WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

Application for Inclusion of Raltegravir Powder on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

Table of Contents General Information ...... 3 1. Summary statement of the proposal for inclusion...... 3 2. Name of the organization consulted and/or supporting the application: ...... 3 3. International Nonproprietary Name (INN, generic name) of the medicine ...... 3 4. Formulations and strengths proposed for inclusion ...... 3 5. International availability- sources-if possible, manufacturers ...... 3 6. Whether the listing is requested as an individual medicine or as a representative of a pharmacological class ...... 3 Information supporting the public health relevance ...... 4 7. Epidemiological information on disease burden: ...... 4 8. Assessment of current use ...... 5 9. Target population ...... 5 Treatment details, public health relevance and evidence appraisal and synthesis ...... 5 10. Reference to existing WHO and other clinical guidelines: ...... 5 11. Dosage regimens and duration ...... 5 Table 1: Recommended Dose for Raltegravir Powder for Oral Suspension in Full-Term Neonates (Birth to 4 Weeks [28 days] of Age) ...... 5 Table 2: Recommended Dosage* for Raltegravir Powder for Oral Suspension in Pediatric Patients at Least 4 Weeks of Age and Weighing at Least 3 kg and Less than 20 kg ...... 6 12. Need for special diagnostic or treatment facilities and skills ...... 6 Review of benefits: summary of comparative effectiveness in a variety of clinical settings ...... 6 Review of harms and toxicity: summary of the evidence on safety ...... 7 13. Description of adverse effects/reactions ...... 7 14. Identification of variation in safety due to health systems and patient factors ...... 8 15. Summary of comparative safety against comparators ...... 8 Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group ...... 8 16. Range of costs of the proposed medicine...... 8 Table 3: Price per Unit and Price per Patient per Year for RAL and other First-Line Products ...... 8 Summary of regulatory status of the medicine ...... 9

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Availability of pharmacopoeial standards (British, International, US, European) ...... 9 Proposed text for WHO model formulary ...... 9 Table 1: Recommended Dose for Raltegravir Powder for Oral Suspension in Full-Term Neonates (Birth to 4 Weeks [28 days] of Age) ...... 10 Table 2: Recommended Dosage* for Raltegravir Powder for Oral Suspension in Pediatric Patients at Least 4 Weeks of Age and Weighing at Least 3 kg and Less than 20 kg ...... 10 References: Comprehensive reference list and in-text citations...... 10

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General Information 1. Summary statement of the proposal for inclusion This document proposes the inclusion of raltegravir powder for oral suspension, 100 mg, in both the WHO Essential Medicines List (EML) and the WHO Essential Medicines List for Children (EMLc), for treatment of HIV among infants and children living with HIV/AIDS. The principal reasons for requesting this inclusion are as follows:  Raltegravir (RAL) represents the first approved drug in the new class of integrase strand transfer inhibitors (INSTIs or integrase inhibitors).  Dosing recommendations were recently approved for use of RAL powder for oral suspension in neonates weighing as little as 2 kg. Very few antiretroviral drugs have dosing recommendations for this age and weight and alternative ARVs have significant drawbacks.  Updated recommendations on first- and second-line HIV therapy by the WHO published in July 2018 state that a RAL-based regimen may be recommended as a preferred first-line regimen for neonates and as an alternative first-line regimen for infants and children for whom approved dolutegravir dosing is not available.

Name of the focal point in WHO submitting or supporting the application Martina Penazzato, WHO/HTM/HIV/ATC 2. Name of the organization consulted and/or supporting the application: Clinton Health Access Initiative (CHAI)

3. International Nonproprietary Name (INN, generic name) of the medicine Raltegravir, ATC code: J05AX08

4. Formulations and strengths proposed for inclusion Raltegravir powder for oral suspension, 100mg/packet

5. International availability- sources-if possible, manufacturers Merck Sharp & Dohme Ltd manufactures Merck Sharp & Dohme Limited Hertford Road Hoddesdon Hertfordshire EN11 9BU

6. Whether the listing is requested as an individual medicine or as a representative of a pharmacological class This medication is currently included in the ‘Antiretrovirals’ category (6.4.2), in the category: ‘Integrase inhibitors’ (6.4.2.4). Inclusion of this new pediatric formulation is proposed as an update to the current listing.

