Retrofitting for Purpose: Treatment Optimization

June 2013

By Polly Clayden

Last year’s Pipeline Report saw the addition of a new chapter exploring research into antiretroviral treatment optimization. This strategy includes the optimization of approved compounds, and possible future opportunities with those in late-stage development. This 2013 chapter is largely an update from the original one, as the goals and target product profile for a “dream regimen” are unchanged. Any resemblance to the previous version is entirely intentional.

Treatment 2.0—a strategic approach by the World Health Organization (WHO) and UNAIDS to the achievement of universal access to antiretroviral therapy and to making the most of the role of antiretrovirals in preventing new infections—includes treatment optimization as one of its critical components.¹

Discussions about optimization—particularly through appropriate dose reduction—of approved antiretrovirals have been ongoing now for over a decade,^2,3 the rationale being that when developing new drugs, the highest tolerated doses in phase II are often selected for phase III and, in turn, approval, where in some cases lower doses may have equivalent efficacy. Efficiencies can also be achieved by reducing the amount of active pharmaceutical ingredient (API) with improved bioavailability through reformulation, or by tweaking the process chemistry.

The Conference on Dose Optimization (CADO)—a collaborative project of the Clinton Health Access Initiative (CHAI), the Johns Hopkins University School of Medicine, and the Bill & Melinda Gates Foundation, held in 2010 and attended by process chemists, clinical pharmacologists, infectious disease specialists and experts in regulatory and ethical issues—led to a consensus statement on optimizing the manufacturing, formulation, and dosage of antiretroviral drugs for more cost-efficient delivery in resource-limited settings.^4,5

As the statement explains, the API is the largest part of the product cost of generic drugs; a reduction in this would potentially decrease the total cost of the product. The cost of a marketed generic drug typically consists of: API (65 to 75 percent of the total market price), formulation (10 to 20 percent), and packaging and profits (5 to15 percent).

There are several ways through dose optimization that API reduction might be accomplished:

Dose reduction. In order to achieve regulatory approval for a dose lower than that currently approved, fully powered non-inferiority studies (phase III)—similar to those conducted by industry for the approval of a new drug—need to be done. It would take about three to six years to generate sufficient data to file with regulatory agencies, plus time to approval (about three months to a year). The estimated cost would be US$15 to 22 million.

Reformulation. This strategy makes use of technologies and/or inactive ingredients to increase the bioavailability of a drug, which enables reduction of the approved dose. A reformulated compound will need bioequivalence studies with the approved formulation (phase I). The estimated time frame to regulatory filing is two to three years, at a cost of US$2 to 8 million.

Process chemistry. It may also be possible to alter the manufacturing process leading to more efficient and less expensive API production. For this strategy to be successful, regulatory authorities would need to see only equivalent stability and purity data. This would take about one to two years, at an estimated cost of US$1 to 2 million.

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In 2011 WHO held a follow up meeting to the first CADO, to work out ways to incorporate treatment optimization into future guidelines and the Treatment 2.0 initiative.⁶ This yielded a number of short-term research priorities and recommendations including increased harmonization of adult and pediatric regimens, through FDCs and other simplified formulations.

Subsequent discussions at meetings led by Médecins Sans Frontières (MSF) and WHO as well as the recent Conference on Dose Optimisation II (CADO2), have explored medium- and longer-term horizons for future treatment strategies. ^7,8,9

The plans, established at the first CADO to increase API cost-efficiencies, remain unchanged, and this research continues to gain momentum. In the three years since the original meeting, there has been an increasing emphasis on patient acceptability and preferences. Discussions have included a broader group of representatives from the community and caregivers with consensus that improved efficiencies of the API need, not only reduce costs, but also improve tolerability and outcomes for people with HIV. It is acknowledged that these factors will be increasingly critical as indications for treatment grow and more asymptomatic people with HIV are offered antiretroviral treatment. All potential treatment options must be measured against these factors.

Dream Regimen

The ideal characteristics of a dream regimen have been variously described, and the target is one that is “so safe, effective, tolerable and durable that the need for switching to a new regimen would be very rare.”⁷

TABLE 1. Target Product Profile of a Dream ARV Regimen

Safe and Effective	Superior or Equivalent to Currently Recommended Drugs
Simple	Possible to be given in decentralized facilities or the community. One pill once a day (less frequently might be possible in the future). No lead-in dosing. No dose adjustments when given with other common medicines. Heat-stable. Shelf life of two or more years.
Tolerable	Minimal toxicity. Reformulation and/or dose reduction might improve tolerability.
Durable	High genetic barrier to resistance. Low pharmacokinetic variability. Forgiving of missed doses. Tolerable for easier adherence.
Universal	Safe and effective across all CD4 strata; in people with high viral load; in men and women; during pregnancy; across age groups and with common coinfections such as tuberculosis or viral hepatitis.
Affordable	ARV coverage does not meet the estimated current need. Meanwhile, evidence is growing for earlier and wider use of treatment.

