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

When to Switch, Resistance Testing and Second and Subsequent Art Regimens

ART regimens may be changed because of treatment failure or toxicity, or during successful treatment for simplification.

Virological Failure – Second and Subsequent Regimens

  • Switching to second-line therapy following virological failure should occur early (VL > 1000 copies/ml) for those failing on combinations including drugs with a low genetic barrier to resistance (NNRTIs or RAL).

  • Where there are blips in VL (detectable VL < 400 copies/ml), blood tests should be repeated within 4 weeks to confirm re-suppression.

  • Reinforcement of adherence support, as the main reason for treatment failure, should be prioritized. Switching treatment when there are ongoing problems with adherence may lead to loss of efficacy of further classes of ART.

  • Table 7 summarizes potential strategies for choosing second-line therapy. If the suggested options are not applicable, seek expert advice.

Virological failure is almost always attributable to poor adherence. In adult practice, ART is switched early if there is detectable viraemia, because of the risk of accumulation of further resistance mutations, which may make subsequent regimens less effective. PENPACT-1 randomized ART-naïve children to two NRTIs with either an NNRTI or a boosted PI. Those experiencing virological failure were randomized to switch to second-line therapy at VL > 1000 copies/ml or > 30 000 copies/ml. Delayed switching (VL > 30 000 copies/ml) on NNRTI-based ART was not associated with poorer clinical outcome but was associated with increased rates of NRTI resistance. Rates of NNRTI resistance were similar irrespective of VL at the time of switching, with NNRTI resistance being acquired early in virological failure. Children failing therapy on boosted PIs showed very low rates of PI and NRTI resistance irrespective of the timing of the switch to second-line therapy. PENPACT-1 is the only paediatric RCT addressing the timing of the switch to second-line therapy.[70] Accumulation of NRTI resistance with delayed switching following VL failure on NNRTI-based ART has also been reported in paediatric cohort studies; however, the impact of this resistance on clinical outcome has not been addressed.[181,182]

Considering the length of time they are likely to require treatment, it is important that children have not used up all ART options before adulthood. Sequencing of newer classes of antiretroviral drugs should take into account the CCR5 receptor antagonists (e.g. MVC), which are only active against viral populations that use the CCR5 co-receptor for cell entry. The proportion of perinatally infected adolescents with R5 variants, for whom MVC is a potential option, is highly variable within cross-sectional studies.[183,184] Co-receptor tropism should be performed within 3 months of the proposed treatment switch that includes MVC for those with detectable viraemia. Paediatric studies of MVC are ongoing in treatment-experienced children aged 2–18 years (http://clinicaltrials.gov/show/NCT00791700).

Of note, as in adults, single VL blips (single VL values > 50 but < 400 copies/ml that subsequently return to < 50 copies/ml) do not predict subsequent virological failure, but these should always be followed up as soon as possible, to make sure that they are not the beginning of significant viral rebound.[185]

In children, switching therapy after virological failure should only be considered when adherence has been reviewed. Failure of an NNRTI-based regimen is often a result of viral drug resistance following poor adherence, and switching to a boosted PI is appropriate. In resource-rich settings, those failing NNRTI-based regimens should not continue on NNRTI-based ART, to avoid the accumulation of further NRTI and NNRTI mutations which will impact on future ART options. Two strategies are available; either a direct switch to PI-based therapy or a short period off ART, if clinical status and CD4 count permit, while adherence is further addressed, followed by PI-based ART.

Failure of a boosted PI-based regimen is more likely to be caused by poor adherence than resistance. Children failing PI-based regimens, without documented resistance mutations, may continue their current regimen while adherence is addressed. Simplified regimens using FDCs and once-daily PIs should be considered. A switch to NNRTI-based second-line therapy is likely to result in rapid development of resistance to the new drugs and is not recommended if adherence has not been addressed. If resistance is detected then switching to an alternative PI without overlapping resistance is the preferred option, with the addition of an agent from a newer class (INSTI or CCR5 receptor antagonist) dependent on the resistance profile but aiming for three active agents.

3TC and ABC may be switched to ZDV and TDF, the latter now licensed for patients from 2 years of age. For infants with first-line failure, ddI may be substituted for TDF; however, recent case reports of noncirrhotic portal hypertension in HIV-infected adolescents following prolonged exposure to ddI are of concern.[126–130] Therefore, ddI exposure should be kept to a minimum with substitution of an alternative agent at the earliest opportunity.

Third and subsequent regimens are more complicated and need to take into account all previous drug histories and cumulative resistance mutations as well as the current regimen. This will always require expert virologist input. While virological failure with triple class exposure was reported in 12% of children in Europe,[186] rates of triple class resistance are variable, ranging from 12 to 32% and increasing with age.[187,188] Construction of effective third-line and subsequent regimens, ideally with at least two and preferably three fully active agents, requires expert advice. Paediatric experience of combinations that include INSTIs,[189] T20,[190] ETR,[191,192] MVC[132] and DRV/r is accumulating.

For patients where a suppressive regimen cannot be constructed with currently available ART, newer agents should be obtained (and may be used off-label with expert advice) through named patient and expanded access programmes and clinical trials. Single agents should not be added to nonsuppressive regimens because of the risk of accumulating further mutations impacting on future treatment options. In this situation, nonsuppressive ART, including 3TC or FTC, may be continued to prevent further immunological decline.

