Paediatric European Network for Treatment of AIDS (PENTA) Guidelines for Treatment of Paediatric HIV-1 Infection 2015

Optimizing Health in Preparation for Adult Life

A Bamford; A Turkova; H Lyall; C Foster; N Klein; D Bastiaans; D Burger; S Bernadi; K Butler; E Chiappini; P Clayden; M Della Negra; V Giacomet; C Giaquinto; D Gibb; L Galli; M Hainaut; M Koros; L Marques; E Nastouli; T Niehues; A Noguera-Julian; P Rojo; C Rudin; HJ Scherpbier; G Tudor-Williams; SB Welch

Disclosures

HIV Medicine. 2018;19(1):e1-e42. 

In This Article

Drug Toxicities and Interactions

  • Toxicities depend on the individual drugs and ART combination and should be assessed at each clinic visit.

  • Drug interactions should be considered when starting new medications in a child on ART. Use http://www.hiv-druginteractions.org/ to check drug interactions and toxicities.

  • See Table 5 for common ART-associated toxicities.

Drug toxicity has been a major limitation of ART to date, and one of the aims of modern ART regimens is to reduce side effects. Side effects can be acute, appearing early (usually within days to a few weeks after initiation), or late, declaring themselves after prolonged use of particular antiretrovirals.

Acute toxicities can be caused by any antiretroviral and include nausea, diarrhoea, headache, rash [mild to severe dermatological manifestations, such as Stevens−Johnson syndrome (SJS)], liver dysfunction (from asymptomatic elevation of liver enzymes to drug-induced hepatitis) and allergic reactions (Table 5). If severe events occur, ART should be discontinued with a subsequent replacement of drugs suspected to have caused the reaction (see Section 11 on switching). Some side effects, such as vomiting and diarrhoea, are transient and tend to resolve with time, but close monitoring and supportive/symptomatic treatment may be required.

Early adherence may be affected by common side effects that cause significant disturbance to daily life – for example diarrhoea caused by LPV/r, dysphoria caused by EFV, and nausea or headache caused by ZDV. Patients and their carers should be counselled appropriately prior to the start of ART and necessary support and close liaison should be assured during the first few weeks.

In the longer term, specific organ dysfunction, haematological complications and metabolic disturbances including mitochondrial toxicity, bone mineral loss, lipodystrophy, elevated cholesterol and triglycerides, and altered glucose homeostasis may occur. A recent cohort study of European children reported that nearly half had signs of fat redistribution and nearly a quarter had an abnormal lipid profile.[103] Risk factors included advanced HIV disease, and use of d4T, NNRTIs, PIs and triple-class ART. The relationship between lipodystrophy and ART is complex because of multiple exposures to different antiretrovirals and physiological changes in body composition during childhood and adolescence. Late side effects should be monitored for and addressed appropriately at every visit (see Section 8).

A number of studies have documented increased rates of cardiovascular and cerebrovascular disease in HIV-infected adults, which appear to be multifactorial and relate both to HIV disease itself and ART, with the greater risk associated with PIs and ABC.[104,105] Several mechanisms have been postulated, including metabolic and lipid derangement (especially related to PI), insulin resistance, direct vascular injury and increased inflammation.[106] Some studies in children have shown an increase in markers of cardiovascular risk such as immune activation markers, carotid intima-media thickness (IMT) and carotid-radial pulse-wave velocity.[107–109] Other adverse effects related to specific organ dysfunction, such as CNS disorders, renal abnormalities, hepatitis or bone loss, may also be attributable to either ART or HIV itself. The SMART trial in adults has been important in demonstrating that treatment with ART results in fewer such problems than withholding drugs.[51]

Common Toxicities With Antiretrovirals Used in Children

NNRTIs. The main toxicity of EFV is neuropsychological symptoms (e.g. bad dreams, mood swings, drowsiness, dizziness, impaired learning and depression) which anecdotally may be worse in older children (possibly secondary to a reporting bias). This should be borne in mind when considering which drug to use in children with established psychological/neurological disturbance. Other complications associated with EFV are dyslipidaemia, abnormal fat distribution[103] and gynaecomastia.

NVP may be associated with skin rash, hepatitis and SJS, which typically occur within the first few months of exposure. Rash and hepatic dysfunction are less common when a 2-week half-dose lead-in dosage is used. NVP should not be used in children with liver dysfunction or co-administration of other hepatotoxic drugs. Prolonged-release tablet formulations are available for children > 6 years old and produce a more even drug exposure, but are not suitable for the 14-day lead-in phase when starting NVP. Rash is much less common with EFV than with NVP; however, there are insufficient data to recommend switching from NVP to EFV in cases of dermatological hypersensitivity reactions, as repeat rash after substitution has been reported to occur in more than 12% of adult patients.[110]

PIs. PIs are associated with dyslipidaemia and lipodystrophy.[103,111–113] However, once-daily PIs, such as ATV/r and DRV/r, in adults tend to cause fewer lipid abnormalities.[114–116] Measures to improve dyslipidemia can include lifestyle modifications (diet and exercise) and change of ART to 'lipid friendly' antiretrovirals (NVP, ATV/r, DRV/r and RAL). In rare cases when no effect is seen from ART substitution, lipid-lowering agents, such as statins, may be used. However, in view of their frequent side effects and drug interactions with antiretrovirals, this ideally should be done in consultation with experts in ART and lipid agents.

The common side effect of ATV in children is hyperbilirubinaemia, which was reported in 45% of treated children in clinical studies.[117] It is not associated with elevation of liver enzymes, and often improves with time. In cases when hyperbilirubinaemia is significant and jaundice is noticeable by the patient's peers, consideration should be given to substitution of the drug with an alternative agent.