For adult first-line treatment, a one pill, once-a-day FDC of efavirenz plus tenofovir disoproxil fumarate (DF) plus lamivudine is agreed—across all expert consultations as well as in the 2013 WHO Consolidated ART Guidelines¹⁰—to be the current preferred option in the short- and medium-term. The 2013 CHAI ceiling price for this FDC is now US$131, which is a 21 percent reduction since 2012.¹¹ With successful optimization work, this regimen could be expected to be less than $100 per patient per year (pppy).¹² Future changes to this regimen must either offer efficiencies with its components (such as a reduced dose with the same durability and improved tolerability), or superiority with new compounds.

The WHO 2013 guidelines-recommended second-line regimen remains ritonavir-boosted protease inhibitor-based and, unlike recommendations in rich countries, boosted lopinavir rather than darunavir is included alongside boosted atazanavir. An optimized boosted atazanavir-based regimen could be expected to be less than $275 pppy.

TABLE 2. 2013 WHO Guidelines–Recommended ART Regimens

First-line	tenofovir DF + lamivudine (or emtricitabine) + efavirenz preferred (including pregnant women) zidovudine alternative to tenofovir DF nevirapine alternative to efavirenz
Second-line	atazanavir/ritonavir or lopinavir/ritonavir preferred + tenofovir DF + lamivudine preferred backbone (if zidovudine or stavudine first-line) + zidovudine + lamivudine preferred (if tenofovir DF first-line)
Third-line	No specific recommendations: Integrase inhibitor (INI) or second-generation PI or NNRTI are mentioned

Treatment-limiting central nervous system toxicities that are a concern with efavirenz could possibly be reduced with a lower dose. Fears about its use during pregnancy are steadily being assuaged, and more permissive recommendations—in line with the British HIV Association guidelines—are made in the WHO 2013 guidelines.^{13,14,15,16,17}

Despite direct comparisons as monotherapy, lamivudine and emtricitabine are largely considered to be interchangeable in terms of efficacy and safety, and the WHO systematic review concluded this to be true.¹⁸ Both are nucleoside reverse transcriptase inhibitors (NRTIs) and are structurally similar molecules with low toxicity, and both are effective against hepatitis B virus. Cost comparisons make lamivudine the preferred option—using emtricitabine instead in combination with efavirenz and tenofovir DF adds an annual patient cost of US$25 to a combined product with tenofovir DF.

Work on the bioavailability of tenofovir DF could bring down the price (currently US$54 pppy as a single agent), and further reductions still might be possible with the new pro-drug, tenofovir alafenamide (AF).

The United States Food and Drug Administration (FDA) has tentatively approved a heat-stable formulation of atazanavir/ritonavir.^19,20 This 300/100 mg one-pill once-daily formulation is now US$220 pppy and compares favourably to heat-stable lopinavir/ritonavir costing US$300 pppy, with four pills a day and twice-daily dosing. Mylan Pharmaceuticals has developed a two pill once-a-day co-packaged regimen of this plus lamivudine and tenofovir DF; the ceiling price is US$306 pppy.

Once-daily heat-stable boosted darunavir would offer a better option to lopinavir second line. At present a suitable formulation (and suitable price) remains elusive. With expected comparable price to boosted lopinavir (there is potential to reduce the current cost of boosted darunavir $900 to below $350 pppy, if it was used in comparable volumes to that of lopinavir currently) and a better profile, boosted darunavir should be a second-line option and not just considered for third-line treatment.

WHO recommendations for third-line treatment were introduced for the first time in 2010 and they remain much the same in 2013, suggesting, as well as
boosted darunavir, the integrase inhibitor, raltegravir, and second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), etravirine in nucleos(t)ide sparing regimens. None of these yet have generic versions, and the cost is considerable.

Can we Do Better with What we Have Already?