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Information supporting the public health relevance 7. Epidemiological information on disease burden: In 2017, UNAIDS reported there were 36.9 million people living with HIV/AIDS globally, 1.8 million new HIV-1 infections, and 940,000 thousand HIV-related deaths1. Over 95% of infected people live in low and middle income countries (LMIC) 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 21.7 million people were receiving antiretroviral therapy (ART) in 2017, but this is estimated to represent only 59% of HIV 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 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. Despite an impressive reduction in mother to child transmission of HIV in recent years, 180,000 new pediatric infections occurred in 2017. There are now 1.8 million children living with HIV, the vast majority in sub-Saharan Africa. Evidence shows that in the absence of ART, over 50% of HIV-infected infants progress to AIDS or death by the age of 2 years2, but the introduction of pediatric ART has changed HIV infection in children from a life-threatening illness to a chronic-but-manageable infection. Despite recognition of the advantages of early treatment, pediatric treatment coverage still only reaches 52% of children eligible for treatment1 and in 2017 an estimated 110,000 HIV/AIDS related deaths occurred in children <15 years of age3. However, with increasing evidence about the beneficial effects of earlier ART initiation and the release of the 2016 WHO Consolidated Guidelines, new recommendations stress the need for early testing and treatment for all infants and children living with HIV. Scaling up early infant testing (including testing at birth) to identify perinatal transmission will allow many more infants to receive life-saving ARVs within the first few weeks of life. Since 2014 and as led by UNAIDS, the global community has set a target to end the AIDS epidemic by 2030, but the particular vulnerabilities of pediatric patients necessitate an even more ambitious goal - ending pediatric AIDS by 2020.4 This super fast-track target aim to reach 1.6 million children with ART by 2018. In order to successfully scale-up treatment of pediatric HIV infection, it is critical that ARV dosage forms for the most effective drugs are appropriate for use in infants and young children and are accessible, particularly in resource limiting settings. Dispersible solid dosage forms including chewable tablets have proven to confer an advantage over liquid dosage forms for older children unable to swallow tablets, and both pellets/mini tablets and granules/powders have been developed for younger children and infants. Recent years has seen the development of a variety of dosage forms for pediatric ARVs but, compared to the demand for adult ARVs, children account for just 5% of patients on ART, thereby rendering the global pediatric market smaller and more vulnerable to supply disruption. The IATT Optimal Pediatric ARV Formulary and Limited-use List was first developed in 2011 to address this challenge and now provides guidance to streamline the selection of pediatric ARV dosage forms to those that conform to a list of criteria, including dosing flexibility, user-friendliness, optimization of supply chain management, and availability of quality assured products in resource limited settings. The IATT Optimal Formulary is also revised on a regular basis to reflect current WHO recommended regimens, most recently in 2018.

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8. Assessment of current use RAL has been widely used in treatment for HIV-infected adults in the U.S. and Europe, for treatment- experienced patients, and more recently for those starting ART. In LMIC, use of RAL-containing regimens is still limited. According to a WHO survey on ARV use in LMICs, approximately 25,000 people with HIV on ART are using RAL in those settings, mostly as third-line therapy. These estimates were made prior to the updated 2018 WHO guidelines recommending RAL as first-line therapy for neonates and potentially other pediatric age group.5 However, the number of infants expected to use RAL powder is expected to be small.

9. Target population The target population for RAL powder for oral suspension includes neonates (infants from birth through 4 weeks of age) and young infants beginning ARV treatment. Older pediatric populations receiving RAL will likely receive it as the chewable tablets already included on the EML and EMLc.

Treatment details, public health relevance and evidence appraisal and synthesis 10. Reference to existing WHO and other clinical guidelines: The 2018 WHO Updated Recommendations on First-line and Second-line Antiretroviral Regimens and Post- exposure Prophylaxis and Recommendations on Early Infant Diagnosis of HIV state that a RAL-based regimen may be recommended as a preferred first-line regimen for neonates and that a RAL-based regimen may be recommended as an alternative first-line regimen for infants and children for whom preferred first- line dolutegravir dosing is not yet available.6 In addition, the 2018 edition of the Limited-use List, which identifies key ARVs that are needed for a limited time or in small volumes, includes RAL powder for suspension for use in neonates.5

11. Dosage regimens and duration Raltegravir must always be given in combination with other antiretrovirals. The recommended doses for RAL powder for oral suspension in neonates and young infants is based on both weight and age and is measured as the reconstituted suspension as shown in Tables 1 and 2 below: Table 1: Recommended Dose for Raltegravir Powder for Oral Suspension in Full-Term Neonates (Birth to 4 Weeks [28 days] of Age)

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Table 2: Recommended Dosage* for Raltegravir Powder for Oral Suspension in Pediatric Patients at Least 4 Weeks of Age and Weighing at Least 3 kg and Less than 20 kg

