a) Paediatric HIV - the disease and the neglected patients

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1 Assessment of R&D Needs for Paediatric Antiretroviral Treatment Acronyms and abbreviations: ART ARV EFV FDC NFV LPV MTCT NNRTI antiretroviral therapy antiretroviral (drug) efavirenz fixed dose combination (drugs) nelfinavir lopinavir mother-to-child transmission (of HIV) non-nucleoside reverse transcriptase inhibitor NRTI nucleoside reverse transcriptase inhibitor PI protease inhibitor PKE pharmacokinetic enhancer PMTCT prevention of mother-to-child transmission (of HIV) UNAIDS Joint United Nations Programme on HIV/AIDS WHO World Health Organization /r low-dose ritonavir Introduction Now seven years into its existence, DNDi has validated its collaborative research model with four new field-relevant treatments for malaria, visceral leishmaniasis, and human African trypanosomiasis now available to millions in endemic countries. We continue to strengthen our R&D portfolio for kinetoplastid diseases with both new chemical entities (NCEs) and combination therapies at discovery, pre-clinical, and clinical trial stages. However, many other infectious diseases continue to plague neglected patients, and significant drug R&D needs still exist. DNDi has been called upon by various organizations, including MSF and UNITAID, to apply our expertise to address the needs for paediatric HIV patients. In 2010, DNDi staff conducted scientific literature review and interviews of selected experts from WHO, MSF, UNITAID and CHAI (The Clinton Health Access Initiative). Initial assessment of the existing gaps in paediatric antiretroviral (ARV) treatments and the R&D priorities has provided the framework to construct a mini-portfolio to address these issues. 1. Background a) Paediatric HIV - the disease and the neglected patients The high mortality rate associated with paediatric HIV infection highlights the vulnerability of the neglected population. It also negatively affects the 2015 Millennium Development Goals-4 (MDG) (two-thirds reduction in mortality rates for children under five) and MDG-6 (halt and begin to reverse the spread of HIV) In 2009, an estimated 2.3 million children under the age of 15 were living with HIV 1 (see Table 1) HIV causes 700 deaths in children every day, mostly in Africa. Although 355,000 children started Antiretroviral (ARV) treatment in 2009, there were 370,000 new infections in the same year. Most (>85%) of infected children are non treated. 2 More than 90% of paediatric infections result from mother-to-child transmission (MTCT) during pregnancy, labor, delivery, or breastfeeding. 1 Page 1 of 15

2 Regionally, Africa accounts for 86% of children living with HIV, 82% of AIDS deaths among children, and 91% of new infections among children. HIV infection has been nearly eliminated in high-income countries thanks to implementation of Prevention of mother-to-child transmission (PMTCT) interventions. (Fig.1) Without treatment, one third of infected children will have died by one year of age, 50% by two years of age 3, and 80% before age 5. 11,12 However if early diagnosis and treatment is provided, HIV-infected infants and children can survive to adolescence and adulthood. Table 1. Number of people living with HIV in 2008 Children HIV in 2008 Adults (<15 years) Total Number of people living with HIV 31.3 million 2.1 million 33.4 million People newly infected 2.3 million million AIDS-related deaths 1.7 million million Source: UNAIDS and WHO, AIDS Epidemic Update, Fig.1. Children (<15 years) living with HIV, 2009 Source: UNAIDS and WHO, AIDS Epidemic Update, b) Mother-to-Child Transmission Perinatal transmission Most children are infected by mother-to-child-transmission (MTCT) during pregnancy, delivery or in postpartum through breastfeeding. Therefore preventing women from acquiring HIV and reducing mother-to-child HIV transmission in HIV-positive pregnant women are most costeffective strategies to prevent children HIV infection. Without intervention, the risk of perinatal HIV Page 2 of 15