Optimization opportunities with some of the approved antiretrovirals could offer several advantages over the current doses and/or formulations, and work is underway or under discussion with several compounds.^21,22

TABLE 3. Approved Antiretroviral Compounds with Potential for Dose Optimization

Compound (current approved dose)	Class	Sponsor/Approach	Outcomes	Status
Tenofovir DF (300 mg once daily)	NtRTI	CHAI Reformulation	Approx 33% reduction anticipated Cost reduction $50 to $35 pppy	Underway
Zidovudine (300 mg twice daily)	NRTI	Geneva University Hospital Dose optimization RCT	Dose reduced to 200mg twice daily Cost reduction $89 to $60 pppy	MiniZID Phase III To be completed January 2014
Stavudine (30 mg twice daily)	NRTI	Wits Reproductive Health Institute Dose optimization and comparison with TDF, RCT	Dose reduced to 20mg twice daily Cost reduction $25 to $20 pppy	WHCS-001 Phase III To be completed end 2015/early 2016
Efavirenz (600 mg once daily)	NNRTI	Kirby Institute Dose optimization RCT CHAI Reformulation	Dose reduced to 400 mg once daily Potential additional 33% reduction by reformulation Cost reduction $63 to $31 pppy	ENCORE 1 Phase III To be completed July 2013 Underway
Atazanavir/ritonavir (300/100 mg once daily)	PI	HIVNAT/Kirby Institute Dose optimization RCT CHAI Process chemistry	Dose reduced to 200/100 Cost reduction $355 to $200 pppy Additional potential price reduction by process chemistry	LASA Phase III To be completed early 2014 Underway
Darunavir/ritonavir (800/100 mg once daily or 600/100 mg twice daily)	PI	Under discussion Process chemistry, dose optimization and reformulation	API reduced from above $2000 to below $1000. Dose reduced from 800/100 to 400/100 mg once daily. Cost reduction $835 to below $350 pppy	Standard of care needs to be established. Process chemistry underway
Ritonavir (100 mg)	Booster	Dose optimization	Boosting dose of atazanavir and darunavir reduced to 50 mg	Under discussion

Source: Crawford KW, et al. Lancet Infect Dis. 2012 Jul; 12(7): 550-60, Hill A. Clinical Pharmacology Workshop. 2013. CADO2 2013. ClinicalTrials.gov

Tenofovir

Tenofovir DF is preferred as part of first-line treatment everywhere. It is considered to be the best NRTI /NtRTI (nucleotide reverse transcriptase inhibitor) on the market, and this is likely to continue for several years.

The price of tenofovir DF has dropped considerably since its introduction into the generic market. This is largely due to efficiencies in raw material sourcing and improved processing, which led to a 57 percent drop in price between 2006 and 2010.^23,24,25 It is now available for US$54 pppy, a 74 percent drop since 2006: a tenofovir DF-based FDC regimen is US$131 pppy.

There are, however, limits to tenofovir DF’s lowest possible price due to its high milligram dose (300 mg) with the current formulation. This also makes it less easy to co-formulate with other antiretrovirals.

Clinton Health Access Initiative (CHAI) is working on reformulation of tenofovir DF in partnership with a generic manufacturer. Through reformulation of the excipients, they aim to increase bioavailability and, in turn, lower the dose of the drug, while maintaining equivalent exposure.²⁶ Although the new dose has yet to be determined, the researchers anticipate a reduction by about a third.

Additionally there are two new pro-drugs of tenofovir in development: tenofovir alafenamide (AF formerly known as GS-7340) and CMX-157 (not much obvious progress but recently acquired by Merck).

Zidovudine

If tenofovir DF remains the preferred first-line NRTI/NtRTI, zidovudine is likely to be used second-line in the short term.

The dose of zidovudine was reduced considerably from the initial 300 mg every four hours to 250 to 300 mg twice daily, after similar efficacy and increased safety was demonstrated.²⁷

Although zidovudine is generally better tolerated than stavudine over a long-term period, its hematologic toxicities (anemia/neutropenia) remain a concern in many resource-limited settings (RLS).

The ongoing MINIZID study is looking at 200 mg versus 300 mg zidovudine twice daily (as part of a regimen with lamivudine plus an NNRTI), with reduction of anemia as the primary endpoint. This is a 48-week phase II study in 136 treatment-naive patients, sponsored by the University of Geneva and being conducted at the Hôpital de la Caisse Nationale de Prévoyance Sociale, Yaoundé, Cameroon. Recruitment began in August 2011 and will be completed in January 2014.²⁸

The study will not generate sufficient data for regulatory approval of the lower dose, but will provide proof of principle.

Some Asian countries such as Thailand and India already use the zidovudine 250 mg tablet twice daily, and Thailand is currently using 200 mg twice daily in patients weighing less than 50 kg.

Stavudine

Of all the dose optimization strategies proposed or ongoing, the decision to use stavudine is the most controversial. Unlike the other antiretrovirals for which these strategies are being suggested or conducted, stavudine is no longer a preferred option in any guideline, anywhere, due to its toxicity profile.

