Approximately 2.5 million
children globally were living with human immunodeficiency virus (HIV) at
the end of 2009 and more than 800 children died daily of AIDS in each
year. In resource-constrained countries, tuberculosis (TB) is the most
common opportunistic infection in children with HIV infection and most
HIV-infected patients with TB have relatively advanced HIV disease [1].
Moreover, both diseases together represent a deadly co-morbidity [2]. With
regard to antiretroviral therapy (ART), nevirapine is recommended as a
preferred drug for children who are <3 years old, while efavirenz is
preferred for those older than 3 years because of lacking data on dosing
in children <3 years. The pediatric nevirapine dosages (age ≥15 days) are
recommended at 200 and 120-150 mg/m2
BSA/dose twice daily in children <8 years and ≥8 years, respectively
(maximum 200 mg/dose). The pediatric EFV dosing is adjusted related to
weight band [3].
Despite growing evidence of ART is gained in children
living with HIV and TB, there remain a number of significant obstacles for
our pediatric care which we need to address. The question of early versus
delayed initiation of ART has been recently answered by randomized
controlled trials in adult patients. SAPIT trial showed that all HIV and
TB patients who had CD4 cell counts less than 500 cells/mm3
should receive concurrent (integrated) TB treatment and ART [4]. A more
recent study, CAMELIA trial, demonstrated that death rate in patients
where ART was initiated after 2 weeks of TB treatment was significantly
higher compared to those in whom ART was initiated after 8 weeks of TB
treatment; although these advantages in early ART initiation was not
reported in HIV-infected patients with TB meningitis [5]. The World health
Organization (WHO) recommended that ART should be initiated in all
children with TB, regardless of CD4, within 2-8 weeks of starting
antituberculous (anti-TB) therapy. Nevertheless, one of the major concerns
is that none of the studies includes pediatric patients and thus a
critical need exists for studies in children.
Studies evaluating the pharmacokinetics of anti-TB
drugs and drug-drug interactions between anti-TB drugs and antiretroviral
drugs are very scarce, especially in pediatric patients. In terms of TB
treatment, rifampicin forms the backbone of first line anti-TB treatment
and has allowed for the use of 6-month therapy for TB. However, current
available rifamycins differ in their potency as CYP3A4 enzyme inducers,
with rifampicin being the most potent inducer. Unfortunately, rifampicin
is the only rifamycin that is available in many resource-constrained
countries, which decreases plasma level of many antiretroviral drugs
including protease inhibitors and non-nucleoside reverse transcriptase
inhibitors (NNRTIs), although the magnitude of effect on NNRTIs is lesser.
Decreased plasma levels of antiretroviral drugs can lead to HIV treatment
failure. Currently, the minimum acceptable plasma concentrations at 12
hours after dosing for efavirenz and nevirapine are 1 and 3.4 mg/L,
respectively [6]. The previous randomized controlled study in HIV-infected
adults demonstrated that plasma nevirapine level is significantly lower in
patients who are concurrently receiving nevirapine with rifampicin, when
compared to efavirenz and low NNRTI exposure is an important independent
predictive factor for subsequent HIV treatment failure [7].
The study by Shah and colleagues [8] aimed to determine
factors affecting serum levels of efavirenz and nevirapine and analyzed
the effect of concomitant rifampicin on nevirapine levels in pediatric
Indian patients. This study has a number of important conclusions.
Firstly, the result showed that concurrent rifampicin administration does
not alter blood levels of nevirapine after the dose of nevirapine was
increased by 20-30%. Secondly, nevirapine-associated adverse effects are
notably not seen with this increase in dose while nevirapine 600 mg per
day was associated with a high rate of hypersensitivity syndrome in
co-infected HIV and TB adult patients. Further studies need to confirm
these discordant findings. Lastly, plasma levels for efavirenz in standard
dose are less compromised by concomitant treatment with rifampicin than
are levels for nevirapine as same as shown in previous studies in
HIV-infected adults; however, the sample size is very limited. A previous
study conducted by Ren Y and colleagues revealed some concerns for
virologic failure among HIV and TB co-infected children receiving
rifampicin containing regimen and had low efavirenz levels [9]. This
emphasizes the need for more studies. It would have been more interesting
to know the long-term outcome in such children.
Another concern is that NNRTIs have demonstrated
inter-individual and inter-racial pharmacokinetic variability because
polymorphisms of CYP2B6 and CYP3A4 are associated with altered activity of
hepatic iso-enzyme and resulting in a variation of plasma NNRTI level,
treatment efficacy and toxicity [10]. Therefore, this result might not be
applicable to all other ethnic populations and close monitoring for liver
toxicity is still needed. In addition, strategy of lead-in dosing of
nevirapine needs to be further explored.
Funding: None
Competing interests: None stated.
References
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