Efficacy and Safety of Single Versus Double Ritonavir-boosted Protease Inhibitor (PI)-Based Antiretroviral Therapy (ART) Regimens
Condition: HIV Infection; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Study type: Observational

Summary: 
      The virological efficacy will be no different in children treated with single versus double
      boosted PI second line ART regimens.
    

Detailed description: 
      A total of 50,620 Thai children have been diagnosed with HIV infection in Thailand between
      1988 and 2005, of whom only 20,000 are still living.1 The production of generic ART by the
      Thai Government Pharmaceutical Organization (GPO), which began in 2002 has given the Thai
      Government the ability to offer highly active antiretroviral therapy for all children.2 As of
      June 2006, there were over 6000 children receiving ART within the government program, and it
      is estimated that another 1500 children are receiving care in the private sector.1

      The Thai National Access to Care program provides two nucleoside reverse transcriptase
      inhibitors (NRTIs) and one NNRTI as the first-line regimen of choice. The most commonly used
      regimen is GPO-vir S, which has been shown to have acceptable pharmacokinetic parameters3 and
      excellent treatment outcome4. A study of 107 children on NNRTI-based treatment, including
      half with GPO-vir S, showed that despite their low baseline CD4 of 3% and high viral load of
      5.4 log, the children had excellent virological response, with 76% having HIV RNA below 50
      copies/ml at week 72.4 In another study of 192 children with advanced HIV disease, the
      hospitalization rate decreased from 31% during the first six months to 2% at three years
      after HAART. The mortality rate decreased from 6% during the first six months of HAART to
      less than 1% after that.5

      Nevertheless, Thailand is faced with growing numbers of children experiencing failure on
      NNRTI-based regimens as 20% or more are expected to fail based on published literature4, 6.
      This could result in 1000 or more Thai children needing to change therapy in the new future.
      Therefore, there is an urgent need to find appropriate second line treatments.

      Developed and developing countries guidelines recommend regimens with a single PI plus
      low-dose ritonavir boosting (boosted PI) in combination with 2 NRTIs for adults and children
      failing NNRTI-based treatments.6-8 There is limited data on the antiviral efficacy of boosted
      PI second line treatment following failure from PI-sparing first line regimens. As the
      success of second line PI regimens in PI-experienced patients depends heavily on the number
      of PI mutations present9, 10, it is reasonable to assume that in NNRTI failures without any
      PI mutations, most of the patients will do well. However, this also depends on the number of
      active NRTIs that can be used in the second line regimens. Meta-analysis has shown that NNRTI
      failures tend to be associated with more NRTI mutations than PI failures.11 This is
      particularly true in developing countries where switching to second line therapy usually
      occur when there is late virological failure, and patients show signs of clinical and/or CD4
      failure.12 A high likelihood of multi-NRTI resistance coupled with limited NRTIs choices can
      render the second line regimens less active. In these circumstances, it is unclear how
      effective a single boosted PI with recycle NRTIs second line treatment would be. Therefore,
      double boosted PIs with or without NRTIs have been proposed as a second line option in the
      2007 Ministry of Public Health Treatment Guidelines for children with HIV infection.13 The
      pharmacokinetic enhancement of 2 different PIs with low-dose ritonavir offers a unique
      benefit in maintaining a high genetic barrier to resistance.

      There are few choices for second-line therapy in children. Lopinavir/ritonavir is the PI of
      choice because it is the only ritonavir-co-formulated drug and the only liquid PI. It also
      has excellent efficacy in trials of single-boosted PI in children.14, 15 Indinavir is a
      commonly used PI in Thailand as it is the least expensive PI. Plipat N, et al. showed
      evidence supporting the efficacy, safety and pharmacokinetics of a lower dose of 230-300
      mg/m2 indinavir boosted with ritonavir and used in combination with 2NRTIs in Thai
      children.16 The efficacy of double boosted PI, saquinavir/lopinavir/ritonavir, was
      investigated in 50 children with NRTI/NNRTI failure. The regimen was effective: 80% and 60%
      had HIV RNA below 400 and 50 copies/ml respectively at week 48. However, the regimen was
      burdensome because of the large pill sizes, and the occurrence of hyperlipidaemia in 44% of
      children at week 48 caused concern 17, 18 Fortunately, no failing children were found to have
      PI mutations.19 A small study in Caucasian adults using the same regimen also show good
      efficacy.20
    

Intervention name(s): ritonavir-boosted PI-based second line treatments; two PIs boosted by low dose ritonavir or one PI plus full dose ritonavir
Intervention type(s): Drug; Drug
Intervention description(s): single PI boosted by low dose ritonavir; two PIs boosted by low dose ritonavir or one PI plus full dose ritonavir
Intervention MeSH terms: Ritonavir
Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Data of children who satisfy the following eligibility criteria will be included.
      
Keywords: single- and double-boosted PI; second line regimen; NNRTI failure; HIV-infected children; Compare virological efficacy and safety of single- or double-boosted PI regimens as second line therapy in children with NNRTI-based treatment failure; treatment experienced