WHO | World Health Organization - Information to be included with … · The 2016 WHO Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection

WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

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Information to be included with an application for inclusion, change or deletion of a medicine

in the WHO Model List of Essential Medicines:

Table of Contents 1. Summary statement of the proposal for inclusion, change or deletion: .............................................. 2

2. Name of the focal point in WHO submitting or supporting the application: ..................................... 2 3. Name of the organization(s) consulted and/or supporting the application: ...................................... 2

4. International Nonproprietary Name (INN, generic name) of the medicine: ..................................... 2 5. Dosage form or strength proposed for inclusion: ................................................................................ 2

6. International availability - sources, if possible manufacturers: ........................................................... 3 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group: ..... 3

8. Information supporting the public health relevance ........................................................................... 3 8.1. Epidemiological information on disease burden: ................................................................................................ 3 8.2. Assessment of current use: ............................................................................................................................................ 3 8.3. Target population: ........................................................................................................................................................... 4

9. Treatment details ................................................................................................................................. 4

9.1. Reference to existing WHO and other clinical guidelines: ................................................................................ 4 9.2. Dosage regimen, duration: ...................................................................................................................................... 4 9.3 Need for special diagnostic or treatment facilities and skills: ............................................................................ 5

10. Summary of comparative effectiveness in a variety of clinical settings: .......................................... 5 10.1. Summary of available data (appraisal of quality, outcome measures, summary of results) .............................. 5 10.2. Summary of available estimates of comparative effectiveness ..................................................................... 8

11. Summary of comparative evidence on safety: .................................................................................. 9 11.1. Estimate of total patient exposure to date ....................................................................................................... 9 Tenofovir disoproxil fumarate, lamivudine, and efavirenz, in a variety of combinations including TEE600 and

TLE600, have been used extensively as first line therapy in HIV-infected adults and adolescents. To date, the

TLE400 FDC has not been used in a clinical setting but the closely related TEE400 regimen (as TE plus EFV)

has been used in the ENCORE1 clinical trial described in Section 10.1 above for a reported duration of 96

weeks. ....................................................................................................................................................................................... 9 11.2. Description of adverse effects/reactions ......................................................................................................... 9

11.3. Drug Interactions ...............................................................................................................................................10

11.4. Identification of variation in safety due to health systems and patient factors ........................................10 12. Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group: .............................................................................................. 10 12.1. Range of costs of the proposed medicine ......................................................................................................10 12.2. Comparative cost-effectiveness presented as range of cost per routine outcome ..................................10

13. Summary of regulatory status of the medicine ................................................................................ 10 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia,

United States Pharmacopoeia) ................................................................................................................... 11 15. Proposed (new/adapted) text for the WHO Model Formulary: ..................................................... 11


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1. Summary statement of the proposal for inclusion, change or deletion:

This document proposes the inclusion of tenofovir disoproxil fumarate/lamivudine/efavirenz 400 mg

(TLE400) for treatment of HIV-1 infection among adults and adolescents living with HIV/AIDS in the

WHO Essential Medicines List (EML).

The principal reasons for requesting this inclusion are as follows:

According to the 2016 WHO Consolidated Treatment Guidelines, TLE400 provides one of the

alternative regimens for first-line treatment in HIV-infected adults and adolescents.

TLE400 has been shown to be safe and highly effective in a large international clinical trial.

All the component drugs in TLE400 are included either singly or in other fixed dose combinations

(FDCs) in the current EML (i.e., tenofovir disoproxil fumarate/ emtricitabine/efavirenz 600 mg).

By virtue of its lower dose of efavirenz (EFV), TLE400 may reduce the incidence of EFV-related

adverse drug reactions.

In this and other FDC products, lamivudine and emtricitabine have been shown to be equivalent

and interchangeable based on understanding of pharmacology, resistance patterns and results of

clinical trials as noted in prior EML Expert Committee writings.

As an FDC with once-daily dosing, this formulation versus single drug formulations, may:

Help to reduce pill burden

Increase patient adherence to treatment;

Delay the development of resistance;

Lower the total cost, including production, storage, transport, dispensing and other health system costs;

Reduce the risk of medication errors by prescribers, dispensers or patients themselves; and

Simplify and increase security of supply systems

2. Name of the focal point in WHO submitting or supporting the application:

Marco Vitoria, WHO/HTM/HIV/ATC

3. Name of the organization(s) consulted and/or supporting the application:

Clinton Health Access Initiative, Inc. (CHAI)

4. International Nonproprietary Name (INN, generic name) of the medicine:

Lamivudine, tenofovir disoproxil, efavirenz, ATC code: J05AR11

5. Dosage form or strength proposed for inclusion:

Each tablet contains tenofovir disoproxil fumarate 300 mg, lamivudine 300 mg, and efavirenz 400 mg.


