WHO 2013 guidelines: what about the missing formulations?
Polly Clayden, HIV i-Base
The launch of the WHO “Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection” at IAS 2013 caused quite a stir.  Glimpses of the top line recommendations in the run up to their release provoked much discussion – particularly about when to start – which continued throughout the conference.
Unlike previous editions of the guidelines, the consolidated guidelines combine recommendations for adults and adolescents, pregnant women and children. They also make recommendations on operations and service delivery.
They call for countries to start treatment in all HIV positive adults with a CD4 count of 500 cells/mm3 or less, and to start at any CD4 count in several populations. The recommendation to start earlier plus widening other criteria immediately increase the number of people eligible for treatment from 16.7 to 25.9 million. The recommendations are based on a mix of evidence for the benefit to individual health , reduction in transmission risk, operational considerations and aspiration.
“Earlier, safer and simpler antiretroviral therapy can push the HIV epidemic into irreversible decline”, the press release announced. This review in HTB only briefly summarises the “earlier” recommendations, which have been discussed at length elsewhere (although any offer of treatment to a healthy, asymptomatic person makes little sense without modern antiretrovirals), and focuses on the “safer and simpler” aspects of the recommended antiretroviral options.
At times the guidelines swerve between aspirational – for children options are largely based on formulations that are not yet commercially available – and unambitious – in the case of the omission of a generally preferred adult PI conversely because a suitable formulation is not currently available – but largely give us plenty to push for, including drugs and formulations not yet included.
Treatment and management of adults and adolescents in 2013 guidelines
When to start?
- At a CD4 count of 500 cells/mm3 or less. People with 350 cells/mm3 or less and/or WHO clinical stage 3 and 4 are prioritised.
- At any CD4 count in people with active TB or HBV co-infection with evidence of severe chronic liver damage.
- At any CD4 count in people with HIV negative partners.
- All pregnant and breastfeeding women – those meeting the eligibility criteria for treatment should remain on lifelong ART. In generalised epidemics particularly, lifelong treatment is recommended for all pregnant women. Some countries can consider stopping ART after the risk of vertical transmission is over.
What to start?
Adult first-line recommendations are certainly simple with a reduced number of preferred regimens. Triple fixed dose combinations (FDCs) of the preferred regimen efavirenz (EFV), tenofovir disoproxil fumarate (TDF) and 3TC are available, as are those for the alternative ones. See Table 1.
|1st line||TDF + 3TC (or FTC) + EFV preferred including pregnant womenAZT alternative to TDFNVP alternative to EFV|
|2nd line||ATV/r or LPV/r preferred+ TDF + 3TC preferred backbone if AZT or d4T 1st line+ AZT + 3TC preferred if TDF 1st line|
|3rd line||No specific recommendations: INI or 2nd generation PI or NNRTI are mentioned|
There is a strong recommendation that “countries should discontinue d4T use in first-line regimens because of its well recognised metabolic toxicities”. The guidance for programme managers’ section also includes a box with key implementation considerations for phasing out d4T. What is not discussed is when to start in settings where a prompt transition from d4T has not occurred and is not happening – an estimated one million people in developing countries are still receiving this drug – see the related article by Simon Collins below.
UNITAID recently announced an initiative to enable better access to TDF-based FDCs by stimulating market competition and reducing prices by at least 30%.  Current annual costs are over 30 percent more for a TDF-based FDC than a d4T-based one – respectively US$ 130 vs US$ 79 per person per year  – this initiative should help to spur along more rapid phase out.
The recommendation to start with EFV includes pregnant women and a number of people have remarked that this is complicated to explain to health workers as the labeling for EFV still says that it is contraindicated in pregnancy.
Widespread EFV use can provoke concern from communities, particularly people that have experienced or witnessed bad CNS side effects. The ENCORE1 study presented at the conference which found 400 mg non-inferior to the standard dose of 600 mg also found significantly fewer participants discontinuing treatment due to EFV-related side effects and fewer reporting them in the lower dose arm. [4, 5] This approach is promising and the 400 mg dose might be a better component of future FDCs but more information is needed on the durability of the lower dose in the presence of concomitant rifampicin.
For second-line boosted PIs the guidelines recommend lopinavir/ritonavir (LPV/r) and atazanavir/ritonavir (ATV/r).
The usually preferred boosted PI, darunavir/ritonavir (DRV/r) is only included in a footnote – puzzlingly in the same sentence as the suboptimal one saquinavir/ritonavir (SQV/r) – which says: “DRV/r can be used as an alternative PI and SQV/r in special situations; neither are currently available as heat-stable fixed-dose combinations, but a DRV + RTV heat-stable fixed-dose combination is currently in development”.