3 transmission is up to 30-40% 4. Proven mother-to-child-transmission (PMTCT) interventions can reduce the risk to < 5%. a Two different approaches are proposed by the new 2010 WHO PMTCT guidelines 4 (Annex 2): Lifelong ART for HIV-infected women in need of treatment for their own health, which is also safe and effective in reducing mother to child transmission of HIV. Short-term ARV prophylaxis to prevent MTC transmission during pregnancy, delivery and breastfeeding for HIV-infected women not in need of treatment. Prophylaxis should be given to all newborn for 4-6 weeks and, based on new scientific evidence, during all breastfeeding, if the mother is not under ART. PMTCT coverage UNAIDS recently set the objective to virtually eliminate mother-to-child-transmission by Despite efforts over the past nine years to implement PMTCT programmes, their coverage remains alarmingly low with 47% of pregnant women in need remaining without access. 2 Fig 2. Percentage of pregnant women living with HIV receiving antiretrovirals for preventing mother-to-child transmission of HIV in low- and middle-income countries by region, 2005, 2008 and Source: WHO. Antiretroviral therapy of HIV infection in infants and children: towards universal access: recommendations for a public health approach revision. c) Paediatric Antiretroviral Therapy (ART) In 2010 WHO published updated treatment guidelines 3 including new criteria for treatment initiation based on trial results (Children with HIV Early Antiretroviral Therapy study). 5 Main recommendations are: To establish HIV exposure status at birth or soon after birth (when uncertain) Test infants by 4-6 weeks of age using virological assays (if HIV-exposed) a PMTCT Interventions will decrease the risk to: 20-25% if there is no breastfeeding 15-25% if short course ARV is given before delivery and breastfeeding continued 6% with short course ARV, post partum ARV and 6 months of breastfeeding 2-4% with short course ARV and no breastfeeding 1% with 2 or 3 ARVs + elective C-section and no breastfeeding. Tin Tin Sint. Joint WHO/UNAIDS Informal Consultation with Pharmaceutical Companies, Geneva, 16 December 2008 Page 3 of 15

4 Infants and children < 2 years of age should start ART immediately upon diagnosis, regardless of clinical symptoms, immune status or viral load. Co trimoxazole prophylaxis is still recommended for all HIV exposed children from 4 6 weeks of age. ARV treatment in children (2010 WHO Guidelines) For infected children < 2 years previously exposed to treatment For infected children < 2 years previously exposed to maternal or infant nevirapine (NVP) or other non-nucleoside reverse transcriptase inhibitor (NNRTIs) used for maternal treatment or PMTCT: 3 Children with perinatal HIV infection can acquire drug-resistant virus from their mothers and should not be treated with nevirapine-based combinations. The only current alternative to NNRTIs is the boosted protease inhibitor (PI) lopinavir/ritonavir. Recommended regimens contain: lopinavir/ritonavir (LPV/r) + 2 nucleoside reverse transcriptase inhibitor (NRTIs) - The 2 NRTIs (the nucleoside backbone) should be one of the following, in preferential order: Lamivudine (3TC) + zidovudine (AZT) or 3TC + abacavir (ABC) or 3TC + stavudine (d4t) Stavudine is no longer recommended due to tolerability concern b For infected children not previously exposed to treatment For infected children not previously exposed to ARVs or older than 2 years the recommended regimens contain: NNRTI + 2 NRTIs - NNRTIs will be Nevirapine (NVP) or Efavirenz (EFV), if the child is older than 3 years. Second-line regimens Lopinavir/ritonavir in co-formulation is the preferred protease inhibitor (PI) for second-line regimen in children. It is the only available PI that can be administered to infants since birth, because of the availability of a paediatric formulation and the extensive experience in this population. Other PIs are only approved for children older than 2 years of age (Fosamprenavir, Tripanavir) or older than 6 years (Atazanavir, Darunavir). Etravirine, a new NNRTI and new families of Integrase inhibitors (Raltegravir) or entry inhibitors (Marivoc) are not registered for children, since they were only tested on adults. Summary tables with recommended paediatric ART regimens and cost of regimens with available FDCs are presented in Annex 3-5. b Lipoatrophy and lactic acidosis. In addition, peripheral neuropathy, elevated hepatic transaminases and pancreatitis have been observed. Page 4 of 15

5 Children ART Coverage Access to early testing and treatment in children exposed to HIV in low- and middle-income countries remains insufficient. In 2009: 2 Only 15% of these children received an HIV virological test within the two first month of life. The number of children below the age of 5 years on ART rose from 275,300 in 2008 to 356,400 in 2009, but still only represents a 28% of the 1,270,000 children estimated in need, compared to 37% coverage in adults. Huge regional variation exists, even between African countries. By December 2009, the coverage among children was 26% for sub-saharan Africa although it reached 70% or higher in Swaziland, Namibia and Botswana. (Fig 3 and Annex 4) Fig 3. Percentage of children living with HIV receiving antiretroviral therapy in low- and middleincome countries, 2005, 2008 and 2009 Source: WHO. Antiretroviral therapy of HIV infection in infants and children: towards universal access: recommendations for a public health approach revision. Page 5 of 15

