HIV IN CHILDREN WHAT WE DO AS KENYA AND WHY WE DO

1. HIV IN CHILDRENWHAT WE DO AS KENYA AND WHY WE DO Dr Laura Oyiengo NATIONAL AIDS STI CONTROL PROGRAM MOH

2. BACKGROUND • As a country with the fourth largest Pediatric HIV epidemic in the world, Pediatricians need to be involved in programming, decision making and management of children and adolescent living with HIV and also in PMTCT programming.

3. Introduction - Children •KenyaHIVEstimates2018: •Children:0–14years Indicator Value %totalPLHIV Childrenlivingwith HIV 105,230 7.0 NewHIV Infections 7,978 15.1 Deaths 4,312 15.3

4. Introduction– Adolescents Adolescentsdefinedas10-19yearold KenyaHIVEstimates2018: • • Indicator Value %totalPLHIV Adolescentslivingwith HIV 105,230 7.0 NewHIV Infections 8,177 15.5 Deaths 2,072 7.3

5. TEENAGE PREGANCIES IN KENYA COUNTY % • TanaRiver 51 • Siaya 48 • Busia 46 • Meru 45 • Narok 43 • Vihiga42 • Trans-Nzoia 42 • Kisii 41 • Kwale 40 • HomaBay 40 • Bomet39 • Nyamira39 • Kericho 38 • Nandi 38 COUNTY % • TaitaTaveta 38 • Bungoma 38 • Kitui 37 • Isiolo37 • Makueni 36 • Kirinyaga 36 • TharakaNithi 35 • Kilifi 35 • WestPokot 35 • Samburu 34 • Laikipia 32 • Baringo 31 • Muranga31 • Lamu30

6. THE SCIENCE BEHIND RECOMMENDATIONS 1. WHEN TO START ART

7. WHO Guidelines: Evolution of When to Start ART in Children More children eligible for treatment

8. CHER (Children With HIV Early AntiretroviralTherapy): Study Design N=377 (ages 6–12 weeks in 2 centers in South Africa) HIV infection diagnosed before 12 weeks and CD4+ >25%13(2234B) Arm 1 Deferred ART n=125 Arm 2 Short-course ART 40 weeks (to first birthday) AZT + 3TC + LPV/r n=126 Arm 3 Long-course ART 96 weeks(to second birthday) AZT + 3TC + LPV/r n=126 ART (start or restart) when CD4+ <20% or clinical event Follow-up for a minimum of 3.5 years Primary endpoint: Death or failure of first-line ART (immunologic, clinical, or toxicity)

9. CHER: Efficacy and Safety • Death comprised 44% of the primary endpoints in ART-deferred vs 34% in ART-40W and ART-96W • Immunologic and clinical failures on ART were more similar between arms, but virologic failure was more frequent in ART-deferred (10 VF) than in early ART (1 VF in each of ART-40W and ART-96W) • HR (95% CI) for death or failure of first-line therapy relative to ART-deferred: • ART-40W: 0.59 (0.38–0.93; P=0.023) • ART-96W: 0.47 (0.29–0.76; P=0.002) • Cumulative probability of clinical disease progression or death by 3.5 years: • ART-deferred: 41% • ART-40W: 28% • ART-96W: 21% • No TAMs and no differences between arms for any resistance • Whereas clinical event rates were significantly higher in ART-deferred (P<0.0001), rates of ART-related lab abnormalities were similar and low (2–3 events/100 patient-years) in all arms • Early limited ART had superior clinical/immunologic outcome, with no evidence of excess disease progression during subsequent interruption, and less overall ART exposure than deferred ART CI, confidence intervals; VF, virologic failure; W, weeks 14. Cotton MF, et al. Lancet 2013;382:1555–1563.

10. PREDICT (Pediatric Randomised Early versus Deferred Initiation in Cambodia and Thailand): Study Design • Rationale: To assess whether ART initiation could be deferred until CD4 percentages decline to <15%, without affecting AIDS-free survival • Primary endpoint: AIDS-free survival at Week 144 N=299 (ages 1–12 years in 9 centers in Thailand and Cambodia) HIV infection; CD4+ 15–24%; ART-naive (except for PMTCT) Early treatment group ART initiated at study entry n=149 Deferred treatment group ART initiated when CD4 <15% n=150 Follow-up to 144 weeks 15. Puthanakit T, et al. Lancet Infect Dis 2012;12:933–941.