In contrast, US Department of Health and Human Services (DHHS) and BHIVA guidelines both recommend ATV/r and DRV/r as preferred PIs and have LPV/r as an alternative. [6, 7]
WHO’s own systematic review including six clinical trials comparing the three boosted PIs used for second line concluded that there was no evidence to support changing the recommendations from the 2010 guidelines. This was despite noting that two of the studies showed better virological response and retention in care for people receiving DRV/r than LPV/r, and its use in high-income settings.
The decision was not based on efficacy, safety, tolerability or sequencing but on the availability of a generic, heat-stable, FDC of DRV/r at a comparable price.
Several generic companies have heat-stable, co-formulated DRV/r in development but they might be reluctant to make the investment without a potential market. FDCs with heat stable RTV are not easy to produce. In the case of both LPV/r and ATV/r, a few attempts were necessary to get a suitable formulation within the regulatory limits of bioequivalence, so the companies will consider this an expensive risk. To have an FDC included in the Expressions of Interest (EOI) list of WHO prequalification (PQ), it needs to be in the guidelines – although there is likely to be an EOI later this year despite this cautious inclusion in a footnote.
If there were some countries prepared to adopt DRV/r, UNITAID could consider an intervention similar to what CHAI previously implemented with ATV/r – which broke the LPV/r monopoly, opened up a competitive ATV/r market, and dramatically increased access to second-line treatment.  Notably, in contrast to the 2013 approach to DRV/r, the 2010 guidelines recommended ATV/r before a suitable heat-stable FDC was available – WHO PQ and FDA tentative approval for the first ATV/r FDC occurred in November 2011.
There is also potential to reduce the current annual patient cost of DRV/r from US$900 to below US$350 – if it is used in volumes comparable to LPV/r – with process chemistry, dose optimisation and reformulation.  Stronger language from the guidelines on DRV/r would encourage investment in this work, as well as generic manufacture, country adoption, and donor investments to scale-up second-line treatment.
SQV/r is a mystifying inclusion. It is not a preferred or alternative option in DHHS or BHIVA guidelines because of a high pill burden and its initiation requires dose escalation and ECG monitoring due to its association with QT interval prolongation.
It is mentioned in the context of concomitant TB treatment at 400/400 mg twice daily. SQV/r is contraindicated with rifampicin at 1000/100 mg twice daily due to drug-induced hepatitis with marked transaminase in a study with HIV negative volunteers.  For 400/400 mg, the only available data is a conference abstract. In this Brazilian study 15/20 naïve patients receiving SQV/r 400/400 mg twice a day with TB treatment dropped out; 14/15 due to adverse effects (mainly hepatic and gastrointestinal). The authors did not recommend this regimen.
Although the relevance of this inclusion is very low as the use and procurement of SQV/r is virtually non-existent – with the occasional exception of west Africa for HIV-2 – it is inappropriate that it is mentioned in the same sentence as DRV/r.
Treatment and management of children in 2013 guidelines
When to Start?
Infants and children should initiate antiretroviral therapy:
- Less than five years old regardless of CD4 count or WHO stage. Strong recommendation for children up to one year and conditional from one to five years.
- At five years and older with 500 CD4 cells/mm3. Strong recommendation 350 cells/mm3 and below, and conditional 350 to 500 cells/mm3.
- With severe or advanced symptomatic disease (WHO stage 3 or 4) regardless of age or CD4 count.
- With a presumptive HIV diagnosis below 18 months.
- With active TB. As soon as possible within eight weeks following the start of TB treatment regardless of CD4 or WHO clinical stage.
What to Start?
First-line for infants and children less than three years old:
- LPV/r-based regimens regardless of previous NNRTI exposure. If LPV/r is not feasible, NVP-based.
- Consider substituting LPV/r with an NNRTI after sustained virological suppression (defined as viral load less than 400 copies/mL at six months, confirmed at 12 months from starting treatment). Conditional recommendation.
- Children who develop active TB while on LPV/r- or NVP-based regimens should be switched to ABC + 3TC + AZT during TB treatment. They should switch back to the original regimen when their treatment for TB is completed.
The backbone should be one of the following (in order of preference): ABC or AZT + 3TC; d4T + 3TC.
First-line for children three years and older:
- EFV preferred and NVP alternative.
