Paediatric antiretroviral pipeline

Polly Clayden

This new chapter of the Treatment Action Group’s Pipeline Report looks at antiretroviral formulations suitable for use in children. In resource-rich countries, most HIV-positive children are treated early with highly active antiretroviral therapy (HAART) employing three or more antiretroviral drugs (ARVs).

As with adults, HAART has changed the course of HIV in children dramatically, and the majority can expect to survive into adulthood.1,2 Furthermore, identifying women of unknown status in pregnancy, and appropriate care and treatment for HIV-positive mothers, has led to a sharp decline in perinatal infections. [3]

However, UNAIDS estimated in 2008 that there were 2.1 million children living with HIV; among them, 430,000 were newly infected (about 1,200 new infections per day), and 390,000 were in sub-Saharan Africa. The overwhelming majority were infected through mother-to-child transmission (MTCT). [4]

One study of nearly 3,500 children enrolled in perinatal trials in Africa estimated that, without treatment, 35% would die before their first birthday and 53% by the time they reached two years of age. By five years of age, it was deemed likely that 62–89% of these children would die. [5]

A more recent analysis, using pooled data from 12 African studies describing almost 11,000 children born to HIV-positive women, has suggested that by one year of age, an estimated 16% infected through breast-feeding and 44 % perinatally infected children would die. [6]

Unfortunately, the rollout of antiretroviral therapy (ART) to treat children with HIV has been gradual and has lagged behind that of adults. More recently, though, there has been significant progress and in 2008 almost 276,000 children received HAART worldwide, compared to 127,300 in 2006. Despite this increase, every year, new infections are nearly double the number of children who gained access to HAART in 2008.

This chapter looks at all new ARVs in the pipeline for children, with the main focus being products (often new formulations of existing medicines) suitable for use in parts of the world with the greatest and most urgent need. The emphasis is also on infants and younger children, as older children are treated with adult antiretroviral formulations.

Why not avoid paediatric HIV in the first place?

That MTCT is almost entirely preventable deserves emphasis. In more richly resourced countries, where use of ARVs in pregnancy and avoidance of breastfeeding are routine, MTCT has been reduced to 1–2%, and new paediatric HIV infections are rare.

In sharp contrast, several areas of unmet prevention, care, and treatment collide to swell the paediatric epidemic in poorly resourced settings. First, in prevention of HIV in women: in 2008, one million women were estimated to have been infected. Second, in prevention of unwanted pregnancies: an alarming proportion of pregnancies have been reported to be unwanted—51%, 74%, 84%, and 93% in studies of HIV-positive women in Cote d’Ivoire, Rwanda, South Africa, and Uganda, respectively. [7, 8, 9, 10] Third, the implementation of prevention of mother to child transmission (PMTCT) interventions has been limited and relied on regimens with poor efficacy. And fourth, few eligible pregnant women receive HAART to treat their own HIV.

This global failure of prevention means that children continue to be infected, and that those children will need treatment with ARVs for life.

When to start children on antiretroviral therapy

Following the announcement of early results from the Children with HIV Early Antiretroviral Therapy (CHER) trial—which found that starting antiretroviral therapy (ART) before 12 weeks of age reduced early mortality by a highly significant 75% when compared to starting at CD4 cell percentages less than 25%, or starting it based on clinical symptoms—international guidelines recommended universal ART for children age one year or less. [11, 12, 13, 14]

Furthermore, new World Health Organization (WHO) guidelines recommend universal ART for children up to two years of age in recognition of the high mortality risk and less-frequent monitoring in this age group in resource-limited settings.

Data to guide when to start ART between one and five years of age are scant, and this is reflected in differences in recommendations among guidelines. After five years of age, guidance is similar to that for adults (see tables 1 and 2).

Table 1. WHO 2010 guidelines: when to start children on ART

Age WHO 2010 guidelines
Less than 24 months
24–59 months
Clinical Stage 3 or 4
Immunological* <25% or <750
5 years and older
Clinical Stage 3 or 4
Immunological <350

Note:*CD4 percentage/absolute CD4 count, cells/mm3

Table 2. Guideline comparison, United States and Europe: when to start children on ART

Age US DHHS 2008 guidelines PENTA 2009 guidelines
Less than 12 months
All All
12–35 months
Clinical CDC stage B CDC stage B or C/ WHO stage 3 or 4
Immunological* <25% <25% or <1000
36–59 months
Clinical CDC stage B CDC stage B or C/ WHO stage 3 or 4
Immunological <25% <20% or <500
5 years and older
Clinical CDC stage B or C CDC stage B or C/ WHO stage 3 or 4
Immunological <25% <350

Note:*CD4 percentage/absolute CD4 count, cells/mm3; DHHS = U.S. Department of Health and Human Services; PENTA= Paedeatric European Network for Treatment of AIDS.