11. PREDICT: AIDS-Free Survival AIDS-free survival at Week 144 Deferred treatment: 148/150; 98.7%(95% CI 94.7–99.7) 100 p=0.6 Early treatment: 146/149; 97.9%(95% CI 93.7–99.3) 95 90 Survival (%) 85 Early treatment Deferred treatment 80 0 12 24 36 48 60 72 84 96 108 120 132 144 Week No. at risk AIDS-free survival in both treatment groups was high; the study was underpowered to detect potential effects of deferring ART therapy 15. Puthanakit T, et al. Lancet Infect Dis 2012;12:933–941.

12. 2. WHAT ARVS TO START IN CHILDREN

13. WHO Guidelines: Evolution of What to Start

14. IMPAACT (P1060): Cohort 1 Overview Locations: 9 sites in 6 African countries Study Population: • 164 HIV-1+ children 6–36 months old • With documented exposure to NVP for PMTCT (and not during breastfeeding) • Not undergoing treatment for TB • Baseline HIV-1 RNA >5000 copies/mL Baseline Characteristics: • 123 were 6–12 months; 41 were 12–36 months • Most were not breastfed • Most had advanced disease • Median CD4+ cell count 19% • 56.1% had WHO stage 3 or 4 disease Primary Endpoint: Treatment failure or death by Week 24 RNA, ribonucleic acid 22. Palumbo P, et al. N Engl J Med 2010;363:1510–1520.

15. IMPAACT (P1060): Study Design LPV/r + AZT +3TC N=82 Primary outcomes: • Virologic failure [VF, <1 log10 decrease in HIV-RNA viral copies/mL (c/mL) between weeks 12–24 or >400 c/mL at Week 24] • Treatment discontinuation or death by Week 24 • Kaplan-Meier curves were used to estimate Week 24 failure rates Cohort 1 with sd-NVP exposure N=164/288 • N=440/576 • Infants age 6–36 months* • Eligible by WHO criteria to begin ART • Stratified by age:<12 mo and ≥12 mo NVP + AZT +3TCN=82 LPV/r + AZT + 3TC N=140 Cohort 2 without sd-NVP exposure N=287/288 22(1511H)23(2380) NVP + AZT +3TC N=147 * Cohort 2 included infants 2–36 months of age. Mo, months; sd-NVP, single-dose nevirapine 22. Palumbo P, et al. N Engl J Med 2010;363:1510–1520. 23. Violari A, et al. N Engl J Med 2012;366:2380–2389.

16. IMPAACT (P1060): Cohort 1 Results Cohort 1 had enrolled 164/288 infants (median: baseline age=0.7 years, CD4+ cell count=19%, median HIV-RNA log10 5.9 copies/mL). Outcomes for Cohort 1 are shown below: Results • Failure rates were higher among children in the younger age stratum than among those in the older age stratum • No significant between-group differences were seen in the rate of adverse events • Baseline NVP resistance was detected in 18 of 148 children tested (12%) • A Y181C mutation was responsible for the resistance in 15 children, and a K103N mutation in 3 children • Among the 18 children with resistance, the estimated proportion of children who reached a primary endpoint was 83.3% in the NVP group versus 18.2% in the LPV/r group • The data andsafety monitoring board called for the enrollment of children in Cohort 1 to be closed 22. Palumbo P, et al. N Engl J Med 2010;363:1510–1520.

17. P1060 Cohort 1: Times to Primary Endpoint and to Virologic Failure, According to Treatment and Age Stratum Time to virologic failure or discontinuation, age <12 months Time to virologic failure or discontinuation, age ≥12 months 100 100 80 80 Ritonavir-boosted lopinavir Ritonavir-boosted lopinavir Nevirapine 60 60 Children receiving treatment with no virologic failure (%) Children receiving treatment with no virologic failure (%) Nevirapine 40 40 Failure rate: Nevirapine, 45.3% Ritonavir-boosted lopinavir, 23.3% Failure rate: Nevirapine, 28.9% Ritonavir-boosted lopinavir, 17.5% 20 20 P=0.02 P=0.40 0 0 0 24 48 72 96 120 0 24 48 72 96 120 Week Week No. at risk NVP LPV/r No. at risk NVP LPV/r 60 63 32 38 18 26 9 10 2 3 22 19 15 14 7 10 5 6 2 5 22. Palumbo P, et al. N Engl J Med 2010;363:1510–1520.