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6. International availability - sources, if possible manufacturers:

TLE400 tablets will be available internationally from:

Mylan Laboratories Limited

H-12 & H-13, MIDC,

Waluj, Aurangabad, 431136,

Maharashtra

India

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group:

This medication is an example of the therapeutic group and is proposed for the ‘Antiretrovirals’ category

(6.4.2), ‘Fixed Dose Combinations’.

8. Information supporting the public health relevance

8.1. Epidemiological information on disease burden:

As of 2015, UNAIDS reported there were 36.7 million people were living with HIV/AIDS globally, 2.1

million new HIV-1 infections, and 1.1 million HIV-related deaths. Over 95% of infected people live in

low and middle income countries with inadequate resources to effectively combat the epidemic. While

some countries have achieved declines in new HIV infections among adults of 50% or more, global data

show that many others have not made measurable progress and others have experienced worrying

increases in new HIV infections. Overall, approximately 17 million people were receiving antiretroviral

therapy (ART) in 2015 but this still represents less than half of infected people1.

Early and effective ART not only significantly improves the health of those living with HIV, but also

reduces transmission of the disease as shown in the recently reported START study. For this reason, the

World Health Organization released new guidelines in 2015 calling for treatment for all people with HIV.

Easy to administer, highly effective, safe treatment options remain desperately needed in many areas of

the world in order to meet the UNAIDS 90-90-90 targets, which call for 90 percent of people living with

HIV to know their status, 90 percent of those with known status to be on ART, and 90 percent of those

on ART to be virally suppressed (i.e., on successful therapy) by the year 2020.

TLE400 represents a new antiretroviral (ARV) single tablet regimen FDC comprised of three widely used

and highly effective ARVs that provides a once daily dosing interval and a favorable safety profile. These

attributes make it an attractive regimen for patients first initiating therapy. In their 2015 HIV treatment

guidelines, WHO added TLE400 as an alternative first-line treatment option. The related FDCs

containing tenofovir disoproxil fumarate/emtricitabine/efavirenz 600 mg (TEE600) and tenofovir

disoproxil fumarate/lamivudine/efavirenz 600 (TLE600) were included in the 2015 EML. At that time,

the EML noted, “emtricitabine (FTC) is an acceptable alternative to 3TC, based on knowledge of the

pharmacology, the resistance patterns and clinical trials of antiretrovirals.”

8.2. Assessment of current use:

The therapeutically equivalent FDC TEE400 has been used in a large randomized clinical trial enrolling

636 HIV-infected patients newly initiating treatment, 324 of whom received TEE400. The WHO does not

yet have data on current use of TLE400 as the FDC product is expected to enter the commercial market

in early 2017 in low- and middle-income countries. As noted in 2016 CHAI ARV market analyses, FDCs


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of TEE600 and TLE600 are widely used globally and represent over 80% of first line treatment in

countries with access to generic ARVs (see Figure 1 below). As it is introduced, TLE400 is expected to

gain over 20% of first line treatment by the year 2020.2

Figure 1: Patient Growth and Share of First-Line NNRTI/INSTI Market in LMICs with Generic

Access

Graphic abstracted from Ref. 2.

8.3. Target population:

TLE400 tablets are intended as an alternative first-line treatment for HIV-infected adults and adolescents

(weighing at least 20 kg). At this time, TLE400 is not recommended for use in pregnant women or

patients undergoing TB treatment with a rifampicin-based regimen because data are lacking in these

populations. Because these are important and sizeable subgroups, studies are in progress to evaluate use of

TLE400 in patients requiring TB treatment and in pregnant women.

9. Treatment details

9.1. Reference to existing WHO and other clinical guidelines:

The 2016 WHO Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing

HIV infection recommend TLE400 as an alternative first-line regimen in adult and adolescent patients.3

9.2. Dosage regimen, duration:

The dosage regimen is one TLE400 tablet taken once daily. TLE 400 can be directly substituted for

TLE600 without any need for viral load assessment.

No dose adjustment is needed in patients with either hepatic or renal insufficiency.

TLE400 should be taken on an empty stomach (commonly defined as 1 hour before or 2 hours after a

meal).

Duration of treatment for HIV is expected to be life-long; for as long as the FDC is well-tolerated and

continues to be effective.