*The weight-based dosing recommendation for the chewable tablet and oral suspension is based on approximately 6 mg/kg/dose twice daily

The following general instructions for dosing RAL powder for oral suspension are provided in the package insert (a reliable source of clean water is required):  Using the provided mixing cup, combine 10 mL of water and the entire contents of one packet of RAL powder for oral suspension and mix. Each single-use packet for oral suspension contains 100 mg of RAL which is suspended in 10 mL of water giving a final concentration of 10 mg per Mr. Maximum daily dose is 100 mg taken by mouth twice daily.  Gently swirl the mixing cup for 45 seconds in a circular motion to mix the powder into a uniform suspension. Do not shake.  Once mixed, measure the prescribed dose volume of suspension with a syringe and administer the dose orally. The dose should be administered orally within 30 minutes of mixing.  Discard any remaining suspension into the trash.  Package insert contains pictorial Instructions for Use for caregivers mixing the suspension. Use in hepatic impairment: Dosage adjustment is not needed in patients with mild to moderate hepatic impairment (Child-Pugh score A or B). Pharmacokinetics of RAL have not been studied in patients with severe hepatic impairment (Child-Pugh score C). Use in renal impairment: Dosage adjustment is not needed in patients with renal impairment.

12. Need for special diagnostic or treatment facilities and skills No special diagnostic or treatment facilities are needed, initiating therapy in infants requires only confirmation of HIV infection using testing as described for early infant diagnosis in national guidelines.

Review of benefits: summary of comparative effectiveness in a variety of clinical settings RAL has been shown to be safe and effective in diverse patient populations enrolled in multiple clinical trials conducted internationally.7,8,9,10,12,13 Comparative effectiveness is described based on information gathered from literature search, review of the current U.S. package insert for Isentress® (RAL, Merck)11 and review of the U.S. FDA Clinical Review of Isentress (raltegravir sodium). The data supporting general effectiveness of RAL in adults was submitted to the EML expert panel at the time of previous application and will not be repeated. Only effectiveness information relevant to the use of RAL powder for oral suspension will be

6 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION reviewed in this document. As the pediatric clinical trials were single-arm studies, pediatric comparative efficacy information is not available. Approval of RAL in pediatric patients was based on IMPAACT P1066, a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of RAL in HIV infected children.14 This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Of the 126 enrolled, 96 children received the ultimately approved dose. Of those who received the approved dose, 93 (97%) subjects 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 66% achieved HIV RNA <400 copies/ml. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%). The safety and pharmacokinetics of RAL powder for oral suspension were evaluated in 42 full-term HIV-1- exposed neonates at high risk of acquiring HIV-1 infection in a Phase 1, open-label, multicenter clinical study (IMPAACT P1110). Cohort 1 neonates received 2 single doses of RAL powder for oral suspension: the first within 48 hours of birth and the second at 7 to 10 days of age. Cohort 2 neonates received daily dosing of RAL powder for oral suspension for 6 weeks: 1.5 mg/kg once daily starting within 48 hours of birth through Day 7 (week 1); 3 mg/kg twice daily on Days 8 to 28 of age (weeks 2 to 4); and 6 mg/kg twice daily on Days 29 to 42 of age (weeks 5 and 6). Sixteen neonates were enrolled in Cohort 1 and 26 in Cohort 2; all infants received a standard of care antiretroviral drug regimen for prevention of mother to child transmission. All enrolled neonates were followed for safety for a duration of 24 weeks. HIV-1 status was assessed by nucleic acid test at birth, week 6 and week 24 and all remained HIV-1 negative.11 IMPAACT P1066 also enrolled HIV-infected infants and toddlers 4 weeks to less than 2 years of age who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission and/or as combination antiretroviral therapy for treatment of HIV infection. RAL was administered as the powder for oral suspension without regard to food in combination with an optimized background regimen. None of the enrolled subjects were completely treatment naïve (all had prenatal/in utero ARV exposure or post-natal prophylaxis or treatment). Of the 26 treated subjects, 24 subjects were included in the Week 48 efficacy analyses. All 26 treated subjects were included for safety analyses. At Week 48, 45% achieved HIV RNA <50 copies/mL and 67% achieved HIV RNA <400 copies/Mr. The mean CD4 count (percent) increase from baseline to Week 48 was 527 cells/mm3 (7.3%).15 A recent follow-up publication reports the outcomes of those patients receiving RAL at the final selected doses through 240 weeks of treatment. In this analysis, 13 of 15 infants receiving RAL oral granules for 240 weeks achieved virologic success (>1 log decrease in HIV RNA from baseline or HIV RNA <400 copies/mL).16 RAL powder for oral suspension is not recommended in pre-term neonates or in pediatric patients weighing less than 2 kg.11