18. P1060 Cohort 1: Conclusions P1060 Cohort 1 Conclusions: • Among children with prior exposure to single-dose NVP for perinatal prevention of HIV transmission, ART consisting of AZT + 3TC + LPV/r resulted in better outcomes than did treatment with AZT + 3TC + NVP • Creative strategies for increasing the availability of LPV/r (and other effective agents) for children—and advocacy for the dissemination of these drugs—are urgently needed in resource-limited settings Authors’ statement: “We believe that the study provides strong evidence that ritonavir-boosted lopinavir should be used as the initial therapy in children younger than 12 months of age who have had prior exposure to single-dose nevirapine, with moderate evidence that this recommendation should be extended to children 12 to 36 months of age.” 22. Palumbo P, et al. N Engl J Med 2010;363:1510–1520.

19. IMPAACT (P1060): Cohort 2 Overview Locations: 1 site in India; 9 sites in Sub-Saharan Africa Study Population: • 287 HIV-1+ infants, aged 2–36 months (median 1.7 years) • 210 (73%) ≥12 months • 77 (27%) <12 months • Unexposed to maternal/infant NVP Baseline Characteristics: • Median CD4+ cell count 15% • Median HIV-1 RNA 535,632 copies/mL Parameters: Infants were randomized to NVP or LPV/r + AZT + 3TC, and stratified by age 2 to <6, 6 to <12, or 12 to 36 months Design Cohort 2: n=147 to NVP arm and n=140 to LPV/r arm Primary Endpoint: Treatment failure by 24 weeks, defined as VF (<1 log10 decline from baseline to ≥12 to 24 weeks or >400 copies/mL at week 24), OR permanent discontinuation of NVP or LPV/r, including death by study week 24 Follow-up: Median duration of follow-up was 72 weeks (IQR 48–120) 23. Violari A, et al. N Engl J Med 2012;366:2380–2389.

20. IMPAACT (P1060): Cohort 2 Efficacy Results 24-week primary endpoint data • Rates of VF or death by Week 24 in children <12 months old were 28.8% in the NVP arm vs 11.1% in the LVP/r arm • Rates of VF or death by Week 24 in children ≥12 months old were 28.5% in the NVP arm vs 13.7% in the LVP/r arm • There were 13 deaths: 10 in the NVP arm vs 3 in the LPV/r arm In October 2010, the Data Safety Monitoring Board recommended unblinding the study results 23. Violari A, et al. N Engl J Med 2012;366:2380–2389.

21. IMPAACT (P1060): Cohort 2 Conclusions • Conclusions: • The data from the P1060 cohort 2 study show superior outcomes with LPV/r, as compared with NVP, for the composite endpoint as well as for virologic failure or death, toxicity, and death alone • These data support LPV/r as the basis for first-line ART in all children <3 years, regardless of whether they have had prior NNRTI exposure • The path forward for pediatric first-line treatment guidelines in resource-limited settings is not simple • Identification of HIV infection early in infancy, with prompt initiation of ART, is critical for increasing survival among HIV-infected children 23. Violari A, et al. N Engl J Med 2012;366:2380–2389.

22. 3. CAN WE SWITCH FROM LPV/r TO EFV or NVP..

23. Switching a Virally Suppressed Patient From PI: Pediatric Switch Study • PI switch to EFV:First open-label switch study in HIV+ children • Assessed the virologic, immunologic, and metabolic effect of PI substitution with EFV and the safety and tolerability of EFV in this population • Study switched 17 NNRTI-naive patients (aged 2–13 years) from PI-based* regimen to EFV for 48 weeks • At Week 48, 16 of 17 patients had HIV-1 RNA levels of <50 copies/mL • 1 patient had HIV-1 RNA of 61 copies/mL • Initial mean CD4+ % remained stable: 35.1% (±2.8) at baseline to 36.8% (±5) at Week 24 (P>0.05) but increased to 38% (±6) at Week 48 (P=0.03) • No AIDS-defining events occurred • No rashes and no changes in liver transaminases • 1x mild, transient insomnia and dizziness • 2x unusual vivid dreams, mostly pleasant, which decreased in intensity and frequency after the first 12 weeks of the study • Switching to an EFV-containing regimen was well tolerated and successfully maintained virologic suppression in all HIV-infected children in this study *PI: nelfinavir (47%), ritonavir (29%), amprenavir (18%); saquinavir/ritonavir (6%). 24. McComsey G, et al. Pediatrics 2003;111:e275–281.