6 2. ART to children in low resource regions a) Challenges of paediatric ART HIV infection in children has specific characteristics that hinder treatment implementation. - Maternal HIV antibodies are passively transferred to the infant during pregnancy and may persist during the 1srt year of life (and exceptionally beyond). Therefore diagnosis of HIV infection in children under 18 months requires high technology virological testing c often absent in poor resource settings. - Children have different viral and immunological responses than adults. HIV infection in children present higher viral loads and mortality with more rapid disease progression and greater risk of central nervous system disease than in adults. - Children may develop virologic failure more rapidly: reports from Africa documented rates as high as 26% at 12 months of ART compared to 14% in adults. 6 ARVs used in children need to be robust with high genetic barrier. - Younger children require higher doses of ARV than adults because of their high drugs metabolism and need changing dose as they develop. Drugs will often need to be given twice a day as oppose to once daily in adults. - Children treatment brings specific issues of toxicity related to maturation, development and long-term therapy. - There is limited availability of affordable and practical paediatric ARV dosage/ formulations: Fewer ARV approved in children than in adults More costly than adult preparations The first paediatric 3-in-1 FDC just became available in 2007, many years later than adult version. 9 Issues in current treatments for children First line for not previously exposed children differs from first line in adults that is once daily FDC: [Tenofovir (TDF)/Emtricitabine (FTC)/Efavirenz (EVF)]. The main reason is the lack of studies of safety for EFV and TDF: - EFV in place of nevirapine (NVP) is recommended for the treatment of Tuberculosis/HIV coinfected patients to avoid NVP interaction with rifampicin. However EFV is still not approved for children less than 3 years. d - TDF is not approved for use in children less than 12 years (Tanner stage 1 3) 3 because of insufficient research on safety and toxicity and concerns related to bone and renal toxicity in younger children. e c HIV DNA on whole blood specimen or dried blood spots (DBS), HIV RNA on plasma or DBS, ultrasensitive p24 antigen (Up24 Ag) on plasma or DBS. d BMS studies age group 3 months - 6yrs end 2016/ IMPAACT P1070 Dose finding and PK of EFV in HIV and HIV/TB infected infants. <3 yrs end 2010 Page 6 of 15

7 First line for previously exposed children and second line options: - Early Infant treatment recommended by WHO requires a formulation suitable for breastfeeding children, unable to swallow pills. To date only Lopinavir/ritonavir co-formulation can be administered to children since birth. - LPV/r children tablets (100/25 mg) can only be given to children over 10 kg and cannot be split or crushed. - LPV/r liquid formulation for infants has a number of limitations: o Poor palatability (bitter taste), which may affect adherence to treatment regimen. o The solution contains 42 % alcohol. o Requires refrigeration 2-8 C until dispensing, after which it must be stored below 25 C for 6 weeks. o LPV/r regimens are more expensive than NVP based regimens ($218 to 329 per patient per year compare to $55 to 209 PPY for NVP containing regimens) (Annex 5) o Ritonavir (RTV) is associated with a large number of drug interactions. Today extra-boosting with Ritonavir is given when LPV/r is used in conjunction with rifampicin. - Ritonavir for peadiatric treatment have similar constraint as LPV/r: the 100 mg heat-stable tablet for adults cannot be split or crushed and the RTV liquid requires cold storage, is unpalatable and has significant gastrointestinal intolerance. - Low-dose RTV is also required to achieve adequate drug levels of other protease inhibitors (Fosamprenavir, Tipranavir and Darunavir) f - Protease inhibitors are more robust than NNRTI as resistance requires multiple mutations, clinical, virologic, and immunologic and efficacy is well documented but their long term use is associated to metabolic complications (dyslipidemia, fat maldistribution, insulin resistance). They have the potential for multiple drug interactions due to metabolism via hepatic enzymes (e.g., CYP3A4) and have a higher pill burden than NRTI- or NNRTI-based regimens for those taking solid formulations. b) Challenges of paediatric ART in low resource settings In addition to the specific constraints of ART in children, other obstacles are hampering access of ART to children in low resource settings. Even though some tools became available to help scale up paediatric ART, (FDC 9, simplified approach with dosing by weight bands, increasing access to early diagnosis and WHO advocacy for early treatment) access to ART for children in low and middle income countries remains far behind. e Gilead: study 2-12 yrs done but not published f Ritonavir inhibits the cytochrome P450 3A (CYP3A) enzyme, which metabolizes many drugs including other protease inhibitors (PIs) Low dose of ritonavir (RTV) can be used to "boost" plasma levels of co-dosed protease inhibitors and other drugs (e.g., elvitegravir, an Integrase Inhibitor) When drug clearance is slowed by ritonavir, concentrations in the body remain higher for longer periods, resulting in lower cost, qd dosing, better compliance, increase durability, better formulation options, easier to use, broad application Page 7 of 15