Additionally, the WHO recommends that uninfected, breastfed infants born to HIV-positive women who are not receiving HAART receive antiretroviral prophylaxis to reduce the risk of MTCT during breastfeeding. [15]

Identifying children with HIV and starting them on treatment

Although the benefits of early treatment are clear, in reality, when children do start treatment it tends to be late. A literature review of 30 paediatric studies or treatment programmes has revealed that children receiving HAART ranged from infants aged two months to adolescents aged 15 years. Five of 26 studies that reported age at HAART initiation, 19 (73%) showed a mean or median age at start of treatment of greater than five years. Only two studies reported a median age at start of treatment of less than two years. [16]

In order to initiate treatment immediately, infants need to be diagnosed at the earliest opportunity. Infants with known HIV exposure—that is, born to mothers in PMTCT programmes—should be tested at four to six weeks of age using HIV virologic assays.

Any infant at a health facility presenting signs or symptoms that may be an indication for HIV should also be tested. All infants should have their HIV status established upon their first contact with the health system, preferably before six weeks of age. There needs to be an evaluation to determine where and with what symptoms, when infants present at a health facility, it is best to test them in order to identify most infections—for example, those presenting with malnutrition are very frequently HIV-infected.

If virological testing is not available, the WHO recommends presumptive diagnosis in accordance with nationally defined algorithms, and serological tests are used. (It is important to note that infants and children younger than 18 months of age will often test positive on an HIV antibody test even if they are uninfected. This is because of the passive transplacental transfer of maternal HIV antibodies to the infant. Therefore, accurate diagnoses require more expensive and complex virological tests.)

If children are identified as HIV-infected in PMTCT programmes this means they will have been infected despite maternal prophylaxis, so they are likely to have resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and a greater proportion are likely to have been infected in utero and have faster disease progression.

Preliminary results from the IMPAACT 1060 study (in which children previously exposed and unexposed to nevirapine were randomised to start treatment with either nevirapine or lopinavir/ritonavir–based regimens) were sufficiently concerning for the study’s data safety monitoring board to stop the nevirapine-exposed, nevirapine-initiating arm early. [17]

Infants with NNRTI exposure through PMTCT are usually recommended to begin treatment with a protease inhibitor–based regimen. Unexposed children or those with unknown or less recent exposure will start with an NNRTI-based regimen.

Data are needed to guide ongoing strategies for children starting treatment. Whether children initiated early on treatment can discontinue it later is unclear (and this is also an important question for adolescents who are at risk for treatment non-adherence). There are also questions about the reuse of NNRTIs in nevirapine-exposed children and whether an initial, more potent, regimen could be a useful strategy.

The NEVEREST (nevirapine resistance) studies are looking at switching children who are initiated on lopinavir/ritonavir–based regimens to nevirapine versus remaining on lopinavir/ritonavir. Early findings suggest reuse of nevirapine may be possible in some circumstances. [18]

The ARROW (Antiretroviral Research for Watoto) study is looking at an induction/maintenance strategy: whether there is an advantage to starting with a more potent combination of four drugs for 36 weeks and then maintaining treatment with three drugs, versus continual treatment with three drugs. [19]

The CHER study is continuing to follow children to look at whether after starting early they can stop treatment after one or two years.

The BANA (Botswana/Baylor Antiretroviral Assessment) II and PENTA 11 studies will determine whether children on stable therapy are disadvantaged by taking CD4-guided planned treatment interruptions. [20, 21]

What to start with?

The WHO’s and some national guidelines recommend starting with lopinavir/ritonavir for nevirapine-exposed infants and young children less than two years of age.

Unexposed children under three years should receive nevirapine, and those over three years efavirenz. All others (including nevirapine-exposed children) should receive an NNRTI (efavirenz is preferred for children receiving TB treatment unless they are less than three years of age).