The Wits Reproductive Health Institute in South Africa is leading a phase IIIb trial comparing 20 mg stavudine twice daily to 300 mg tenofovir DF once daily in approximately 1,000 patients in South Africa, India and Uganda. The trial is sponsored by the Bill & Melinda Gates Foundation.

The primary objective is to demonstrate the non-inferiority of stavudine to tenofovir DF (both in a regimen with lamivudine plus efavirenz) in treatment-naive patients. The proportion of patients receiving each regimen with undetectable viral load (less than 200 copies/mL) at 48 weeks, will determine this. The secondary endpoints are to evaluate the tolerability, overall safety, and efficacy of 20 mg stavudine compared to tenofovir DF.

The trial is concerning, as it will not answer stavudine’s long-term toxicity question. The 20 mg stavudine dose might be acceptable in a short-term 48- or even 96-week virological endpoint study. However, because mitochondrial toxicity is both dose- and time dependent, many of stavudine’s most serious side effects (such as peripheral neuropathy and lipoatrophy) would not necessarily emerge until after such a study was completed. Although it looks at lipoatrophy, this study does not include monitoring of surrogate markers for mitochondrial toxicity, so it cannot shed light on the incidence of this serious adverse event.

The stavudine parallel track program, which randomized over 10,000 patients to receive 40 (30) mg or 20 (15) mg (between October 1992 and February 1994), showed a higher incidence of neuropathy in the high-dose arm (21percent). Nonetheless, the incidence of neuropathy observed in the lower dose arm was also unacceptably high (15 percent).²⁹

In addition to concerns about cumulative toxicities, stavudine-related cost savings might become irrelevant by the trial’s end. Through other dose optimization strategies and the expected approval of promising pipeline compounds (such as tenofovir AF and dolutegravir), alternatives are likely to become available in a similar time frame that could drive regimen costs down with less risk to patient safety.

Importantly, stavudine is extremely unpopular with people with HIV and activists all over the world. Many of us have expressed our opposition.^30,31,32 In South Africa and India, people with HIV and activists have had several protests and petitions against the trial and the slow phase out of stavudine.^33,34,35 As Bad Science’s Ben Goldacre asked: “Why is the Gates Foundation supporting this trial of a rubbish AIDS drug?”³⁶

Efavirenz

Efavirenz is currently the preferred anchor drug. Price and possibly central nervous system (CNS) toxicities could be reduced if a lower dose than the currently recommended 600 mg is possible.

The ENCORE1 study, which began recruitment in September 2011 and will be completed in July 2013, is looking at 600 mg versus 400 mg of efavirenz in 630 treatment-naive patients. The ENCORE studies are designed to compare lower doses with approved doses of antiretrovirals. Pharmacokinetic studies of lamivudine and lopinavir (ENCORE2 and ENCORE3) have already been conducted as part of this program, with the conclusion that neither is a suitable candidate for dose reduction.^37,38,39

The primary endpoint for ENCORE1 is the comparison between treatment groups of proportions of patients with viral load less than 200 copies/mL 48 weeks after randomization. The complete follow up is 96 weeks, and there are sites in Europe, Australasia, Latin America, Asia, and Africa.

ENCORE 1 has two substudies designed to look at pharmacokinetics and CNS exposure.40,41 If successful, this trial should generate sufficient data to gain regulatory approval and change WHO and other key treatment guidelines.

There are concerns about the drug/drug interaction with rifampicin used in TB/HIV coinfection if the efavirenz dose is reduced.

The high API of efavirenz is due in part to its poor water solubility. CHAI is looking at reformulation, targeting the inactive ingredients, to improve this.

Nanosuspensions of efavirenz, using freeze-drying technology are also in development, which could result in improved bioavailability and possibly greater antiviral activity.^42,43 The research group at the University of Liverpool developing an efavirenz nanosuspension will begin studies in HIV-negative volunteers to evaluate bioequivalence later this year.

Atazanavir

Dose reduction may also be possible with atazanavir, and the HIV Netherlands Australia Thailand Research Collaboration, with some support from the Kirby Institute, is conducting a trial that will provide some evidence for this strategy.⁴⁴

The low-dose atazanavir/ritonavir versus standard-dose atazanavir/ritonavir (LASA) study is comparing the efficacy and safety of atazanavir/ritonavir at either 200/100 mg or 300/100 mg once daily in Thai patients in combination with two NRTIs. This non-inferiority, phase IV study with about 600 patients began recruiting in March 2011 and will be completed in early 2014.