- Less than 12 years (or weighing less than 35 kg) the backbone should be (in order of preference): ABC+3TC; AZT or TDF + 3TC or FTC. Conditional recommendation.
- Adolescents 12 years (weighing more than 35 kg) should align with adults, the backbone should be: TDF+ 3TC or FTC; ABC or AZT + 3TC.
- After first-line NNRTI failure, a LPV/r regimen is preferred.
- After failure of first-line LPV/r, children less than three should remain on the regimen with improved adherence support.
- After failure of first-line regimen containing ABC or TDF + 3TC or FTC, the preferred backbone is AZT + 3TC.
- After failure of first-line regimen containing AZT or d4T + 3TC or FTC, the preferred backbone is ABC or TDF + 3TC or FTC.
Missing triple fixed dose combinations
By contrast, the recommendations for children are not so simple and very aspirational. In order to make the simplified first and second line recommendations for children feasible across all age groups nine possible regimens are needed, which could be facilitated with six triple FDCs. Only one (AZT/3TC/NVP) is currently available. [12 ] See Table 2.
|FDC||Doses||Status and comments|
|ABC/3TC/NVP||60/30/50 mg||Alternate 1st line.|
|ABC/3TC/EFV||120/60/ 100 mg||Preferred 1st line >3 to 10 years|
|TDF/3TC/EFV||75/75/ 150 mg||Preferred 1st line >10 years|
|AZT/3TC/LPV/r||30/15/40/ 10 mg||Preferred 1st line <3 years. Preferred second line >3 years.|
|ABC/3TC/LPV/r||30/15/40/ 10 mg||Preferred 1st line <3 years.|
Sources: WHO recommended urgently needed formulations Table 6, Annex 7: Dosages of recommended antiretroviral drugs. Juneja S. Licensing technology and intellectual property for the development of paediatric formulations.
ABC/3TC/NVP is quite far along but ABC/3TC/EFV might not be feasible because of tablet sizes. EFV/3TC/TDF should be possible will scaled down or scored versions of adult tablets.
The LPV/r based combinations are also underway.
For older children on second line, heat stable ATV/r aligned with adults would probably be preferable to LPV/r.
The challenges with the current formulations – particularly the LPV/r syrup currently available for infants and young children – and pipeline paediatric antiretrovirals are described in the 2013 i-Base/TAG Pipeline Report. 
A satellite sponsored by the Drugs for Neglected Diseases initiative (DNDi) – who are currently developing a granule formulation of LPV/r with Cipla – The Medicines Patent Pool and UNITAID also focused on some of the shortcomings with current formulations. 
- World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. June 2013.
- UNITAID press release. UNITAID to provide USD 77 MILLION for better HIV medicines. 11 June 2013.
- Clinton Health Access Initiative. ARV Ceiling Price List. May 2013.
http://www.clintonhealthaccess.org/news-and-information/ARV-Ceiling-Price-List-May-2013 http://www.clintonhealthaccess.org/files/CHAI%20ARV%20Ceiling%20Price%20August%202013.pdf (PDF)
- Puls R et al. A daily dose of 400mg efavirenz (EFV) is non-inferior to the standard 600mg dose: week 48 data from the ENCORE1 study, a randomised, double-blind, placebo controlled, non-inferiority trial. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June – 3 July 2013, Kuala Lumpur. Oral late breaker abstract WELBB01.
- Collins S. Efavirenz at 400 mg compared to standard 600 mg dose has similar efficacy with fewer side effects. HTB. 5 July 2013.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services.
- British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012.
- UNITAID second line project.
- Ripin D. CHAI. What have we got to play with: What is in the ARV Pipeline? Conference on Antiretroviral Dose Optimization II (CADO2) April 16-18, 2013 Cape Town, South Africa. (Report forthcoming)
- US Food and Drug Administration. Drug Interaction Warning: Saquinavir/ritonavir and Rifampin.
- Rolla et al. Safety, efficacy and pharmacokinetics of ritonavir 400 mg- saquinavir 400 mg and rifampicin combined therapy in HIV naïve patients with tuberculosis. 3rd IAS, Rio de Janiero, Brazil, 2005. Abstract WePe33C03.
- Juneja S. Licensing technology and intellectual property for the development of paediatric formulations. Closing the treatment gap for children. IAS , Kuala Lumpur, Malaysia, 2013. Non-commercial satellite MOSA03.
- Clayden P. The paediatric antiretroviral pipeline. HTB supplement. June 2013.
- Closing the treatment gap for children. IAS , Kuala Lumpur, Malaysia, 2013. Non-commercial satellite MOSA03.