Recommended nucleosides are zidovudine plus lamivudine, abacavir plus lamivudine, or stavudine plus lamivudine.

Appropriate formulations are available to facilitate all these combinations, including many generics and fixed-dose combinations (FDCs) pre-qualified by the WHO and/or with tentative approval (for use outside the U.S., particularly for PEPFAR programmes) from the U.S. Food and Drug Administration [22, 23] see Table 3).

Table 3: Antiretroviral formulations suitable for paediatric use with tentative approval from the FDA and/or pre-qualified by the WHO

Drug Formulation and strength Supplier/applicant FDA TA WHO PQ
Abacavir Oral solution 20 mg/mL GlaxoSmithKline •
Abacavir sulphate Oral solution 20 mg/mL Cipla •
Abacavir sulphate Tablet 60 mg Aurobindo Pharma •
Abacavir sulphate Oral solution 20 mg/mL Aurobindo Pharma •
Abacavir sulphate + lamivudine Tablet 60 mg/30 mg Aurobindo Pharma •
Abacavir sulphate Tablet 60 mg Matrix Laboratories •
Abacavir sulphate + lamivudine Tablet 60 mg/30 mg Matrix Laboratories •
Abacavir sulphate + lamivudine + zidovudine Tablet 60 mg/30 mg/60 mg Matrix Laboratories •
Didanosine Powder for solution 2 g Bristol-Myers Squibb •
Didanosine Tablet 25 mg/50 mg/100 mg Bristol-Myers Squibb •
Didanosine Delayed release capsules 125 mg, 200 mg, 250 mg, and 400 mg Matrix Laboratories •
Didanosine Delayed release capsules 125 mg, 200 mg, 250 mg, and 400 mg Aurobindo Pharma •
Didanosine Oral solution 10 mg/mL Aurobindo Pharma •
Efavirenz Oral solution 30 mg/mL Merck Sharp & Dohme •
Efavirenz Capsule 50 mg. and 200 mg Merck Sharp & Dohme •
Efavirenz Tablets 50 mg. and 200 mg Merck Sharp & Dohme •
Efavirenz Capsule 200 mg Ranbaxy •
Efavirenz Tablet 200 mg Strides Arcolab • •
Efavirenz Tablets 50 mg, 100 mg, and 200 mg Matrix Laboratories •
Efavirenz Capsule 200 mg Cipla •
Efavirenz Tablet 200 mg Aurobindo Pharma •
Efavirenz Capsule 50 mg, 100 mg, and 200 mg Aurobindo Pharma •
Lamivudine Oral solution 10 mg/mL GlaxoSmithKline •
Lamivudine Oral solution 10 mg/mL Cipla • •
Lamivudine Oral solution 10 mg/mL Aurobindo •
Lamivudine + stavudine Tablets for oral suspension 60 mg/12 mg and 30 mg/6 mg Cipla •
Lamivudine + stavudine +nevirapine Dispersible tablets 30 mg/6 mg/50 mg and 60 mg/12 mg/100 mg Cipla • •
Lamivudine + zidovudine Tablet 30 mg/60 mg Aurobindo Pharma •
Lamivudine + zidovudine Tablet 30 mg/60 mg Matrix Laboratories •
Lamivudine + zidovudine + zidovudine Dispersible tablets 30 mg/50 mg/60 mg Matrix Laboratories • •
Lopinavir/ritonavir Oral solution 80 mg/mL and 20 mg/mL Abbott Laboratories •
Lopinavir/ritonavir Capsules 133.3 mg/33.3 mg Abbott Laboratories •
Lopinavir/ritonavir Tablet 100 mg/25 mg Abbott Laboratories •
Lopinavir/ritonavir Tablet 100 mg/25 mg Matrix Laboratories •
Lopinavir/ritonavir Tablet 100 mg/25 mg and 200 mg/50 mg Aurobindo Pharma Ltd •
Nelfinavir Powder for oral solution 50 mg/1 g F. Hoffman-La Roche •
Nevirapine Oral suspension 10 mg/mL Boehringer Ingelheim •
Nevirapine Oral suspension 10 mg/mL Aurobindo Pharma Ltd •
Nevirapine Tablet for oral suspension 50 mg Aurobindo Pharma Ltd •
Nevirapine Oral suspension 50 mg/5 mL Aurobindo •
Nevirapine Oral suspension 50 mg/5 mL Cipla •
Ritonavir Oral solution 80 mg/mL Abbott Laboratories •
Stavudine Powder for oral solution 1 mg/mL Bristol-Meyers Squibb •
Stavudine Capsules 15 mg and 20 mg Bristol-Meyers Squibb •
Stavudine Capsules 20 mg Aspen Pharmacare •
Stavudine Powder for oral solulion 1mg/mL Aurobindo Pharma •
Stavudine Oral solution 1 mg/mL Aurobindo •
Stavudine Capsules 15 mg, 20 mg, 30 mg, and 40 mg Hetero Drugs Ltd •
Stavudine Oral solution 1 mg/mL Cipla Ltd •
Stavudine Capsules 15 mg, 20 mg Aurobindo Pharma Ltd •
Stavudine Capsules 15 mg, 20 mg, 30 mg, and 40 mg Aurobindo •
Zidovudine Capsule 100 mg GlaxoSmithKline •
Zidovudine Oral solution 10 mg/mL GlaxoSmithKline •
Zidovudine Infusion solution 10 mg/mL GlaxoSmithKline •
Zidovudine Tablet 60 mg Aurobindo Pharma Ltd •
Zidovudine Oral solution 50 mg/5 mL Cipla Ltd • •
Zidovudine Capsule 100 mg Cipla Ltd • •
Zidovudine Capsule 100 mg Aurobindo Pharma Ltd •
Zidovudine Oral solution 50 mg/5 mL Aurobindo •
Zidovudine Oral solution 10 mg/mL CombinoPharm S.L •
Zidovudine Tablet 100 mg Matrix Laboratories •