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9.3 Need for special diagnostic or treatment facilities and skills:

Not needed.

10. Summary of comparative effectiveness in a variety of clinical settings:

The FDCs TEE600 and TLE600 have been shown to be safe and effective in diverse patient populations

enrolled in multiple clinical trials conducted internationally. These data have been previously reviewed in a

2013 EML dossier for TLE600 and were considered compelling. At that time, both EML Reviewers

recommended inclusion of TLE600 on the EML but a decision was deferred pending completion of WHO

treatment guidelines revisions. In 2015, TEE600 was added to the EML with the notation that emtricitabine

and lamivudine were considered therapeutically equivalent and interchangeable. In an effort to reduce adverse

drug reactions and also reduce cost of treatment, a regimen containing EFV 400mg was evaluated in a large,

randomized clinical trial, the ENCORE1 study.4 This study was funded by the Bill and Melinda Gates

Foundation.

10.1. Summary of available data (appraisal of quality, outcome measures, summary of results)

ENCORE1 was a randomized, double-blind, placebo-controlled, non-inferiority trial that recruited

participants from 38 clinical sites in Argentina, Australia, Chile, Germany, Hong Kong, Israel, Malaysia,

Mexico, Nigeria, Singapore, South Africa, Thailand, and the UK. The objective of the ENCORE1 study

was to compare a reduced-dose ARV regimen containing EFV 400mg to the approved regimen

containing EFV 600mg in terms of efficacy, durability, tolerability and toxicity profile, and emergence of

resistance. All patients received emtricitabine/tenofovir disoproxil fumarate (TE, Truvada®, Gilead

Sciences) at the recommended/approved doses and were randomized to receive either EFV 600mg or

EFV 400mg as three 200mg capsules or two 200mg capsules plus a placebo capsule. Study participants

were monitored for safety and virological and immunological success and the primary efficacy

comparison was performed after 48 weeks of dosing. The study continued after the primary analysis and

results have now been reported through 96 weeks of dosing. Safety analyses included clinical and

laboratory adverse events. The key efficacy analysis was the comparison of the proportion of participants

in each treatment arm with a plasma HIV-1 viral load less than 200 copies per mL at week 96.

Overall, 636 eligible participants were enrolled in ENCORE1 and randomly assigned to the two

treatment arms. Cohorts of 321 in the 400mg arm and 309 in the 600mg arm (N=630) received at least

one dose of study drug and attended one follow-up visit and made up the modified intention-to-treat

(MITT) population at week 96. Baseline demographic and disease characteristics were similar in the two

arms. At week 96, the MITT analysis showed that 289/321 (90.0%) patients in the EFV 400mg arm and

280/309 (90.6%) in the 600mg arm had a plasma HIV-1 viral load less than 200 copies per mL

(difference –0.6% [95% CI –5.2 to 4.0]; relative risk 0.99 [95% CI 0.94 to 1.05]), which met the pre-

specified non-inferiority criteria (see Figure 2).4 As shown in the figure, efficacy results were consistent

across different analysis populations (MITT, non-completer=failure, or per protocol) and endpoint

measurements (viral load <50 copies/mL) and regardless of viral load strata (<100,000 copies/mL or

>100,000 copies/mL). The investigators also noted that mean change from baseline to week 96 in log10

plasma HIV-1 viral load did not differ between the arms in the MITT analysis (EFV 400mg –3.0 [95% CI

–3.09 to –2.92] compared to EFV 600mg –2.98 [–3.07 to –2.89]; difference –0.02 [–0.14 to 0.10] (see

Figure 3).4 In addition, ENCORE1 found no association between rapid metabolizer single nucleotide

polymorphisms (SNPs) and treatment failure at 96 weeks.5


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Figure 2: Results of non-inferiority comparisons at week 96 of HIV RNA viral load less than 200

copies per mL and less than 50 copies per mL by population and baseline HIV RNA strata

The x-axis is the diff erence in the percentage of patients with plasma viral HIV RNA load less than 200 copies per

mL or less than 50 copies per ml. Point estimates are the diff erence in the percentage of participants with viral load suppression less than 200 copies and less than 50 copies per mL at week 96. The primary comparison (circle) is stratified by plasma HIV RNA strata at screening (≤100 000 copies per mL [open diamond] vs >100 000 copies per mL [black diamond]) and is presented for modified intention-to-treat, NC=F, and per-protocol populations. The dotted vertical line at –10% is the non-inferiority boundary. NC=F represents noncompleter=failure. *Error bars

are 95% Agresti-Caffo exact CIs for point estimates. The test for interaction is presented for viral load strata only. Source: Ref 4.


