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Research Alert: Study Casts Doubt on "Shock and Kill" Cure Strategy

The Pediatric Antiretroviral Pipeline

September 2011

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Table of Contents


Introduction

Fewer antiretroviral options exist for children than for adults. Last year's Pipeline Report introduced a new chapter looking at pediatric formulations of antiretrovirals.1 The chapter detailed some of the hurdles to be overcome to ensure access to antiretrovirals in appropriate forms for children with HIV. It also showed some recent advances.

Since last year's report, new pediatric development has been scant. Despite incentives and penalties from regulatory authorities to innovator manufacturers designed to ensure that children benefit from these drugs, the disincentives to develop and produce them are considerable. Pediatric drug markets are generally smaller and less interesting to industry than those of adults. In rich countries pediatric HIV has been almost eliminated, meaning there is decreasing demand in these markets.

The best way to deal with pediatric HIV is to prevent it from happening in the first place. At present the elimination of mother-to-child transmission continues to elude most poor countries. Paradoxically, if maternal health and prevention of mother-to-child transmission (PMTCT) programs become more effective, the advantages in child health this brings will reduce demand further in the pediatric antiretroviral market.

Children are also unaffected by the growing case to provide treatment as prevention.

All this not withstanding, there has been significant progress in recent years in terms of both research and treatment scale-up. United Nations agencies, nongovernmental organizations (NGOs) such as Médecins Sans Frontières (MSF) and the Clinton Health Access Initiative (CHAI); and UNITAID and other major donors have made a concerted effort to highlight children with HIV and ensure that they have access to the medicines they need.

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However, an analysis of the global pediatric antiretroviral market performed in 2010 revealed only a few generic fixed-dose combinations (FDCs) in solid and dispersible forms quality certified by the World Health Organization (WHO) Prequalification Programme or the US Food and Drug Administration (FDA) since 2005.2 One qualitycertified manufacturer produced most (67%) of these FDCs, and they combine only older antiretrovirals. UNITAID accounted for 97-100% of 2008-2009 FDC market volume.

Price reductions for pediatric FDCs do not have the same potential as those for adults due to small volume. The analysis reported low uptake of FDCs, but this is likely to be largely due to the time required to register products and phase out syrups rather than countries not wanting to use them.

Meanwhile, in 2009 an estimated 2.3 million children were living with HIV. Although an impressive 355,000 children started antiretrovirals that year, 370,000 were newly infected. HIV kills 700 children every day.3

Data produced by CHAI, as part of an internal review, illustrate the pediatric antiretroviral development inertia.4 They show that pediatric determination (PD) -- which occurs when manufacturers have completed all FDA requested studies and pediatric exclusivity is awarded -- took an average of 6.5 years to achieve after approval for use in adults. This ranged from a laudable less than a year for abacavir to a spectacularly sluggish 14.9 years for saquinavir, which was never approved for children (see Table 1).


Table 1. Time Frames Between Adult Approval and PD for Antiretrovirals With Pediatric Exclusivity
DrugCalendar YearsTime in Years Between Adult Approval and PDManufacturer
Didanosine1991-20019.9Bristol-Myers Squibb
Lamivudine1995-20015.7GlaxoSmithKline
Saquinavir*1995-201014.9Roche
Stavudine1995-20015.7Bristol-Myers Squibb
Ritonavir1996-20059.3Abbott
Nevirapine1996-20015.5Boehringer Ingelheim
Nelfinavir1997-20036.5Agouron
Abacavir1998<1GlaxoSmithKline
Lopinavir/ritonavir2000-20077.5Abbott
Emtricitabine2003-20052.9Gilead
Tipranavir2005-20072.7Boehringer Ingelheim

Source: CHAI

* Still not approved.


When drugs are approved for children, multiple label changes may take place because pediatric populations are studied in sequence. As pediatric investigation plans work in de-escalated age bands, the youngest age groups will have the most prolonged delay in labeling.

Sometimes there is no indication or appropriate formulation for the very youngest children, complicating the implementation of universal treatment as early as possible in infancy.5

Perhaps the most notable change since the 2010 Pipeline Report is that Drugs for Neglected Diseases Initiative (DNDi) has recently entered the field. That this organization considers pediatric HIV to be a neglected disease speaks volumes.6

This chapter gives an update on recent results from clinical trials that will help inform guidance, new approvals and contraindications, the generic and innovator pipelines, "ones to watch," and how the new drugs might be used.


What to Start With?

WHO guidelines recommend that young children less than two years who have been exposed to maternal or infant nevirapine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs) for maternal treatment or PMTCT, start antiretroviral therapy with a lopinavir/ritonavir-based regimen. Nevirapine- or NNRTI -unexposed children, or children older than two years, should start with an NNRTI-based regimen of nevirapine, or efavirenz if the child is older than three years.