As discussed above (Section 6), RAL and DTG have recently been licensed for paediatric use. ETR, a second-generation, twice-daily NNRTI, is licensed for treatment-experienced children aged > 6 years. It is not fully cross-resistant with NVP and EFV, but once more than two NNRTI mutations are present its efficacy significantly decreases.[193] RPV, a once-daily NNRTI, is licensed for patients > 18 years old. It is available as once-daily FDC with TDF and FTC (Eviplera). Although it has fewer CNS side effects than EFV, a smaller pill size, and the possibility of co-administration with oral contraceptives, the significant disadvantages of increased virological failure rates in patients with VL > 100 000 copies/ml and CD4 count < 200 cells/μL, higher overall rates of resistance mutations compared with EFV-containing regimens (phase 3 TMC278-C209 and TMC278-C215 trials; FDA pooled analysis[194]), and administration with a meal requirement preclude its use as a first-line drug in most situations, but it can be considered in specific circumstances (e.g. patient preference or substitution for EFV intolerance). In young people with fully suppressed HIV and a regular meal pattern (absorption requires ingestion with a meal),[195] Eviplera may be considered for simplification, for example where there is intolerance to EFV-based therapy. Ongoing studies in children will provide important information on the place of ETR and RPV in paediatric treatment strategies [IMPAACT P1090 (http://clinicaltrials.gov/show/NCT01504841); IMPAACT P1111 (http://clinicaltrials.gov/show/NCT01975012)].

Table 7 summarizes potential strategies for choosing second-line therapy.

Resistance Testing

  • Resistance testing should be performed prior to switching regimens when there is virological failure. Resistance testing should be undertaken while the patient is still on the failing regimen. If this is not possible, ideally test for resistance within 4 weeks of stopping the failing regimen.

  • Resistance testing may include reverse transcriptase/protease/integrase/V3 loop/envelope sequencing.

  • The interpretation of resistance results can be guided by the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu/).

  • Substituting single drugs in a failing regimen without prior resistance testing is not recommended.

Adding or substituting single drugs in a failing ART regimen risks giving the new drug as effective monotherapy, which may result in rapid development of further resistance. It is therefore recommended that all changes in therapy with detectable viraemia be preceded by a resistance test. Ideally, resistance testing should be performed on a sample taken while the patient was still on the old regimen, or within a few weeks of stopping, when mutant quasispecies of HIV are most likely to be detected. Standard resistance testing includes sequencing of reverse transcriptase and protease; however, those failing on INSTIs and T20 require sequencing of integrase and envelope, respectively. Children failing on CCR5 receptor inhibitors require tropism assay/V3 loop sequencing to assess whether dominant viral variant remains R5-tropic. Expert opinion should be sought in interpreting resistance genotypes. Guidance relating to specific mutations is beyond the scope of these guidelines. The Stanford database (http://hivdb.stanford.edu/) is a useful, regularly updated resource. Resistance testing results should be discussed with an expert centre. If no local expertise is available then we recommend seeking advice from the PENTA network.

Simplification

Where possible, regimens should be simplified (once-daily, fixed dose combinations), but switching to NNRTI-based regimens or PI monotherapy is not advised if there are adherence issues.

Treatment simplification may involve reducing the number of drugs or tablets as a child becomes older, changing from twice- to once-daily therapy, or changing from a boosted PI-based regimen to an NNRTI-based regimen once viral suppression is achieved and adherence is assured. Simplification should not be carried out with detectable viraemia because of the risk of selecting for resistance mutations. Simplification is much easier as children reach 35−40 kg as adult co-formulations are available and once-daily options include the following.

Three-drug FDCs:

EFV, TDF and FTC (Atripla);
RPV, TDF and FTC (Eviplera);
EVG, cobicistat, TDF and FTC (Stribild).

Dual NRTI combinations:

TDF and FTC (Truvada);
ABC and 3TC (Kivexa).

Children virologically suppressed on twice-daily boosted LPV-based ART may benefit from simplification to once-daily boosted PIs (ATV/r or DRV/r) when they are able to swallow larger tablets, typically reducing daily pill burden from five to three pills for those over 40 kg. Switching to once-daily boosted PIs has been associated with improved lipid profiles in adult studies and now this has been demonstrated in a paediatric population.[196]

Children suppressed on ART may also switch to reduce the likelihood of ART toxicity. The Nevirapine Resistance Study (NEVEREST), a randomized trial of switching NVP-exposed infants from suppressive LPV/r- to NVP-based ART (after at least 3 months of VL < 400 copies/ml), showed that this strategy can be successful in infants without evidence of transmitted NVP resistance on conventional testing.[64,197] Children switched to NVP had less long-term dyslipidaemia and subcutaneous fat loss.[112] Furthermore, the recently reported results of the NEVEREST-3 study[198] indicate that switching children fully suppressed on LPV/r to EFV-based ART is a safe and effective strategy in the context of prophylactic NVP exposure.

High rates of virological failure (without development of resistance limiting future treatment options) were reported in the Protease Inhibitor Versus Ongoing Triple-therapy (PIVOT) trial of PI monotherapy in adults.[199] Reducing the number of drugs below a standard three-drug regimen is not currently recommended in children outside clinical trials. The lack of CNS penetration of such regimens is of potential concern for children with HIV encephalopathy.[190,200,201]

processing....