24. Switching a Virally Suppressed Patient From PI: Pediatric Switch Study Metabolic parameters that changed significantly during the 48-week study period Mean fasting triglycerides, LDL cholesterol, and cholesterol:HDL ratio 130 4 125 3.9 120 3.8 115 3.7 110 LDL 3.6 105 100 Triglycerides, LDL (mg/dL) 3.5 Cholesterol:HDL ratio 95 3.4 90 Triglycerides 3.3 85 3.2 80 3.1 Cholesterol:HDL ratio 75 70 3 0 12 24 32 48 Week • This study demonstrated significant improvement in fasting total cholesterol, low-density lipoprotein cholesterol, triglycerides, and more importantly, the cholesterol:HDL ratio HDL, high density lipoprotein; LDL, low density lipoprotein 24. McComsey G, et al. Pediatrics 2003;111:e275–281.

25. Switching a Virally Suppressed Patient From PI: Switch to EFV in NVP-exposed Children Despite the advantages over the use of EFV, there are concerns over possible reduced viral efficacy in children exposed to NVP for PMTCT • Children in the EFV group had lower total cholesterol, LDL and triglycerides than those in the LPV/r group Continue LPV/r-based ART (n=148) • N=298 children, NVP-exposed for PMTCT • ≥3 years old • HIV RNA <50 c/mL on LPV/r-based ART randomized 48 weeks Switch to EFV-based ART (n=150) Cumulative probabilities of primary endpoints • Switching to EFV-based therapy in children exposed to NVP for PMTCT did not result in significantly higher rates of viral rebound or failure 25. Coovadia A, et al. JAMA 2015;314:1808–1817.

26. Switching a Virally Suppressed Patient From PI: Switch From LPV/r to NVP • PI switch to NVP:Randomized trial to assess whether NVP-exposed infants who initially achieve viral suppression with PI-based therapy can maintain viral suppression when switched to NVP-based therapy (South Africa) • Criteria26(1082) • N=195 children, NVP-exposed • Initiated LPV/r-based ART before 24 months of age • Virally suppressed <400c/mL for ≥3 months Control group (n=99) LPV/r + d4T+ 3TC 52 weeks Switch group (n=96) NVP + d4T+ 3TC Primary endpoint: Any viremia >50 c/mL after randomization Safety endpoint: Confirmed viremia >1000 c/mL (2 measurements) was used as a criterion to consider regimen changes for children in either group Primary endpoints through 52 weeks after randomization 26. Coovadia A, et al. JAMA 2010;305:1082–1090.

27. Switching a Virally Suppressed Patient From PI: Switch From LPV/r to NVP • Confirmed viremia >1000 copies/mL occurred more frequently in the switch group (0.201; 95% CI, 0.125–0.289) than in the control group (0.022; 95% CI, 0.004–0.069), P<0.001 • Major NNRTI resistance was detected in 13/15 children in the switch group who were tested and 0/2 children in the control group • Predictors of viremia: • Older age (RH,1.71; 95% CI, 1.08–2.72) was associated with viremia >50 c/mL in the control group • Inadequate adherence (RH, 4.14; 95% CI, 1.18–14.57) was associated with confirmed viremia >1000 c/mL in the switch group • Pre-treatment NNRTI mutations (RH, 4.04; 95% CI, 1.40–11.65) was associated with confirmed viremia >1000 c/mL in the switch group • A majority of NVP-exposed children who are successfully treated with initial LPV/r-based regimens and achieve viral suppression, could benefit from the switch strategy • However, switching should only be undertaken with adequate virologic monitoring RH, relative hazard 26. Coovadia A, et al. JAMA 2010;305:1082–1090.

28. Switch From LPV/r to NVP: Long-term Follow-up Results at median follow-up of 156 weeks: • Children switched to NVP were less likely to experience non-suppression >50 c/mL than the control group, P=0.01 • More children had virologic failure in the switch group (22) vs the control group (10), P=0.009 • All 22 failures in the switch group were detected by 52 weeks vs 5 in the control group • Virologic failure was related to non-adherence and pretreatment drug resistance • Criteria • N=195 children, NVP-exposed • Initiated LPV/r-based ART before 24 months of age • Virally suppressed <400c/mL for ≥3 months Control group (n=99) LPV/r + d4T+ 3TC 90–232 weeks Primary endpoint: Any viremia >50 c/mL after randomization Safety endpoint: Confirmed viremia >1000 c/mL (2 measurements) was used as a criterion to consider regimen changes for children in either group Switch group (n=96) NVP + d4T+ 3TC • Viral-load testing through 52 weeks can identify all children likely to fail this PI switch strategy 27. Kuhn L, et al. Lancet Infect Dis 2012;12:521–530.