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Figure 3: Mean change in HIV RNA viral load from baseline to week 96 for the modified

intention-to-treat population

Plotted points are mean log10 copies per mL; error bars are SDs. Source: Ref 4

One of the key secondary endpoints in ENCORE1 was change in CD4 cell count over the study period. Mean CD4 cell counts increased in both cohorts, however, the mean change was significantly higher in the EFV 400mg arm. At week 96, mean change from baseline was 235 cells per μl (95% CI 218–252) in the EFV 400mg arm and 209 cells per μl (194–226) in the 600mg arm (see Figure 4).4 In their discussion,

the investigators note the clinical significance of this difference is unclear. However, they suggest the observation is consistent with previously reported EFV-mediated lymphocyte toxicity.


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Figure 4: Mean change in CD4 T cells from baseline to week 96 for the modified intention-to-treat population

Plotted points are mean cells per μl; error bars are SDs. Source: Ref 4.

These analyses support the efficacy and durability of TEE400 treatment in patients initiating their first ARV regimen and because of the accepted therapeutic equivalence of FTC and 3TC, consequently, support the use of TLE400.

10.2. Summary of available estimates of comparative effectiveness

Antiretroviral therapy generally requires the use of three or more active drugs. Including all drugs of an

optimal ARV regimen in an FDC is expected to have a number of benefits which TLE400 provides:

Allows for once-daily dosing using one pill, reducing the pill-burden;

Delays the development of resistance;

Lowers the total cost, including production, storage, transport, dispensing and other health system costs compared to single products;

Increases patient adherence to treatment with the combination of attributes listed above.

Both 3TC and FTC have been proven to be effective when used as part of once-daily, three-drug

regimens. Although head-to-head comparisons of once daily 3TC to once daily FTC have not been

conducted, available evidence suggests that once-daily 3TC and FTC are equivalent with respect to

clinical efficacy and safety. Based on the available data, both WHO Treatment Guidelines and the U.S.

FDA accept the therapeutic equivalence of 3TC and FTC.


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11. Summary of comparative evidence on safety:

11.1. Estimate of total patient exposure to date

Tenofovir disoproxil fumarate, lamivudine, and efavirenz, in a variety of combinations including TEE600

and TLE600, have been used extensively as first line therapy in HIV-infected adults and adolescents. To

date, the TLE400 FDC has not been used in a clinical setting but the closely related TEE400 regimen (as

TE plus EFV) has been used in the ENCORE1 clinical trial described in Section 10.1 above for a

reported duration of 96 weeks.

11.2. Description of adverse effects/reactions

The overall safety profile of TEE600 and TLE600 in adults compared favorably to other ARV regimens

and was reviewed in detail in past Expert Committee proceedings. This dossier will focus on the safety

data to support use of the reduced dose of efavirenz contained in TLE400 and generated in the

ENCORE1 clinical trial.

Over 90% of study participants in both treatment arms experienced at least one adverse event. Most of

these reported events were deemed to be mild (73%) or moderate (22-23%) and the numbers of severe

events were similar and small in both arms (5-6%). More patients in the EFV 600mg arm experienced an

adverse event considered related to EFV and, of those patients, a higher proportion discontinued EFV

because of their treatment-related event (see Table 1).4 Otherwise, the pattern and numbers of adverse

events reported in both arms was similar. The most common adverse events were dizziness, upper

respiratory tract infection, and rash; when events were grouped according to System Organ Class, the

SOCs most frequently involved were infections and infestations, gastrointestinal (GI) disorders, and

vascular disorders.

Table 1: Adverse events and serious adverse events

Source: Ref 4.

Overall, these data confirm that the safety and tolerability of TEE400, and by extrapolation TLE400, are

acceptable in a variety of international patient populations. These data also support the original

hypothesis that the reduced dose of EFV 400mg may lead to fewer EFV-related adverse drug reactions.


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11.3. Drug Interactions

Both TDF and EFV have drug interactions that have been well characterized and reviewed by the Expert

Committee at the time of review of the TEE600/TLE600 dossier. These interactions are expected to be

similar for TLE400. There is not sufficient data available to determine whether the reduced dose of EFV

in TLE400 will modify the known drug interactions attributed to EFV 600mg. Neither FTC nor 3TC are

expected to have significant drug interactions.