This study is enrolling patients who are already virologically suppressed to switch to the lower or standard dose of atazanavir. This research is important for Thailand as patients tend to have a lower body weight, and hyperbilirubinemia occurs quite frequently. It will be difficult to generalize the results from this research beyond the study population, but positive results would provide good reason to conduct a study in treatment-naive patients from a broader population.

CHAI is also working on optimizing the process chemistry.

Darunavir

Darunavir is generally considered to be the most durable protease inhibitor, but there is no generic formulation, and cost has been a barrier to its wide use. As it is not yet recommended for second-line treatment by WHO there has been limited work on its optimization.

This drug has different approved doses for treatment-naive (including treatment-experienced but with no darunavir-associated mutations) and protease inhibitor-experienced patients. Treatment-naive patients receive darunavir/ritonavir at an 8:1 (800/100 mg) ratio once daily, and experienced patients at a 6:1 ratio (600/100 mg) twice daily. There might be potential for dose reduction to 400/50 mg.

The ratios also vary for children depending on their weight band and treatment experience.

The establishment of single ratios for adults and children (as well as recommendations for when best to use it) would make simpler darunavir-based regimens and formulations more feasible.

CHAI is working on optimizing the process chemistry.

Ritonavir

It might be possible to give atazanavir and darunavir with a lower boosting dose of ritonavir. Lower doses could be better tolerated, cheaper, and easier to
co-formulate with PIs than the current dose.

If a 50 mg heat-stable tablet of ritonavir could be manufactured or 50 mg co-formulated with either protease inhibitor, new bioequivalence trials would be needed to ensure that boosting effects were similar to those that have been achieved previously in small pharmacokinetic trials with the liquid formulation.
A 50 mg ritonavir tablet would also be very useful for pediatric dosing, as the liquid is expensive, impractical (particularly for resource-limited settings) and tastes dreadful.⁴⁵

Opportunities with Pipeline Drugs—Ones to Watch

Antiretrovirals in the pipeline might also offer advantages, in the future, over those currently recommended.

The integrase inhibitor dolutegravir, expected to be approved this year, is a compound with high potential, and it is predicted to cost US$30 pppy: 90 percent cheaper than raltegravir.^46,47 The milligram dose is relatively low (50 mg), compared to elvitegravir (150 mg once daily plus 150 mg cobicistat) and raltegravir (400 mg twice daily), with once-daily dosing in treatment-naive patients. Early data suggest that a dose increase (to 50 mg twice daily) will be needed with TB treatment.⁴⁸

Dolutegravir appears well tolerated, and with the potential to be low-cost might replace efavirenz first-line or be used second-line. Trials in children, including in neonates, are underway or planned and a granule formulation is in development.

Tenofovir AF is in phase III and also could also be a useful new drug. With doses 10 times or more lower than that of tenofovir DF, the cost of tenofovir AF is predicted to be appropriately lower, and could come in at an annual patient cost of as little as US$20.⁴⁹

The dose and plans for development as a single agent are still to be announced, but it is expected to be 25 mg.⁵⁰ It is critical that Gilead recognizes the potential for this compound as a component of FDCs other than its own incestuous ones. For the single tablet regimen tenofovir AF-containing combinations currently being investigated (with boosted elvitegravir or darunavir plus emtricitbine) an interaction with cobicistat makes it possible to use a 10 mg dose when it is co-formulated with the boosting agent.⁵¹ After approval, data from these products will not inform the development of other, potentially more useful, FDCs. It will not look good if tenofovir AF miraculously appears as a standalone just as the patent for tenofovir DF expires.

Unlike Gilead, which gained approval for its latest FDC Stribild before making New Drug Applications (NDAs) for two components, elvitregravir and cobicistat (and recently got its fingers burned when these were rejected by the FDA⁵²), ViiV has submitted the NDA for dolutegravir first as a standalone. But, it too has an incestuous FDC in the pipeline of dolutegravir, abacavir and lamivudine.⁵³

New compounds with the potential for high impact worldwide must be studied in rational combinations and compared to the first-line standard of care of efavirenz plus tenofovir DF plus lamivudine. Dolutegravir needs to be studied in combination with tenofovir DF, and with tenofovir AF, and efavirenz in combination with tenofovir AF (all plus lamivudine or emtricitabine).⁵⁴

This must be done in a timely way, long before the expiry of the various patents, and will require commitments from both innovator and generic companies as well as WHO, regulatory agencies and investigators.

