serum phosphate, parathyroid hormone, vitamin D level and urinary calcium excretion, which implies that TFV stimulates bone reabsorption. Higher bone turnover in children as well as nutritional factors could possibly explain why TDF-related changes in BMD may be more obvious in children than in adults. For example, the Brazilian study reported low calcium and vitamin D intake in 72.9% and 91.5% of HIV-infected children, respectively.
In summary, the adverse impact of TDF on bone is well documented but its clinical significance remains controversial. More long-term studies are needed to see whether any clinically significant events occur. When TDF is prescribed for children, counseling on a balanced diet and age-appropriate exercise is warranted to minimize possible risks associated with low BMD.
Hepatitis B Virus and HIV Coinfection
Although the natural history of HIV infection is generally not influenced by HBV coinfection, there is an increased rate of antiretroviral-related hepatotoxicity, and immune-reconstitution hepatitis. A low rate of hepatitis B clearance resulting in chronic infection has been reported. Furthermore, in HIV-infected individuals with HBV infection, progression to liver cancer may occur at a younger age when compared to those with HBV infection alone. Treatment of HBV/HIV co-infected adults is aimed at suppressing HBV viral replication to undetectable levels, to reduce liver inflammation, and to stop or delay progression of hepatic fibrosis. Early introduction of ART is recommended in HBV/HIV co-infected patients regardless of immune status; an ARV regimen with TDF and lamivudine/emtricitabine as a backbone is advised for ARV naive patients with wild-type virus who have no contraindications to either drug. A retrospective Austrian cohort has reported that 91% of HBV/HIV-co–infected adults achieved complete HBV suppression despite high baseline viremia. TDF-containing cART led to high rates of hepatitis B "e" antigen seroconversion (50–57%) and hepatitis B surface antigen loss (25–29%) after 5 years of follow-up.
TDF is currently recommended for treatment of chronic hepatitis B infection in children 12 years of age and older; thus, initial choice of cART for co-infected children who are old enough to receive TDF is similar to adults. Regimens with both TDF and lamivudine/emtricitabine are advised; although there are no data that demonstrate better HBV outcomes with treatment of HBV infection in the immune tolerant phase. While cART containing lamivudine (or emtricitabine) without TDF is not recommended for adults with coinfection because of the emergence of HBV lamivudine resistance, such cART regimens are standard for infants and young children with coinfection. Most children with coinfection acquired both infections in infancy; however, lack of HBV screening in routine HIV care for children results in delayed diagnosis of HBV. Those children will likely have TDF incorporated into their cART regimen as they age, and, based on evidence from studies in co-infected adults with prior lamivudine exposure, this approach is expected to result in high rates of HBV suppression.
TDF is active against HBV, including virus with the lamivudine-selected tyrosine-methionine-aspartate-aspartate mutation. Combination HBV therapy with TDF and lamivudine has been reported as being linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HBV/HIV co-infected individuals than monotherapy. So far there has been no report of emergence of HBV resistance to TDF.
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