Page 68 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 3 of 7 Opinion Paper

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patients at risk of virological failure. There is a similar interaction 247 pregnancies (1.2%; 95% CI: 0.3%, 3.5%). No specific
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with rifabutin. This means that all patients on rilpivirine who teratogenic concerns have emerged to date.
develop rifamycin-sensitive tuberculosis would need to be
switched to alternative ART. This adds to programmatic Affordability
complexity, as well posing a risk to patients who may be
switched to a less well-tolerated regimen, potentially risking In South Africa, rilpivirine currently has a ‘single exit’ price
virological failure. However, this is not a problem unique to of around ZAR 50.00 (around US $3.70) for a 30-day supply
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rilpivirine, as many ARVs require either a treatment change versus ZAR 175.00 (around US $13.00) for efavirenz.
(such as atazanavir) or a change in dose (such as ritonavir- Efavirenz is unlikely to decrease in price any further and is
boosted lopinavir and dolutegravir) when co-administered therefore unlikely to achieve price parity with rilpivirine.
with rifampicin. With the move to ‘test and treat’ resulting in This does not include any costs related to managing side
earlier ART initiation at higher CD4+ counts, and with increased effects related to the use of efavirenz, which is associated
rollout of various TB prevention therapies, this may become less with higher adverse event-related discontinuations compared
of an issue as incident TB rates are likely to decline. to rilpivirine across several studies. 14
Role of rilpivirine in programmes
Convenience

Fixed-dose combinations are preferred in large programmes, not using efavirenz-based first-line
only for their benefits in terms of adherence but also for the therapy
benefits they offer in terms of simplicity of supply chain, Internationally, treatment guidelines have moved to
distribution, stock management, storage and prescription. recommending ART initiation irrespective of WHO clinical
Internationally, both rilpivirine and efavirenz are available co- stage or CD4+ count. Benefits of ART initiation are modest
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formulated with either TDF and FTC, or tenofovir alafenamide for those with earlier stage disease, and need to be weighed
(TAF) and FTC. TAF is a prodrug of tenofovir, which is potentially up against the potential harms, which include side effects
associated with less bone and renal toxicity than TDF because of and toxicity from ART when initiated in asymptomatic
lower plasma tenofovir exposure. 24,25 Unfortunately, none of the patients at high viral loads.
rilpivirine fixed-dose combinations, or formulations of either
drug containing TAF, are currently available in South Africa. A systematic review including 42 randomised controlled
trials found that the relative risk for discontinuations because
Paediatric formulations of adverse events was higher for efavirenz compared to most
other first-line options, including low-dose efavirenz (400
Currently, there are no specific paediatric formulations of mg), rilpivirine, TDF, atazanavir and maraviroc, and that
rilpivirine available and the adult formulation can only be used neuropsychiatric adverse events were common with
in children from 12 years and weighing 35 kg or more. Where efavirenz. Notably, most of the studies included were
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possible, within large-scale programmes, harmonisation of conducted in predominantly white populations. Black
adult and paediatric regimens is preferred. This is not currently Africans have a much higher prevalence of efavirenz slow
possible with rilpivirine.
metaboliser genotypes than white people (17% vs. 3% in
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South Africa), which may result in more frequent efavirenz-
Safety in pregnancy related neuropsychiatric adverse events.
Pregnancy can affect rilpivirine concentrations by its effect
on cardiac output, protein binding, volume of distribution Efavirenz is superior to rilpivirine for programmatic use in a
and cytochrome P450 3A4 activity. Rilpivirine concentrations standard first-line ART regimen because it has higher
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are reduced during pregnancy, especially during the third virological efficacy at high viral loads, is available in fixed-
trimester, 26,27 as is seen with many other antiretrovirals. In dose combination formulations, can be prescribed with
two studies that investigated the pharmacokinetic rifampicin and is safe in pregnancy. Rilpivirine cannot be
characteristics of rilpivirine in pregnant women, nearly all prescribed with rifamycin-containing TB treatment. Although
the women had rilpivirine concentrations above the IC (the rilpivirine is cheap, it has reduced efficacy at high baseline
90
concentration of drug required to inhibit viral replication by viral loads and cannot therefore be used for first-line therapy
90%). This suggests that no dose adjustment is required without pre-ART initiation viral loads. Pre-ART viral loads
despite the reduced rilpivirine exposures during pregnancy. are not routinely performed in southern African ART
In both studies, the women maintained virological programmes and would considerably increase total cost to
suppression and the infants were not HIV-infected. 26,27 the healthcare system of the first-line regimen. In addition,
data on rilpivirine use in pregnancy are limited and the
The Antiretroviral Pregnancy Registry (APR) still has reduction in rilpivirine exposure during the third trimester of
relatively low numbers of rilpivirine-exposed pregnancies. pregnancy is concerning. 26,27,32
For first trimester exposures to rilpivirine, there was one
birth defect in 202 pregnancies (0.5%; 95% CI: 0.0%, 2.7%); for However, for patients with a contraindication to efavirenz
second trimester exposures, there were three birth defects in (e.g. history of psychosis) or who experience severe

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