Looking to the Future? Long Acting Formulations

With the potential to completely alter standard of care, discussions about, and early development of, long-acting formulations are also under way for monthly or weekly depot injections. Potential candidates might be the NNRTI rilpivirine and the integrase inhibitor GSK1265744, both in early stages of development and studies are planned with the two together.⁵⁵ CMX-157, a novel version of tenofovir, also has a long half-life. Last seen in phase I, it has recently been acquired by Merck, but so far there has not been a lot of news about the plans.^56,57

For long acting formulations, there is not yet clarity on the target product profile—both for the molecules and for patient acceptability—nor is it clear if the right combination of compounds required to construct a suitable regimen are available or even in development.

What Needs to Be Done?

• Treatment optimization must be in the interests of people with HIV.
• Trials, like the low dose stavudine one, conducted for the sake of cost alone, and against much opposition from people with HIV and activists, are unacceptable. Activist and patient acceptability is always important. This will become increasingly so as indications for starting become broader and more asymptomatic people with HIV are offered treatment.
• Drugs and regimens need to be designed with resource-limited settings in mind. The target product profile has been widely described by now. Currently approved and pipeline compounds fit for this purpose need to be studied and produced in appropriate formulations.
• The time between full FDA/EMA approval and WHO prequalification, FDA tentative approval, and approval by local regulatory agencies must be shortened.
• Delays with the registration process, in addition to production by generic manufacturers and recommendations in national guidelines, means that it takes years from promising results in trials and initial approval to wide availability for the majority of people in need of antiretroviral treatment. Despite over150 single agents and combination products having FDA tentative approval, the majority are older drugs and those with expired patents.

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Endnotes

All links last accessed May 29 2013.