Review of harms and toxicity: summary of the evidence on safety 13. Description of adverse effects/reactions The safety and tolerability profile of RAL is favorable. The most common adverse events noted in adults receiving RAL were abdominal distension, diarrhea, nausea, vomiting, fatigue, pyrexia, and headache. Overall, the safety profile in pediatric patients, including neonates, is similar to that observed in adults. RAL is metabolized primarily by UGT1A1 (the same metabolic pathway as bilirubin) and UGT1A1 activity is greatly reduced in neonates. Concerns regarding potential competition with bilirubin for albumin binding sites and resulting jaundice in infants have not been borne out. The dose recommended in neonates takes into consideration the rapidly increasing UGT1A1 activity and drug clearance in this age group.11 Severe, potentially life-threatening, and fatal skin reactions have been reported rarely. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported

7 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. RAL should be discontinued if these events occur. Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with RAL. Myopathy and rhabdomyolysis have been reported. RAL should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

14. Identification of variation in safety due to health systems and patient factors No clinically significant differences in safety have been identified due to differences in health systems and patient factors.

15. Summary of comparative safety against comparators During the adult registrational trials, headache was the only adverse reaction of moderate to severe intensity occurring in >2% of patients receiving RAL and more than in comparison group. The rates of discontinuation due to adverse events were 4% in subjects receiving RAL and 5% in subjects receiving optimized therapy. As the pediatric clinical trials were single-arm studies, pediatric comparative safety information is not available. However, the overall safety of RAL in pediatric patients, including neonates, was noted to be similar to that observed in adults.

Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group 16. Range of costs of the proposed medicine As illustrated in Table 3 below, the Médecins Sans Frontières (MSF) price per patient per year (PPPY) for RAL (100 mg) Granules is US$260.

Table 3: Price per Unit and Price per Patient per Year for RAL and other First-Line Products RAL (100 mg) LPV/r (80/20 AZT/3TC/NVP Granules mg/ml) Oral Solution (60/30/50 mg) Dispersible Tablet Reference Price Source Price/Unit PPPY* Price/Unit PPPY* Price/Unit PPPY*

Global Fund PPM, July - - $.103 $94 $.050 $45.63 2018 GHSC-PSM, - - $.103 $94 $.048 $43.80 August 2018 MSF, July $0.95 $260 $.103 $94 $.050 $45.63 2018 Average $0.95 $260 $.103 $94 $.049 $45.02 All prices in USD. Please note that the GHSC-PSM prices are not reference prices but represent the latest blended average pricing of actual procurement

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*Price per patient per year based on WHO dosing guidelines for the 3.0 - 9.9kg weight band (recommended weight band for RAL (100 mg) Granules), 365 days a year

In the WHO’s 2018 updated recommendations on first-line and second-line antiretroviral regimens, RAL- based regimens are recommended as preferred treatment (with AZT+3TC) for neonates, alternative treatment for children, and used “for the shortest time possible, until a solid formulation of LPV/r or DTG can be used.”6 In the WHO’s 2018 optimal formulary and limited-use list for paediatric ARVs, RAL (100 mg) granules are listed as “limited-use” for the time-limited treatment of neonates. However, as the table above illustrates, RAL powder for oral suspension (100 mg) is more expensive than other options for treating infants and young children. However, both of the alternative ARVs for this age group have significant challenges. LPV/r oral solution has very poor palatability and requires refrigeration. NVP-based regimens are generally less effective than other regimens at suppressing viral replication and this problem is exacerbated by rapidly increasing rates of transmitted NNRTI resistance among perinatally infected infants.17 At the time of submission, no cost-effectiveness analyses or special pricing arrangements have been conducted for RAL (100 mg) granules. However, there may be indirect cost savings compared to LPV/r (80/20 mg/ml) oral solution as the RAL (100 mg) granules do not require cold chain storage (unlike the LPV/r oral solution).

Summary of regulatory status of the medicine Raltegravir powder for oral suspension (produced by Merck Sharp & Dohme Corporation) was approved by the US FDA for use in neonates and young infants in December 2013 and by the EMA in June 2018.

Availability of pharmacopoeial standards (British, International, US, European) Raltegravir is available in the United States Pharmacopoeia. RAL is not available in the International Pharmacopoeia.