Paediatric dosing can be complicated. There are often insufficient pharmacokinetic (PK) data to determine target concentrations, and there is wide interpatient variability, particularly in very young children. In industrialized countries providers usually use a body surface area calculation to determine dosing, which is not feasible in many healthcare settings with less-experienced health workers. In order to simplify dosing, the WHO has developed weight-band tables offering a single, harmonized dosing schedule. [24]

Notably, manufacturers (particularly generic manufacturers) have produced dosing forms to use with these dosing schedules—including FDCs, such as 200mg tablets of efavirenz scored in two directions (approved) or 600mg scored once on one side and twice on the other (awaiting approval)—to enable accurate division of tablets and, in turn, dosing. Triomune Baby, an FDC from Cipla (stavudine 6 mg/lamivudine 30 mg/nevirapine 50 mg) is suitable for dosing infants down to 3kg and is dispersible in breast milk.


Some, but not all, approved adult ARVs have paediatric formulations for children who are too young to swallow tablets; traditionally these have been liquids or syrups. These formulations are expensive (about six times more costly than solid forms), often require a cold chain, have a short shelf life, and are not easy to store or transport. Cost and logistical barriers have prohibited their widespread use. Besides transport to and storage at the dispensary, the following example illustrates the lack of practicality for the caregiver:

A 10 kg child being treated with standard doses of stavudine, lamivudine, and nevirapine, for whom a 3-month supply of drugs is dispensed at a clinic visit, would require 18 bottles of liquid weighing almost half as much as the child (4.3kg). For a rural family who may have walked a long distance to reach the clinical centre, this is a significant issue. [25]

For manufacturers, development of liquid formulations is not always as simple as it sounds. Development of a liquid formulation of efavirenz has been besieged by set-backs for years. Efavirenz has potential for oral mucosa irritation; it also has poor aqueous solubility. Early development focused on palatable alternatives to the aqueous suspensions using oily vehicles that were known to mask irritation. The original oral solution, a suspended sugar solution, was found to have a low level of bacterial contamination; the culprit was confectioner’s sugar. A heating step was then incorporated into the process to destroy the bacteria, but this then led to clumping. The current formulation is a sugar-free strawberry mint flavor 30mg/mL solution. It does not provide sufficient drug exposure for children less than three years of age.

It was not possible to formulate tenofovir as a liquid; this formulation would have required huge volume and tasted very nasty. The paediatric formulation will now be a powder of coated granules, which will mask the taste (although anecdotally it may still be fairly unpalatable) but the powder does not dissolve. Nor was it possible for etravirine, which will be a dispersible mini-pill, or atazanavir, which will be a powder.