1. World Health Organization. The treatment 2.0 framework for action: catalysing the next phase of treatment, care and support. Geneva: World Health Organization; 2011. http://www.who.int/hiv/pub/arv/treatment/en/index.html
2. Hill A. HAART for $125 a year: how can it be done? Paper presented at: 8th European Conference on Clinical Aspects and Treatment of HIV-Infection; 2001 October 28–31; Athens, Greece.
3. Hill A, Ananworanich J, Calmy A. Dose optimisation: A strategy to improve tolerability and lower antiretroviral drug prices in low and middle-income countries. Open Infect Dis J. 2010;(4): 85–91. http://www.benthamscience.com/open/toidj/articles/V004/SI0031TOIDJ/85TOIDJ.pdf.
4. Crawford KW, Brown Ripin DH, Levin AD, et al. Optimising the manufacturing, formulation, and dosage of antiretroviral drugs for more cost-efficient delivery in resource-limited settings: a consensus statement. Lancet Infect Dis. 2012; 12(7): 550–60.
5. Clinton Health Access Initiative. Conference on antiretroviral dose optimization: meeting summary. http://www.clintonhealthaccess.org/files/CADO_priorities_121310.pdf.
6. World Health Organization. Short-term priorities for antiretroviral drug optimization; meeting report (London, UK, 18–19 April 2011). Geneva: World Health Organization; 2011. http://whqlibdoc.who.int/publications/2011/9789241501941_eng.pdf.
7. Médecins Sans Frontières (MSF), Solidarité thérapeutique hospitalière en réseau (Esther), Solidarité thérapeutique contre le sida (SOLTHIS). Antiretroviral sequencing meeting report; 22–23 September 2011. Geneva: Médecins Sans Frontières; 2011. http://www.msfaccess.org/sites/default/files/MSF_assets/HIV_AIDS/Docs/AIDS_Event_SequencingMtg_Report_ENG_2011_FINAL.pdf.
8. World Health Organization. WHO informal consultation on medium- and long-term priorities for ARV drug optimization. (Montreux, Switzerland, 29-31 May 2012). http://www.who.int/hiv/pub/meetingreports/think_tank/en/index.html.
9. Conference on Antiretroviral Drug Optimization (II) April 16 – 18, 2013, Cape Town, South Africa. (Report forthcoming)
10. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. 2013. (forthcoming)
11. Current prices are from the CHAI ARV Ceiling Price List. 2013. http://www.clintonhealthaccess.org/files/CHAI_ARV_Ceiling_Price_List_May_2013.pdf, and the Médecins Sans Frontières (MSF) Access Campaign. Untangling the Web of Antiretroviral Price Reductions Drug Prices & Patent Status list. http://utw.msfaccess.org/drugs.
12. Forecasted prices in this chapter are from the Clinton Health Access Initiative (CHAI) estimations presented at Conference on Antiretroviral Drug Optimization (II) April 16 – 18, 2013, Cape Town, South Africa.
13. Ford N, Mofenson L, Kranzer K, et al. Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS. 2010 Jun 19;24(10):1461–70.
14. Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2011 Nov 28;25(18):2301–4.
15. World Health Organization. Technical update on treatment optimization. Use of efavirenz during pregnancy: A public health perspective. Geneva: World Health Organization; 2012 June.
    http://whqlibdoc.who.int/publications/2012/9789241503792_eng.pdf.
16. World Health Organization. Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Programmatic update. Geneva: World Health Organization; 2012 April. http://www.who.int/hiv/pub/mtct/programmatic_update2012/en/.
17. British HIV Association. Guidelines for the management of HIV infection in pregnant women 2012. 2012 April 30. http://www.bhiva.org/documents/Guidelines/Pregnancy/2012/hiv1030_6.pdf.
18. World Health Organization. Pharmacological equivalence and clinical interchangeability of lamivudine and emtricitabine: a review of current literature. Geneva: World Health Organization; 2012. http://www.who.int/hiv/pub/treatment2/lamivudine_emtricibatine/en/.
19. Food and Drug Administration (U.S.). Tentative approval of atazanavir sulfate and ritonavir fixed dose combination tablets. 2011 November 18. http://www.fda.gov/ ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm280673.htm.
20. Food and Drug Administration (U.S.). Approved and Tentatively Approved Antiretrovirals in Association with the President’s Emergency Plan. Number 136. NDA 22282. http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm
21. Crawford KW, Brown Ripin DH, Levin AD, et al. Optimising the manufacturing, formulation, and dosage of antiretroviral drugs for more cost-efficient delivery in resource-limited settings: a consensus statement. Lancet Infect Dis. 2012;12(7):550–60.
22. Hill A. Antiretroviral dose optimization: what are the opportunities? Clinical Pharmacology Workshop, Turin, Italy January 2013. http://www.fcarvturin.it/FCARVs_2013_pdf/03_venerdi/01_Hill.pdf.
23. Crawford KW, Brown Ripin DH, Levin AD, et al. Optimising the manufacturing, formulation, and dosage of antiretroviral drugs for more cost-efficient delivery in resource-limited settings: a consensus statement. Lancet Infect Dis. 2012;12(7):550–60.
24. Brown Ripin DH, Teager DS, Fortunak J, et al. Process improvements for the manufacture of tenofovir disoproxil fumarate at commercial scale. Org Process Res Dev 2010; 14: 1194–201.
25. Houghton SR, Melton J, Fortunak J, Brown Ripin DH, Boddy CN. Rapid, mild method for phosphonate diester hydrolysis: development of a one-pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester. Tetrahedron 2010; 66: 8137–44.
26. Brown Ripin DH. Conference on Antiretroviral Drug Optimization (II) April 16 – 18, 2013, Cape Town, South Africa. (Report forthcoming)
27. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. N Engl J Med 1990; 322: 941–49.
28. National Institutes of Health (U.S.). Safety of reduced dose zidovudine (AZT) compared with standard dose AZT in antiretroviral-naïve HIV-infected patients (AZTlowdose). http://clinicaltrials.gov/ct2/show/NCT01540240.