Proposed text for WHO model formulary The following information should be added to the current model formulary listing for RAL: Dosage forms: RAL powder for oral suspension (100mg/packet) Uses: Treatment of HIV in combination with at least two other antiretrovirals. A RAL-based regimen may be recommended as a preferred first-line regimen for neonates and as an alternative first-line regimen for infants and children. In pediatric patients RAL powder for oral suspension is dosed according to both age and weight as shown in the tables below.

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Table 1: Recommended Dose for Raltegravir Powder for Oral Suspension in Full-Term Neonates (Birth to 4 Weeks [28 days] of Age)

Table 2: Recommended Dosage* for Raltegravir Powder for Oral Suspension in Pediatric Patients at Least 4 Weeks of Age and Weighing at Least 3 kg and Less than 20 kg

*The weight-based dosing recommendation for the chewable tablet and oral suspension is based on approximately 6 mg/kg/dose twice daily

Adverse effects: Overall, the safety profile in pediatric patients, including neonates, is similar to that observed in adults and older children.

References: Comprehensive reference list and in-text citations. 1. Global AIDS Update 2018 – Miles to Go, Breaking Barriers, Righting Injustices. UNAIDS. August 2018, http://www.unaids.org/sites/default/files/media_asset/miles-to-go_en.pdf 2. Newell ML, Coovadia H, Cortina-Borja M, et.al. “Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis.” Lancet. 2004 Oct 2-8;364(9441):1236-43. 3. UNAIDS Core Epidemiology Slides. UNAIDS. July 2018, http://www.unaids.org/en/resources/documents/2018/core-epidemiology-slides. 4. Start free, stay free, AIDS free: A super-fast-track framework for ending aids in children, adolescents and young women by 2020. UNAIDS, 2016, https://free.unaids.org. 5. The 2018 Optimal Formulary and Limited-Use List for paediatric ARVs. Geneva, Switzerland: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. http://apps.who.int/iris/bitstream/handle/10665/273153/WHO-CDS-HIV-18.15-eng.pdf?ua=1

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6. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.18). Licence: CC BY-NC-SA 3.0 IGO. http://apps.who.int/iris/bitstream/handle/10665/273632/WHO-CDS-HIV-18.18-eng.pdf?ua=1 7. Steigbigel RT, Cooper DA, Teppler H, et al. “Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug- resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials.” Clin Infect Dis. 2010 Feb 15;50(4):605-12. 8. Gatell JM, Katlama C, Grinsztejn B, et al. “Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study.” J Acquir Immune Defic Syndr. 2010 Apr 1;53(4):456-63. 9. Steigbigel RT, Cooper DA, Kumar PN, et al. “Raltegravir with optimized background therapy for resistant HIV-1 infection.” N Engl J Med. 2008 Jul 24;359(4):339-54. 10. Grinsztejn B, Nguyen BY, Katlama C, et al. “Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial.” Lancet. 2007 Apr 14;369(9569):1261-9. 11. Isentress U.S. package insert. U.S. Food and Drug Administration. March, 2018, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022145s038,205786s007,0203045s015lbl.p df 12. Amin J, Boyd MA, Kumarasamy N, et al. “Raltegravir non-inferior to nucleoside-based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomized open label study for the treatment of HIV-1 infection.” PLoS ONE. 2015;10(2): e018228. 13. Paton NI, Kityo C, Hoppe A, et al. “Assessment of second-line antiretroviral regimens for HIV therapy in Africa.” N Engl J Med. 2014:371:234-47. 14. Nachman S, Zheng N, Acosta EP, et al. “Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years.” Clin Infect Dis. 2014 Feb;58(3): 413-422. 15. Nachman S, Alvero C, Acosta E, et al. “Pharmacokinetics and 48-week safety and efficacy of raltegravir for oral suspension in human immunodeficiency virus type-1-infected children 4 weeks to 2 years of age.” J Ped Infect Dis Soc. 2015 Feb;4(4): e76-e83. DOI:10.1093/jpids/piu146 16. Nachman S, Alvero C, Teppler H, et al. “Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial.” Lancet HIV 2018; e715-22. https://www.thelancet.com/pdfs/journals/lanhiv/PIIS2352-3018(18)30257-1.pdf 17. Jordan M, Penazzato M, Cournil A, et al. “Human immunodeficiency virus (HIV) drug resistance in African infants and young children newly diagnosed with HIV: A multi-country analysis.” Clin Infect Dis. 2017;65(12):2018–25.

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