8 Factors that need to be addressed to achieve universal coverage are: Limited screening for HIV and lack of affordable, simple diagnostic testing technologies for children less than 18 months of age. Lack of human resources with the capacity to provide the care that is required Limited experience with simplified, standardized treatment guidelines. Lack of monitoring and tracking of activities relating to children Limited functional linkages or integration of service delivery (ANC/CH/RH) High relative cost of interventions. Complexity of therapy in context multiple co- morbidities (TB, malaria, malnutrition...) Liquid drugs transport/storage problems. Insufficient advocacy and understanding that ART is efficacious in children Lack of data for demand and forecasting. Up to now UNITAID funded projects provided over 80% of the market for paediatric ARVs. 10 Sustainable funding Paediatric ARVs market has no incentive for industry for the following reasons: 9 Much smaller market than adult Children HIV infection has nearly been eliminated in United States and Europe. Paediatric antiretroviral demand will further diminish, with the success of PMTCT reducing any returns on investment for developing paediatric ARVs. Costly clinical trials, bioequivalence, bioavailability, dose-ranging, and pharmacokinetic studies will be needed to implement new ARV treatment in developing countries. Production cost of paediatric ARVs will be high because small quantities impede the realization of economies of scale in production and distribution. Complexity of paaediatric market with different strength and dosing per weight band. Drug research needs for pediatric ART in low resource settings a) Drug research priorities - Alternative to LPV/r solution for first line treatment of children exposed to NNRTI to apply WHO expert recommendations. - Second line treatment for children: PI used as second line treatment in adults, new NNRTI like etravirine and new families of ARVs, specifically the promising integrase inhibitors (raltegravir), deserve further research in children. They may replace, in the long term, LPV/r for first line treatment in MTCT exposed children. g - A better fixed dose combination for first line treatment for NVP non-exposed children that will decrease adverse events and improve compliance, replacing AZT/3TC/NVP and d4t/3tc/nvp. Alternative FDC regimens could be: ABC/(3TC or FTC)/(NVP or EFV) TDF/(3TC or FTC)/EFV - Once daily administration regimen will facilitate treatment compliance. Some drugs with long half-life are good candidates: EFV, ABC, and FTC (and possibly also 3TC), TDF. g IMPAACT P1066 : ongoing Merck study Safety, PK, ARV activity in HIV+ age 4 weeks-18yrs. Children years in phase I/II. Paediatric indication schedule for Neonatal Study PK and safety in HIV-exposed neonates (planned). Chewable tablets for < 12 y.o. and granules for suspension have been developed for < 2 y.o., but are not yet marketed. Page 8 of 15

9 - New children formulations of existing ARVs are urgently needed, according to WHO analysis: (see Annex 6) o o o o o o o NVP: 20 mg scored tablets, FDC: ABC/3TC/NVP (60/30/50mg) ABC: Scored adult 300/150mg tablet TDF/3TC with 75/75mg and scored existing 300/300 tab LPV/r: 40/10 mg heat -stable formulation for infants. Co-formulated DRV/r but still ratio unclear for different age groups RTV: 50mg heat-stable sprinkle or tablet to boost PI and super boost during TB treatment - Need for effective HIV drugs for Tuberculosis and Hepatitis B co-infection b) Ideal HIV therapy for children Regimen: Durable and potent antiviral activity, with high threshold to development resistance especially after MTCT ARV, to keep children on first-line longer. Robust Well tolerated High genetic barrier Forgiving (for missed doses) Minimal toxicity and drug-drug interactions Co-formulated or co-packaged Once (or max twice) daily dosing Dosing forms: Adapted Compatible with paediatric population (soluble, QD or depot, stable, taste.) Simplicity (simple regimens, ease-to-use drugs) Sprinkle, granular crushable or dispersible solid forms No food restrictions Acceptable taste or masking Affordable Easy to store & no requirement for refrigeration Long shelf-life at room temp DNDi s Strategy: Mini-portfolio approach and/or advocacy Based on the R&D needs assessment, that reveals urgent needs for the HIV infected paediatric population, DNDi wishes to develop a mini portfolio approach on ad hoc projects within the coming months. - A particular focus will be put on the subpopulation of under three year old - The identified gaps in first-line treatments will be given top priority - The developed drugs must address the challenges of cost and compliance Several R&D opportunities already exist in all three major drug classes, such as candidate compounds and improved drug formulations that could address these needs. DNDi will also advocate with partners to engage, for instance, manufacturers to produce paediatric FDCs, in the context of UNITAID patent pool. Page 9 of 15