29. Anderson RE, Dunkle LM, Smaldone L, et al. Design and implementation of the stavudine parallel-track program. J Infect Dis. 1995 Mar;171 Suppl 2:S118–22.
30. Treatment Action Group. Letter opposing low-dose stavudine trial. 2011 December 14. https://www.treatmentactiongroup.org/hiv/2011/lowdose-stavudine-trial.
31. Andrieux-Meyer, Clayden P, Collins S, et al. Why it’s time to say goodbye to stavudine… everywhere. South Afr J HIV Med. 2012;13(1). http://www.sajhivmed.org.za/index.php/sajhivmed/article/view/813/652.
32. Nkhoma P. Manet+ wants ARV d4T phased out. The Daily Times (Malawi). 2012 January 30. http://www.bnltimes.com/index.php/daily-times/headlines/national/4079-manet-wants-arv-d4t-phased-out.
33. Thom A. Stavudine trial causes split. Health-e. 2012 June 11. http://www.health-e.org.za/news/article.php?uid=20033573.
34. Collins S. Stavudine (d4T) phase-out festival in Dehli. HIV Treatment Bulletin. 2012 June. http://i-base.info/htb/16625.
35. Clayden P. d4T – time to move on. HIV Treatment Bulletin. 2012 December. http://i-base.info/htb/20629.
36. Goldacre B. Why is the Gates Foundation supporting this trial of a rubbish AIDS drug? 2011 December 20. http://bengoldacre.posterous.com/why-is-the-gates-foundation-supporting-this-t.
37. Else LJ, Jackson A, Puls R, et al. Pharmacokinetics of lamivudine and lamivudine-triphosphate after administration of 300 milligrams and 150 milligrams once daily to healthy volunteers: results of the ENCORE 2 study. Antimicrob Agents Chemother. 2012 Mar;56(3):1427–33. http://aac.asm.org/content/early/2011/12/13/AAC.05599-11.abstract.
38. Jackson A, Hill A, Puls R, et al. Pharmacokinetics of plasma lopinavir/ritonavir following the administration of 400/100 mg, 200/150 mg and 200/50 mg twice daily in HIV-negative volunteers. J Antimicrob Chemother. 2011 Mar;66(3):635–40. http://jac.oxfordjournals.org/content/66/3/635.full.
39. National Institutes of Health (U.S.). Safety and efficacy of reduced dose efavirenz (EFV)
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40. National Institutes of Health (U.S.). The efavirenz (EFV) central nervous system exposure sub-study of Encore1 (ENCORE1-CNS). http://clinicaltrials.gov/ct2/show/NCT01451333.
41. National Institutes of Health (U.S.). The intensive pharmacokinetics sub-study of Encore1 (ENCORE1-PK). http://clinicaltrials.gov/ct2/show/NCT01271894.
42. Patel GV, Patel VB, Pathak A, Raiput SJ. Nanosuspension of efavirenz for improved oral bioavailability: formulation optimization, in vitro, in situ and in vivo evaluation. Drug Dev Ind Pharm. 2013 Jan 16. doi: 10.3109/03639045.2012.746362 [Epub ahead of print]
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44. National Institutes of Health (U.S.). Low dose atazanavir/r versus standard dose atazanavir/r (LASA). http://clinicaltrials.gov/ct2/show/NCT01159223.
45. Hill A, Khoo S, Boffito M, et al. Should we switch to a 50 mg boosting dose of ritonavir for selected protease inhibitors? J Acquir Immune Defic Syndr. 2011 Dec 15;58(5):e137–8.
46. More extensive details and references for the investigational antiretrovirals are provided in the ARV chapter of this report, and for their respective investigational plans in children in the pediatric ARV chapter.
47. ViiV (Press Release). ViiV Healthcare announces FDA priority review designation for dolutegravir as a potential treatment for HIV infection. 2013 February 15. http://www.viivhealthcare.com/media-room/press-releases/2013-02-15.aspx.
48. Dooley K, Purdy E, Sayre P, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin: results of a phase I study among healthy subjects (Abstract 148). Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections; 2012 March 5–8; Seattle, WA. http://www.retroconference.org/2012b/Abstracts/43754.htm.
49. i-Base/TAG estimate based on fixed cost of tenofovir DF API, inactive ingredients, and packaging.
50. Ruane P, DeJesus E, Berger D, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir 300 mg in a 10-day monotherapy study of HIV-1+ patients (Abstract 103). Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections; 2012 March 5–8; Seattle, WA. http://www.retroconference.org/2012b/Abstracts/44081.htm.
51. Ramanathan S, Wei X, Custodio J, et al. Pharmacokinetics of a novel EVG/COBI/FTC/ GS-7340 single tablet regimen (Abstract O_13). Paper presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; 2012 April 16–18; Barcelona, Spain. http://regist2.virology-education.com/2012/13hivpk/docs/20_Ramanathan.pdf.
52. Gilead (Press Release). Gilead Receives Complete Response Letters from U.S. Food and Drug Administration for Elvitegravir and Cobicistat. 2013 April 29. http://www.gilead.com/news/press-releases/2013/4/gilead-receives-complete-response-letters-from-us-food-and-drug-administration-for-elvitegravir-and-cobicistat.
53. ViiV (Press Release). Shionogi-ViiV Healthcare Starts Phase III Trial for “572-Trii” Fixed-Dose Combination HIV Therapy. 2011February 11. http://www.viivhealthcare.com/media-room/press-releases/2011-02-03.aspx.
54. Conference on Antiretroviral Drug Optimization (II) April 16 – 18, 2013, Cape Town, South Africa. (Report forthcoming)
55. Collins S. ARV pipeline: long-acting formulations of rilpivirine, GSK-744 and nanoformulations. HIV Treatment Bulletin. 2013 April 1. http://i-base.info/htb/21069.
56. Lanier ER, Ptak RG, Lampert BM, et al. Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV. Antimicrob Agents Chemother. 2010 Jul;54(7):2901–9.
57. Merck. (Press Release). Merck signs two deals for novel HIV drug candidates and initiates phase II clinical trial of MK-1439 for HIV. 2012 July 24. http://www.merck.com/newsroom/news-release-archive/research-and-development/2012_0724.html.