The extremely unpleasant taste is not uncommon, and taste has been documented as a factor in treatment failure. Conversely, masking taste and developing palatable flavors for children can also be a barrier to creating a successful oral solution.

More recently, manufacturers (notably generic manufacturers) have developed more useful ARV formulations such as crushable mini-pills, scored tablets, dispersible formulations, “sprinkles” and FDCs that can be used by very young children. This has been a very important aspect of paediatric drug development in recent years, and along with the simplified dosing tables has overcome two significant barriers to widespread paediatric treatment (see Table 4).

Table 4: Desirable qualities

Liquid Solid (preferred)
Stable at room temperature Stable at room temperature
Small dose/volume Crushable, granular or dispersible
Long shelf life Long shelf life
Suitable dosage forms for convenient weight-band dosing Scored tablets
Masking of bad taste Masking of bad taste
Dispensing tools (e.g., syringes) included

An ARROW substudy looked at the acceptability of tablets and syrups (NNRTI plus two of zidovudine, abacavir, and lamivudine). The children in this substudy received syrups on enrollment and switched to crushable tablets. Eight weeks after switching, 93% of caregivers and 56% of their children (median age at switch, 2.9 years) preferred tablets. [26]

Protease inhibitors, however, have poor bioequivalence with crushed tablets. In a recent study, investigators observed significantly lower exposure with crushed lopinavir/ritonavir compared to the reference product. [27] For young nevirapine-exposed children, lopinavir/ritonavir “sprinkles” are currently being studied in the Children with HIV in Africa—Pharmacokinetics and Acceptability of Simple Antiretroviral Regimens trials. [28]

These trials have looked at or are looking at simplifying antiretroviral regimens—for example, toxicity and adherence/acceptability profiles of new paediatric FDCs that contain abacavir or zidovudine rather than stavudine, and simplification strategies such as once-daily regimens and whether it is necessary to dose-escalate nevirapine. The trials use WHO weight-band tables.

Approval of paediatric formulations

There are now considerable incentives and/or penalties from regulatory agencies to ensure that any new drug that may be of benefit to children must be studied in children.

This is mandatory on the part of both the FDA, which also extends six-month patent protection to companies that perform requested paediatric studies (voluntary), and the European Medicines Agency (EMA), which enforces penalties for companies that do not provide a paediatric investigational plan as part of their application (or request a waiver). [29]

Companies must include PK data for all age groups of children, efficacy, tolerability, and differences in side effects. They must have stability and palatability data for formulations and demonstrate that they are able to achieve PK targets associated with efficacy in adults.

Most paediatric development programmes take a staggered approach, starting with the older cohorts of children and working down in age. The studies are conducted in children as soon as there are sufficient data from studies in adults.

Applications for generic formulations must demonstrate bioequivalence. A single product needs to be compared to the reference product (innovator). Generic FDCs need to be compared to the individual reference drugs taken together. Preferred bioequivalence studies are randomised, single-dose, two-way crossover studies. Bioequivalence studies need not be done in children.

Dissolution testing is required when evaluating solid or suspension formulations to assure reproducible drug release.

The innovator pipeline

Nucleotide reverse transcriptase inhibitors

Gilead’s tenofovir disoproxil fumarate is one of the most widely used antiretroviral drugs in adults. Development of a paediatric formulation has been slow, and there have been concerns about loss of bone mineral density in children. There has been considerable off-label use with adult tablets in drug-experienced children; the FDA recently gave a new indication for children and adolescents from 12 to 18 years of age. Gilead plans to file the oral powder formulation with regulatory agencies in the second half of 2010.

Protease inhibitors

Atazanavir is approved for children over six years of age in capsule formulation. Trials of atazanavir powder are ongoing for younger age groups, with and without ritonavir boosting, within the Bristol-Myers Squibb–supported PACTG 1020 programme.

The darunavir oral suspension, boosted with a ritonavir solution, is currently in phase II studies in treatment-experienced children ages three to six, twice daily; there is a waiver for children under three years of age. Tibotec’s darunavir is approved for children over six years, and there is a 75mg tablet.

Nonnucleoside reverse transcriptase inhibitors

Tibotec’s etravirine is in the phase II safety and efficacy stage of its paediatric development programme using 25mg mini-pills.