11.4. Identification of variation in safety due to health systems and patient factors

No specific safety issues associated with TLE400 are expected to pose a differential risk in the

international health setting. No specific laboratory safety monitoring is required for safe use.

12. Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group:

12.1. Range of costs of the proposed medicine

**Price per patient per year based on WHO dosing guidelines; 365 days a year **Given variation in MSF reference prices, obtained average of reference prices of 3TC and EFV singles across all generic suppliers (excluding Aspen since it primarily supplies South Africa) ***Mylan agreed to make TLE400 available for $99/pppy per CHAI/UNAIDS press release in November 2015, subject to regulatory approval; potential further refinement to price expected

12.2. Comparative cost-effectiveness presented as range of cost per routine outcome

Mylan has initially committed to make TLE400 available at $99 PPPY or up to 8 percent less than the TLE600 triple FDC price. Since TLE400 is still under FDA review, the launch price is to be determined. As shown in table 12.1, the current price of the TLE400 triple FDC is slightly lower than the TLE600 triple FDC in PPPY terms at the commodity level. Since lower-dose EFV has been shown to be non-inferior to and have fewer treatment-limiting side effects than EFV 600mg, it is expected to yield moderate cost-savings at the broader health systems level as well.

Although the average cost (PPPY) of the triple FDC is higher than the dual FDC and single combination for both EFV 400mg and EFV 600mg, it is expected to encourage stronger adherence with its lower pill burden, thereby improving health outcomes, which in turn could reduce health systems level costs.

13. Summary of regulatory status of the medicine

The FDA is currently reviewing TLE400 for "tentative approval" as part of the President's Emergency Plan

for AIDS Relief (PEPFAR) drug review program for use in resource-limited countries. A final decision is

expected sometime in early 2017.

SourcePrice/Unit

(USD)

PPPY

(USD)*

Price/Unit

(USD)

PPPY

(USD)*

Price/Unit

(USD)

PPPY

(USD)*

Price/Unit

(USD)

PPPY

(USD)*

Médecins Sans Frontières Price, July 2016** n/a n/a $0.229 $84 $0.292 $106 $0.237 $87

Global Fund Pricing, July 2016 n/a n/a $0.264 $96 $0.266 $97 $0.248 $91

CHAI Reference Price, 2016*** $0.271 $99 n/a n/a $0.273 $100 $0.263 $96

Average of reported prices $0.271 $99 $0.246 $90 $0.277 $101 $0.250 $91

TDF/3TC/EFV FDC

Tablet (300/300/400mg)

TDF/3TC Tablet

(300/300mg) + EFV

Capsule (200mg) +

EFV Capsule (200mg)

TDF/3TC/EFV FDC

Tablet

(300/300/600mg)

TDF /3TC Tablet

(300/300mg) + EFV

Tablet (600mg)


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14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia,

United States Pharmacopoeia)

Tenofovir disoproxil fumarate, lamivudine, and efavirenz are all listed individually in the International

Pharmacopoeia Sixth Edition.

15. Proposed (new/adapted) text for the WHO Model Formulary:

Tenofovir/lamivudine/efavirenz 400

Dosage forms: fixed dose combination tablet containing tenofovir disoproxil fumarate 300mg, lamivudine

300mg, and efavirenz 400mg


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References

1. “AIDS by the numbers — AIDS is not over, but it can be.” UNAIDS. November, 2016,

http://www.unaids.org/en/resources/documents/2016/AIDS-by-the-numbers.

2. ARV Market Report: The State of the Antiretroviral Drug Market in Low- and Middle-Income Countries,

2015-2020. Clinton Health Access Initiative, Inc. Issue 7, October, 2016.

3. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection:

recommendations for a public health approach. World Health Organization. June, 2016,

http://www.who.int/hiv/pub/arv/arv-2016/en/.

4. ENCORE1 Study Group. “Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week

data from the randomized, double-blind, placebo-controlled, non-inferiority ENCORE1 study.” Lancet

Infect Dis 2015; 15: 793–802.

5. Dickinson L, Amin J, Else L, et. al. “Pharmacokinetic and pharmacodynamic comparison of once-daily efavirenz (400 mg vs. 600 mg) in treatment-naıve HIV-infected patients: results of the ENCORE1 study. Clin Pharmacol and Therapeutics 2015; 98: 406-416.

http://www.unaids.org/en/resources/documents/2016/AIDS-by-the-numbers

http://www.who.int/hiv/pub/arv/arv-2016/en/

Documents

WHO | World Health Organization - Information to be included with … · The 2016 WHO Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection