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

Coinfections

HBV and HCV

  • Untreated HIV infection increases the progression of liver disease in HBV or HCV coinfection.

  • HBV and HCV coinfections both increase the risk of hepatotoxicity with ART (especially NVP).

  • Drugs used to treat HBV may select for resistant HIV and vice versa.

  • Liver disease in children with HBV or HCV coinfection should be managed jointly with paediatric experts in viral hepatitis.

  • HCV coinfection is an indication for starting ART.

  • For HBV coinfection, if treatment of HIV is not indicated and there is no evidence of liver disease, HIV treatment should be considered but may be deferred.

Screening for viral hepatitis. Baseline screening: All children with HIV infection should be screened for viral hepatitis when they first present. Screening should include the following:

  1. Testing for coinfection, past infection or immunity to HBV. This should include the following markers: HBV surface antigen (HBsAg), HBV core antibody (HBcAb) and HBV surface antibody (HBsAb). Children diagnosed with HBV coinfection should be screened for hepatitis delta virus (HDV) with HDV immunoglobulin M (IgM) and IgG and HDV RNA PCR.

  2. Testing for coinfection with HCV. This should include HCV antibody and HCV RNA PCR when available, as rates of 3–13% of HCV-seronegative infection have been reported in HIV-infected adult and paediatric cohorts.[133–135] HCV antigen might be used by some laboratories in screening algorithms. As data on the use of this marker in paediatric infection are lacking, HCV RNA is currently preferred.

  3. Testing for immunity to hepatitis A virus (HAV) infection (HAV IgG).

Vaccination for hepatitis A and B of seronegative children should be recommended if a child is found to be seronegative and levels of HBV antibody should be assessed regularly and booster vaccinations or repeated courses given as required.[21] Annual screening for HCV is recommended in adolescence and adults in case risk factors exist such as use of recreational drugs and/or sexual exposure.

Screening of infants exposed to HBV or HCV: When the mother is coinfected with HBV, screening of the exposed infant should include HBsAg, HBsAb and HBcAb at around 14–15 months of age following the last (fourth) vaccination at 1 year of age. Infants born to women coinfected with HCV should be screened for evidence of HCV. In most centres this screening includes a combination of PCR for detection of HCV RNA in infancy as well as HCV antibody at 12–18 months when maternal antibody is expected to wane. HCV RNA-positive results in infancy do not equate to long-term infection, and follow-up is required as a small proportion of HCV-monoinfected children will undergo spontaneous clearance of infection within the first 3–5 years of life.[136,137] Published data are sparse on the rates of spontaneous HCV clearance in HIV coinfected children.

Investigation of deranged liver function tests: In the case of unexplained deranged liver function tests and/or liver disease, viral hepatitis should be considered, including HAV, HBV, HCV, CMV and Epstein−Barr virus (EBV) infection. Screening should ideally include: HAV IgM and IgG, HBsAg, HBcAb, HBV DNA, HCV RNA, HEV IgM and IgG, HEV RNA, CMV IgM and IgG, and EBV serology. Alternative diagnoses for persistent transaminitis, such as nonalcoholic fatty liver disease, autoimmune hepatitis, Wilson's disease, alpha-1 antitrypsin deficiency, coeliac disease and muscular dystrophy, should be considered.

HBV or HCV coinfection is a risk factor for hepatocellular carcinoma (HCC). HCC is rare in childhood and more data are required to evaluate the best approach to monitoring for this complication. Adult guidelines recommend monitoring for HCC with 6–12-monthly serum alpha-fetoprotein and liver ultrasound in all HBV-coinfected patients and in HCV-coinfected patients with cirrhosis.[138,139] In the absence of better monitoring methods, this guidance is endorsed for children and adolescents.

HBV coinfection. In adults, there is a well-documented interaction between HIV and HBV infection, with increased rates of liver disease. Long-term follow-up data for coinfected children are sparse but, in view of the concern about an increased risk of liver disease progression in adult life, ART should be considered in coinfected children regardless of clinical stage or CD4 cell count. 3TC, FTC and TDF have activity against HIV and HBV. They therefore should only be administered as part of fully active ART in order not to select for HIV resistance. In addition, treatment with 3TC or FTC without TDF may quickly select HBV resistance to these drugs and also reduce sensitivity to entecavir, thus compromising future HBV treatment options.[140] Combinations of TDF with FTC or 3TC have been shown to increase HBV viral clearance in HBV-coinfected adults.[139] We recommend that two active drugs against HBV (TDF/3TC or TDF/FTC) should be given, unless this is not possible because of prior treatment that has selected for resistant HBV strains. In children > 2 years of age, we recommend starting TDF/3TC or TDF/FTC. In children with HBV infection under 2 years of age, for whom TDF is not yet licensed, if treatment for HBV infection is not required (see treatment algorithm for paediatric patients with chronic hepatitis B infection[141]), there are two options: either starting (1) 3TC/FTC-sparing ART (unless HLA B*5701 positive this would be ABC/ZDV) in order to avoid 3TC/FTC monotherapy and selection for HBV resistance or (2) TDF-containing ART (off-licence TDF in this age group) with careful monitoring of TDF bone and renal toxicity.

Children with evidence of past HBV infection (HBsAg negative and HBcAb positive) are at risk of reactivation and ideally ART should include an agent active against HBV. The clinical implications of the rare phenomenon of occult hepatitis B (HBsAg negative, with low replication in the liver and plasma; usually HBV DNA well below 1000 IU/ml) are not clear. These patients should also be treated with ART that contains an agent active against HBV.

Some anti-HBV drugs (such as entecavir and telbivudine) have partial activity against HIV, which is insufficient to fully suppress HIV but is sufficient to select for resistance mutations. These drugs should not be used to treat HBV infection in HIV-coinfected patients without an accompanying fully suppressive ART regimen. In an HBV-coinfected child on ART who develops TDF toxicity or intolerance, the options are very limited. Extrapolating from adult guidelines,[139] entecavir as an add-on drug to fully suppressive ART can be used in older children with TDF intolerance. Children with HBV coinfection who discontinue anti-HBV antivirals are at risk of HBV reactivation and need to be monitored closely with clinical reviews and liver function tests. Seek expert advice for the appropriate management of HBV-coinfected children.

HCV coinfection. HCV coinfection also increases the risk of liver disease, but long-term follow-up data for coinfected children are sparse. No anti-HIV ART drugs are effective against HCV. In older children and adults, HCV coinfection is associated with more rapid HCV progression[142,143] and may also have an adverse effect on HIV progression,[142] and therefore early HIV treatment is recommended. Currently in children only combination treatment with pegylated interferon (PEG-IFN) and ribavirin can be used to treat HCV infection. New direct-acting antiviral agents (DAAs) against HCV have been approved for treatment of liver disease in adults, and phase III trials of many other compounds are under way. It is anticipated that PEG-IFN-free regimens will be available for adults and children in the near future, particularly for genotype 1 and 4 infection.

In children with HCV coinfection, debate is ongoing as to whether clinicians should treat HCV infection immediately or wait for better treatment options. Some experts prefer starting treatment earlier as there is better treatment response and tolerability of PEG-IFN and ribavirin in children compared with adults.[144,145] This may be especially relevant for patients with HCV genotypes 2 and 3, for whom sustained virological response with PEG-IFN and ribavirin over 24 weeks is much better than for genotype 1 (sustained virological response in HCV-monoinfected children 89–93%.[146,147] However, PEG-IFN has an adverse effect on growth in children, and the risk−benefit ratio should be carefully considered during growth spurts.[148] Some specific interactions to consider include:

  • ribavirin enhances intracellular phosphorylation of ddI; fatal lactic acidosis has been described, and therefore ddI should be avoided;

  • ribavirin and ZDV both may cause anaemia;

  • ABC may reduce ribavirin efficacy;

  • d4T may cause mitochondrial (liver) toxicity;

  • ATV may increase hyperbilirubinaemia, but there is no clear evidence that this is worse in HCV-coinfected children.

Seek expert advice for the appropriate management of HCV-coinfected patients.

TB Coinfection

  • All HIV-infected children exposed to an individual with infectious TB and all children with evidence of latent TB infection should have preventive TB treatment (once active TB disease has been excluded).

  • In children with active TB disease, TB treatment should be started at TB diagnosis. ART should be started as soon as practicable, and within 2 and 8 weeks of TB treatment in children with severe and moderate immunosuppression, respectively. ART may be deferred at higher CD4 counts until TB treatment is completed.

  • There is significant interaction between ART and TB therapy. TDM, where available, should be used in the context of potential significant interactions.

  • Children with TB coinfection should be managed in consultation with an expert in the treatment of paediatric TB. A specialist in DRTB should be involved in the management of DRTB contacts and cases.

  • See Table 6 for ART choices in children with TB.

HIV-infected children are at increased risk of acquiring TB infection and progression from latent to active TB compared with HIV-negative children.[149,150] In the combination ART era, in both high and low TB prevalence countries, TB incidence is decreasing, but remains substantially higher in HIV-positive children.[151–154]

Management of children with TB exposure and latent TB infection. All HIV-infected children should be screened for TB infection at HIV diagnosis with clinical examination, TST or IGRA and chest X-ray (see Section 3). Preventive TB treatment has been shown to effectively reduce the incidence of TB disease in HIV-positive children exposed to an infectious TB source case.[155] We recommend that all HIV-infected children exposed to an individual with infectious TB and all those with evidence of latent TB infection (positive TST or IGRA) and no clinical or radiological signs suggestive of TB disease should have preventive TB treatment.

A Cochrane review of preventive regimens in HIV-infected individuals aged over 13 years found no difference in incidence of TB disease between a 6-month regimen with isoniazid monotherapy and 3 months of treatment with co-administered isoniazid and rifampicin. However, the combination regimen was associated with more discontinuations because of adverse effects.[156] A few paediatric studies have shown that a 3-month regimen of isoniazid and rifampicin treatment is safe and effective.[157,158] Therefore, we recommend that children with HIV infection who have been exposed to TB or have latent TB infection and who are not receiving ART can be treated with either 3 months of isoniazid and rifampicin or 6−9 months of isoniazid (according to local policy in HIV-uninfected children); for those on ART, in view of drug interactions, the preferred preventive treatment is 6–9 months of isoniazid. For children exposed to drug-resistant TB, preventive therapy should be decided on an individual basis in consultation with a TB expert. Preventive treatment should only be administered once active TB has been excluded. Children with nonspecific chest X-ray changes, and no improvement after the course of treatment for their suspected underlying respiratory illness (lymphocytic interstitial pneumonia, chest infection), should be treated for possible TB disease (see below).

TB disease in HIV-infected children. There are particular difficulties relating to TB diagnosis, drug interactions and immune reconstitution disease in HIV-infected children coinfected with TB. Negative results of a TST or IGRA cannot be used to rule out TB disease.[159,160] Every effort should be made to make a confirmatory microbiological diagnosis but this is often not possible. New technologies such as Genexpert (Cepheid, California, USA) can expedite diagnosis while providing early information on rifampicin sensitivity.[161] Anti-TB treatment should always be started at TB diagnosis. All HIV-infected children diagnosed with TB should also be started on ART; however, the optimal timing of ART initiation depends on the degree of immunocompromise. Adult RCTs showed significant reduction in mortality and progression to AIDS with earlier ART in patients with CD4 counts < 50 cells/μl (Starting ART at 3 Points in TB (SAPIT),[162] Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA)[163] and Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis (STRIDE)[164]). A retrospective study in South African children, most of whom were severely immunocompromised with median CD4 percentage < 12%, also showed that delay of ART for longer than 2 months was associated with increased mortality and worse virological response.[165] Therefore, children with severe immunosuppression should start ART within 2 weeks of beginning TB treatment, and those with moderate immunosuppression within 8 weeks. Data in adults suggest that delayed ART in patients with no or mild immunocompromise is not associated with worse outcomes. The potential benefits of delayed ART in this group are decreased pill burden and drug interactions, which may lead to better drug tolerance and adherence, as well as reduced occurrence of IRIS. There are insufficient data in children with no or mild immunocompromise but, based on the results of adult studies, delaying ART until TB treatment is well tolerated (or even completed) can be considered. The optimal time for ART initiation in the context of TB meningitis remains to be determined.

In the absence of TB drug resistance, standard TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol is recommended. Rifampicin, a potent CYP3A4 inducer, has significant interactions with other medicines metabolized through CYP450 enzymes, reducing their blood levels. Considerable interaction occurs when rifampicin is co-administered with NVP or PIs, whereas interaction with EFV is less significant and achieving therapeutic levels is possible without dose alteration. If available, rifabutin may be used instead of rifampicin to reduce drug interactions. In settings where TDM is available, dose adjusting of antiretrovirals and rifampicin/rifabutin is recommended. The choice of ART in children co-treated for TB depends on the child's age, whether the child is receiving ART or starting ART, history of previous ART exposure and availability of TDM (Table 6).

In ART-naïve children less than 3 years of age on TB therapy, it is recommended to start with LPV/r-based ART with added ritonavir to achieve an LPV/ritonavir ratio of 1:1 (superboosting).[166,167] Alternatively, ART-naïve children under 3 years of age can be started on NVP-based ART but without lead-in dose and at the maximum recommended dose (200 mg/m2 twice daily). A PK study in children aged < 3 years co-treated for TB with rifampicin showed suboptimal exposure to NVP on a 300–400 mg/m2 daily dose.[168] In order to obtain better exposure in younger children, the maintenance dose can be further increased by 20–30% 2 weeks after starting treatment (H. Lyall and S. Welch, unpublished data). The doses of both rifampicin and NVP can be further adjusted with the results of TDM. NVP should be decreased back to a regular 300–400 mg/m2 daily dose 1–2 weeks after stopping rifampicin. In settings where TDM is not available, superboosted LPV/r-based ART is a preferable option in children under 3 years of age initiating ART. Recently, EFV sprinkles were approved by the FDA for children aged 3 months to 3 years.[74,75] Further PK, efficacy and safety studies in children < 3 years old receiving anti-TB treatment are under way. Until the results are available, the use of EFV sprinkles in younger children receiving treatment for TB cannot be widely recommended.

In children aged below 3 years who are already on ART, the options for adjusting doses of antiretrovirals discussed above are applicable. A recent RCT[71] showed that a triple-NRTI maintenance regimen (ABC + 3TC + ZDV) is immunologically and clinically similar to NNRTI-based ART and can be valuable in children with controlled HIV infection who develop TB, and is an alternative regimen.

For children aged over 3 years initiating ART, the preferred regimen is EFV-based ART. Children aged > 3 years who have been receiving NVP should be switched to EFV. If EFV cannot be used (because of NNRTI resistance, neurocognitive problems or suboptimal predicted adherence), an alternative option is superboosted LPV/r as above or other PI-based ART. For PI-based ART, TDM should be used where available.

Children aged over 3 years who have been receiving PI-based ART can continue on their regimen with adjustment of PI doses as above, or they can be switched to EFV. A triple-NRTI regimen is another alternative option.

RAL has been shown to be an effective option in the treatment of HIV/TB-coinfected adults.[169] There are no data available for coinfected children. RAL cannot therefore be routinely recommended as a treatment option at present; however, its use can be considered with specialist advice and TDM. Data on the use of DTG in this context are awaited. The duration of TB treatment depends on the response to TB, which in turn depends on the degree of immunocompromise and the extent of TB disease. There are no comparative studies suggesting that the duration of TB treatment should be prolonged in HIV-infected children. In uncomplicated TB, the duration of treatment should be the same as in non-HIV-infected children; however, if at the end of the treatment there is an incomplete response, then TB treatment may be extended.[170] Adherence, drug levels, drug resistance and IRIS should be adequately addressed.

Drug-resistant TB should be managed in conjunction with an expert. It should be treated with a TB regimen chosen according to bacterial drug resistance and national TB guidelines. Care needs to be taken to anticipate potential drug interactions and cumulative toxicities between ART and the TB regimen; the choice of ART may be simpler in TB regimens that do not contain rifampicin.

TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) is not uncommon in children starting ART.[171–175] TB-IRIS usually develops within 3 months of starting ART, with higher risk in those patients with advanced HIV disease, low pre-ART CD4 count and shorter interval to starting ART after initiation of TB treatment.[175–177] ART should be continued, but steroids may be necessary to manage IRIS. Further details on management of TB in HIV-infected children can be found in the WHO and The International Union Against Tuberculosis and Lung Disease (IUATLD) guidelines.[6,170,178,179]

Opportunistic infections. The management of children presenting with opportunistic infections can be complex, especially when a child presents very unwell. These patients should ideally be managed on a case-by-case basis. Generally it is recommended that ART should be initiated as early as possible, apart from in the context of cryptococcal meningitis, where a single RCT in adults has shown that delaying ART may be associated with reduced mortality.[180]

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