Rilpivirine (TMC 278), also manufactured by Tibotec, is beginning pediatric trials with an oral granule formulation following bioavailability and palatability trials in healthy adult volunteers of three concept formulations.

Integrase inhibitors

Merck’s raltegravir has two paediatric formulations, a chewable tablet for children under 12 years old, and granules for children less than two years old. They are being studied in the IMPAACT P1066 study.

Plans for elvitegravir from Gilead include both liquid and solid age-appropriate dosage forms for children. Gilead will also attempt, if the doses of all four drugs are similarly scalable with age/body weight, to make a coformulated quad pill (an FDC with elvitegravir, cobicistat, tenofovir, and emtricitabine) for children able to swallow tablets.

Pharmacokinetic enhancers

Gilead’s cobicistat (GS-9350) is a heat stable boosting agent that will also be produced as a stand-alone to boost other antiretrovirals as an alternative to ritonavir. Gilead plans to make it available in both age-appropriate liquid and solid forms for children. It is hoped that cobicistat will offer an alternative to ritonavir, which is only available as 100mg or as an unpleasant-tasting liquid.

CCR5 receptor antagonists

Pfizer’s maraviroc is currently being evaluated in children 2–18 years of age infected with CCR5-tropic HIV-1. As with adults, this drug is expected to have less clinical utility than other ARVs in children, as it requires an expensive CCR5 tropism assay.

Table 5: The innovator paediatric pipeline

Drug Formulation Comments
Tenofovir Oral powder formulation Filing with FDA/EMA second half of 2010
Atazanavir Oral powder formulation PACTG 1020: Phase II study of atazanavir and atazanavir/ritonavir powder/capsules in treatment-naive and treatment-experienced children 3 months–21 years.
Darunavir Oral suspension 100 mg = 1 mL ARIEL: Phase II study in treatment-experienced children 3–6 years. Needs to be boosted with ritonavir.
Etravirine Solid formulation: 25 mg tablet Phase II safety and efficacy study in children 6–17 years.
Rilpivirine Oral granules for dispersal Pediatric investigation trials beginning in second half of 2010.
Raltegravir Chewable table Oral granules for suspension IMPAACT 1066: granules < 2 years; chewable tablets <12 years.
Elvitegravir/ Cobicistat (booster) Age-appropriate solid and liquid forms in development, separately and coformulated. Paediatric investigational plan to FDA/EMA, second half of 2010. Also development plan for paediatric quad pill.
Maraviroc Liquid solution (20 mg/mL) A4001031: Children 2–12 years of age infected with CCR5 tropic HIV-1.

Generic pipeline/wish list

Many of the new paediatric formulations will not be available for some time; moreover, some of them may be too expensive or complicated to use in resource-limited settings. WHO and national guidance in resource-limited settings (for both adults and children) is weak beyond second-line therapy. Table 6 lists formulations, either known to be in development by generic companies or will be needed, that will work with dosing according to WHO weight band tables.

Table 6: Paediatric formulations needed

Drug Formulation (mg) Comments
Drugs needed for PMTCT
Nevirapine Scored tablet 20 mg Used for infant prophylaxis from 6 weeks onward.
Drugs needed for paediatric ART
Lopinavir/ritonavir Sprinkle 40/10 mg Heat-stable formulation that will be equivalent to 0.5 mL of liquid and used in treating infants and children who are unable to take the paediatric tablet.
Abacavir/lamivudine Scored adult tablet 300/150 mg Used in children over 25 kg.
Abacavir/lamivudine/nevirapine Tablet 60/30/50 mg Triple FDC to align with the dual FDC.
Ritonavir Sprinkle or tablet 50 mg heat stable Useful for coadministration with unboosted protease inhibitors and for superboosting when protease inhibitors need to be dosed with rifampicin.
Tenofovir/lamivudine tablet 75/75 mg; scored 300/300 mg tablet
Darunavir Unclear Current labeling calls for different ratios of darunavir to ritonavir for different age brackets. It is unclear what the correct ratio should be to produce a coformulated FDC, but this is a priority formulation.
Raltegravir Unclear Raltegravir is not yet approved for paediatric use but this is high priority formulation.

Adapted from World Health Organization 2010 Paediatric guidelines Annex E.


All web references were retrieved on 24 June 2010.

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Links to other websites are current at date of posting but not maintained.