Nucleoside reverse transcriptase inhibitor (NRTI) backbones should be one of the following pairs: lamivudine plus zidovudine, lamivudine plus abacavir, or lamivudine plus stavudine. Stavudine is no longer preferred due to its toxicity.

Results from two recent studies may have an impact on future guidance with regard to the use of NNRTIs versus protease inhibitors (PIs) for younger children.

Findings from the IMPAACT P1060 study showed about 20% higher rates of failure at 24 weeks in children aged two months to three years receiving NNRTIbased regimens compared with those receiving PI-based regimens with or without NNRTI exposure.7,8 These results are unsurprising for the NNRTI-exposed children. What is surprising and controversial is the superiority of the PI regimen for NNRTIunexposed children in this trial -- particularly for providers with experience in using NNRTIs in this population in resource-limited settings.

In reality, many caregivers in resource-limited settings prefer nevirapine first-line, even for children exposed to it in utero, due to cost constraints, ease of use, and to preserve lopinavir/ritonavir for second-line.

The NEVEREST trial, also recently presented, showed that children started on lopinavir/ritonavir-based regimens who remained on them had about 10% higher rates of virological failure than children switched to nevirapine.9,10

Currently, WHO guidelines remain unchanged from last year, and opinion differs as to whether it is better to start with a PI or an NNRTI for all young infants. It is argued that many children will still not have been NNRTI- exposed through PMTCT, but this is usually poorly documented. NNRTI-based regimens remain attractive because of cost constraints, formulation, and palatability. PI-based regimens are more potent and can be used in exposed or unexposed children. NEVEREST data suggest it may be possible to switch to an NNRTI after initial suppression with a PI, but this would depend on access to virological monitoring.

There is agreement, however, that current drugs are far from perfect and a suitable first-line agent, to fit with current guidance, could be a cheaper, more user-friendly PI or a more robust NNRTI suitable for exposed or unexposed children (see Table 2).

As far as older children are concerned, data from the PENPACT-1/PACTG 390 study showed no significant difference at four years with viral suppression with regimens containing either an NNRTI or a PI.11 The PLATO II/Cohere study showed no difference in triple-class failure by initial regimen at four years of age in European children starting treatment with three or more antiretroviral drugs.12


Table 2. Use of NNRTIs Compared to PIs in Young Children in Resource Limited Settings
VariableNNRTIPI
CostNeviripine-based: US$55-209 per patient yearLopinavir/ritonavir- based: $218-329 per patient year
FormulationSeveral pediatric nevirapine-based FDCsNo three-in-one FDCs with lopinavir/ritonavir; heatstable liquid must be used for very young children*; children over 10 kg may be able to use a 100/25mg heat-stable tablet (cannot be crushed)
RobustSingle-point mutation can confer resistanceMultiple mutations needed
Following NNRTI exposure for PMTCTNot recommendedRecommended exposed or unexposed
Use with TB medicinesEfavirenzComplicated: lopinavir requires extra ritonavir boosting or higher dose
Aligned with adultsYesBoosted PI is an adult second-line drug
All age groupsYes, nevirapine. Efavirenz not recommended less than 3 yearsYes, lopinavir/ritonavir
Use second linePIsSecond-generation PIs
ToxicityNevirapine:
Rash
Hepatoxicity

Efavirenz:
Increased lipids
Central nervous system
Lopinavir/ritonavir:
Increased lipids
Gastrointestinal problems

Premature infants at increased risk of toxicity associated with lopinavir/ritonavir oral solution†
PalatabilityFDCs OKLopinavir/r liquid unpleasant bitter taste

* At temperatures higher than 25°C, the oral solution of lopinavir/ritonavir requires refrigeration. There are no stability data at temperatures higher than 25°C for lopinavir/ritonavir. Some providers cannot safely prescribe this to infants in households without a fridge.

† Sometimes called "baby grappa"! The lopinavir/ritonavir syrup contains 42% ethanol and 15% polyethylene glycol.

Induction/maintenance strategies (where people are started on very potent combinations of drugs which are then reduced in number once full viral suppression is achieved) are underexplored in children, -- as are questions as to whether a child starting treatment in infancy can ever stop.

Data from several ongoing studies, which will give more information about these issues are still awaited:

  • ARROW is investigating a strategy of induction/maintenance -- starting with a potent combination of four drugs and maintaining treatment with three versus continual treatment with four drugs.13
  • CHER, which demonstrated a big AIDS-free survival advantage from universally starting children on treatment at birth, will continue to follow these children's progress and look at whether after starting early they can stop treatment after one or two years.14
  • BANA and PENTA 11 will determine whether taking CD4-guided planned interruptions disadvantages children on stable therapy.15,16
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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
 

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