10 REFERENCES report on the global AIDS epidemic. Geneva, UNAIDS, accessed 22 July 2010). 2. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector: progress report Geneva, World Health Organization, ( accessed on 5 October 2010). 3. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach, 2010 revision. Geneva, World Health Organization, 2010 ( accessed on 10 September 2010). 4. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: recommendations for a public health approach, 2010 version. Geneva, World Health Organization, 2010 ( accessed on 10 September 2010). 5. Violari A, et al Early Antiretroviral Therapy and Mortality among HIV-Infected Infants. N Engl J Med 2008;359: Annette H. Sohna, James J.C. Nuttallb and Fuije Zhangc.Sequencing of antiretroviral therapy in children in low- and middle-income countries. Curr Opin HIV AIDS 2010; 5: Van Dyke, R., et al., Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in hiv-infected children. J Infect Dis, (11): ) 8. R van Heeswijk, et al Tibotec BVBA, Mechelen, Belgium. The effects of CYP3A4 modulation on the pharmacokinetics of TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) Poster presented at the 7th International Workshop of Clinical Pharmacology, April 2006, Lisbon, Portugal. Peeters, K Boven, P Belgium 9. Waning B, Diedrichsen E, Jambert E, Bärnighausen T, Li Y, Pouw M, Moon S. The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children. BMC Pediatrics 2010, 10: UNTAID. Annual report The demographic impact of HIV/AIDS. Report on the Technical Meeting, 10 November New York, United Nations, 1999 (Report No. ESA/P/WP.152). 12. Jacob Adetunji, Bulletin of the World Health Organization, 2000, 78 (10) Page 10 of 15

11 ANNEXES Annex 1: Current ARV Medications oral and 1 injectable drugs available Nucleoside Reverse Transcriptase Inhibitor (NRTI) Abacavir (ABC) Didanosine (ddi) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4t) Tenofovir (TDF) Zidovudine (AZT, ZDV) Integrase Inhibitor Raltegravir (RAL) Protease Inhibitor (PI) Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) Fusion Inhibitor Enfuvitide (ENF,T-20) (injectable) Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) CCR5 Antagonist Maraviroc (MVC) Annex 2: (A) Antiretroviral treatment options recommended for HIV-infected pregnant women who are eligible for treatment Page 11 of 15

12 (B) ARV-prophylaxis options recommended for HIV-infected pregnant women who do not need treatment for their own health Annex 3: (A) Preferred first- and second-line regimens for antiretroviral therapy in children Source: WHO. Antiretroviral therapy of HIV infection in infants and children: towards universal access: recommendations for a public health approach revision. Page 12 of 15

13 (B) Recommended second-line regimens in infants and children in the event of treatment failure of first-line regimens Source: WHO. Antiretroviral therapy of HIV infection in infants and children: towards universal access: recommendations for a public health approach revision Annex 4: Estimated number of children living with HIV younger than 15 years receiving antiretroviral therapy, children needing antiretroviral therapy and percentage coverage in low- and middle-income countries according to region, December 2009a Source: WHO. Antiretroviral therapy of HIV infection in infants and children: towards universal access: recommendations for a public health approach revision. Annex 5: Page 13 of 15

14 Regimen costs using existing Fixed Drug Combinations for infants: ARV Weight range PPY(US$) Supplier 1 AZT/3TC/NVP 3-6 kg 102 Matrix Labs 2 d4t/3tc/nvp 3-6 kg 55 Cipla, Matrix Labs 3 ABC/3TC + NVP 3-25 kg 209 Matrix Labs + Cipla 4 AZT/3TC/ABC* 3-25 kg 244 Matrix Labs 5 LPV/r + AZT/3TC 3-10 kg 245 Cipla + Matrix Labs 6 LPV/r + d4t/3tc 3-10 kg 218 Cipla 7 LPV/r + ABC/3TC 3-10 kg 329 Cipla + Matrix Labs Source UNITAID PPY for a child weighting 10kg. *Untangling the web, MSF access July Annex 6: Urgently needed dosing strengths of drugs not yet available in child-friendly formulations Source: Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach, 2010 revision. Geneva, World Health Organization, 2010 ( accessed on 10 September 2) Page 14 of 15

15 Annex 7. CHAI forecast for LPV/r use Page 15 of 15