NRTIs. A rare but clinically important early side effect is ABC hypersensitivity associated with the presence of HLA B*5701. This may be fatal if the drug is reintroduced after a reaction. Possible cardiovascular toxicity of ABC in adults remains controversial. A meta-analysis of RCTs did not find an increased cardiovascular risk[118] and the biological mechanism of possible cardiovascular toxicity of ABC has not been established. To date, no link to cardiovascular toxicity has been found in ABC-exposed children.

TDF is associated with bone and renal toxicity, precluding its use as a preferred NRTI in younger children. Studies of TDF-associated bone toxicity in treatment-experienced children yielded conflicting results.[119] A significant loss of bone mineral density (BMD) was observed in young and pre-pubertal children, and in those who received higher exposures to TDF because of higher doses or concomitant use of PIs.[120,121] Reassuringly, in most children on TDF-containing ART, BMD z-scores after an initial decrease tend to stabilize.[121–123] Although the clinical significance of delayed bone mineralization has not been established, the concern is that suboptimal bone accrual in childhood and failure to achieve expected peak bone mass could result in increased fractures in adulthood. Paediatric data on TDF renal toxicity are also controversial, showing conflicting results from no renal dysfunction to increased rates of proteinuria and hypophosphataemia.[124] Extrapolating from adult studies showing that renal dysfunction is associated with increased TDF plasma levels and PI use,[125] dosing accuracy and meticulous attention to monitoring for renal dysfunction in children, especially in those who are on concomitant PIs, are of particular importance.

The use of NRTIs, in particular d4T, ddI and to a lesser extent ZDV, is associated with lipoatrophy, peripheral neuropathy, lactic acidosis and other toxicities linked to mitochondrial damage. Noncirrhotic portal hypertension has been reported as a rare complication of exposure to ddI in adults[126–128] and children,[129,130] may be associated with a genetic predisposition[126] and can become evident after ddI has been discontinued. PENTA does not support the use of d4T or ddI in first- or second-line ART. However, in cases of multiple resistance, if no alternatives are available, ddI may be used to construct a fully active ART regimen. It should be noted that ddI should not be used together with TDF in view of increased toxicity. ZDV, still frequently used in paediatrics, affects bone marrow, causing macrocytic anaemia and neutropenia, and rarely thrombocytopenia or bone marrow suppression with pancytopenia.[131] 3TC and FTC are generally well tolerated; however, they can cause allergic reactions and constitutional symptoms.

INSTIs. RAL and DTG have a very good safety profile in adults and are well tolerated, although data on long-term exposure are more limited. The most common adverse effects reported in adult patients are constitutional symptoms (fatigue, nausea, dizziness, insomnia and headache), rash, diarrhoea, abnormal liver function tests and raised creatinine kinase. Hypersensitivity reactions have been reported and were characterized by rash and, in some cases, hepatic failure.

Fusion and entry inhibitors. These two classes of drug are not recommended for first-line use and are discussed in more detail in Section 11. The CCR5 receptor antagonist maraviroc (MVC) is not licensed for patients under the age of 18 years. Paediatric studies on safety and efficacy in children are ongoing.[132] In adults, MVC is generally well tolerated but has been associated with hepatic toxicity, severe skin and hypersensitivity reactions and postural hypotension. The HIV fusion inhibitor enfuvirtide (T20) is almost universally associated with injection site reactions but is otherwise well tolerated apart from mild constitutional symptoms.

For detailed side effects of individual medicines, useful resources include the Electronic Medicines Compendium (http://www.medicines.org.uk/emc/), DHHS website (http://aidsinfo.nih.gov/drugs) and EMA website (http://www.ema.europa.eu/ema/). For all drugs, the effects of prolonged use for decades remain to be seen, and this will be of greater significance as more children start ART at an earlier age.

Drug Interactions

It is widely known that drug−drug interactions are important in HIV treatment in adults; this is true for children as well, although the frequency and type of comorbidities and related co-medication may be different. ART can both be affected by drug interactions (i.e. the plasma concentrations of the ART may be changed) and/or be the cause of a drug interaction (i.e. the ART influences the plasma concentration of another drug). Increased toxicity or therapy failure may occur.

Many of the drug interactions occur as the result of drug-induced modification of cytochrome P450 (CYP450) enzyme activity, although other systems, such as membrane transporters [e.g. P-glycoprotein (P-gp) or UDP-glucuronyltransferase (UGT)], may be relevant too.

ART as the cause of a drug interaction. There are a few general rules to remember: PIs are generally inhibitors of CYP450 3A (CYP3A and other isoenzymes) or P-gp and can lead to increased levels of co-administered medication. This is, for instance, the case with inhaled corticosteroids, oral contraceptives, benzodiazepines, statins, antidepressants, etc. Both ritonavir and cobicistat are specifically used together with PIs or EVG for their ability to strongly inhibit liver enzymes and increase blood concentration of their co-administered antiretroviral. The NNRTIs NVP, EFV and etravirine (ETR) are enzyme inducers. They generally reduce the plasma levels of any agents metabolized via the CYP450 pathways with potentially suboptimal therapeutic response.

Drug interactions affecting ART. The greatest risk for ART in terms of drug interaction is when antiretroviral drugs are combined with other enzyme inducers such as rifampicin, carbamazepine and phenytoin. Lower plasma concentrations of the ART can lead to the development of resistance and treatment failure.

Management of drug interactions. In the large majority of cases, drug interactions can be managed by selecting the appropriate co-medication or change in ART. TDM of the ART or co-medication might be helpful. We recommend referring to http://www.hiv-druginteractions.org to assess potential drug interactions with ART, and that a pharmacist is included in the multidisciplinary team.

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