29. PREVIOUS STUDIES SHOWED THAT SWITCHING FROM A PI BASED REGIMENT TO A NNRTI BASED REGIMENT WAS FEASIBLE AND SAFE… • HOWEVER IN 2018 – WHO RELEASED NEW GUIDANCE STATING CHILDREN ON PI BASED REGIMENT (LPV/r) SHOULD NOT BE SWITCED TO EFAVIRENZ OR NEVIRAPINE DUE TO HIGH TREATMENT FAILURE RATES WITNESSED IN MUCH LONGER TERM FOLLOW UP OF CHILDREN IN WHOM THAT SWITCH HAD BEEN MADE

30. ARV regimens for CALHIV – KENYA 2018 ART GUIDELINES

31. 4. TB HIV CO-INFECTION IN CHILDREN

32. TB Co-treatment in Children <3 Years • ART should be started in any child (at any age) with active TB as soon as possible and within 8 weeks following initiation of TB treatment, regardless of CD4 cell count and clinical stage • Since 2010, WHO has recommended the approach of “super-boosting” LPV/r with additional RTV (1:1 instead of 4:1 LPV/r ratio) to manage rifampicin-based TB co-treatment in children on an LPV/r-based regimen RTV, ritonavir 3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016.

33. TB Co-treatment in Children ≥3 Years 3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016.

34. Isoniazid Preventive Therapy in Children • Children living with HIV who do not have poor weight gain, fever, or current cough are unlikely to have active TB • Children living with HIV who are >12 months of age and who are unlikely to have active TB on symptom-based screening and have no contact with a TB case should receive 6 months of IPT (10 mg/kg/day) as part of a comprehensive package of HIV prevention and care services • In children living with HIV who are <12 months of age, only those who have contact with a TB case and who are evaluated for TB (using investigations) should receive 6 months of IPT if the evaluation shows no TB disease • All children living with HIV, after successful completion of treatment for TB, should receive IPT for an additional 6 months IPT, isoniazid preventive therapy3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016.

35. TREATMENT OF CLHIV INFECTED WITH TB • Children on LPVr should have their regimen super-boosted with Ritonavir • Children on NVP should be switched to EFV if above 3 years or to super-boosted LPVr if below 3 years • For those children unable to tolerate super-boosted LPVr, they should be switched from LPVr to RAL

36. 5. TREATMENT FAILURE IN CHILDREN LIVING WITH HIV

37. WHO Definitions for Clinical, Immunologic, and Virologic Failure in Children 3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016.

38. Clinical Failure Is Just the Tip of the Iceberg VIROLOGIC FAILURE can lead to IMMUNOLOGIC FAILURE which can lead to CLINICAL FAILURE Clinical Failure Immunologic Failure Virologic Failure 36. DHHS, USA. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 2009. Available at: https://aidsinfo.nih.gov/contentfiles/adultandadolescentgl001561.pdf. Accessed December 2016.

39. Consequences of Staying on a VirologicallyFailing Regimen VIROLOGIC FAILURE IMMUNOLOGIC FAILURE CLINICAL FAILURE CD4+ CELL COUNT DRUG RESISTANCE VIRAL LOAD TIME 36. DHHS, USA. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 2009. Available at: https://aidsinfo.nih.gov/contentfiles/adultandadolescentgl001561.pdf. Accessed December 2016.

40. ART Resistance in Children: Summary of Trial Data TAM, thymidine analogue mutations 31. Fitzgerald F, et al. J Infect Dis 2013;207:S85–92.

41. ART Resistance in Children: Summary of Cohort Data 31. Fitzgerald F, et al. J Infect Dis 2013;207:S85–92.

42. WHO 2016 Guidelines: Viral Load Testing Strategies Targeted viral load monitoring (suspected clinical or immunologic failure) Routine viral load monitoring (early detection of virologic failure) Test viral load Viral load >1000 copies/mL Evaluate for adherence concerns Repeat viral load testing after 3–6 months Viral load ≤1000 copies/mL Viral load >1000 copies/mL Maintain first-line therapy Switch to second-line therapy 3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016.

43. 6. SWITCHING TO SECOND LINE TREATMENT IN CHILDREN

44. WHO 2016 Guidelines: Second-line ART in Children 3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016.

45. Proportion of Children Failing First-line ART Who Have Treatment-Emergent Resistance Mutations DRM, drug resistance mutation; SGS, second-generation sequencing 42. Babiker A, et al. Lancet Infect Dis 2011;11:273–283. 14. Cotton MF, et al. Lancet 2013;382:1555–1563. 43. Lange CM, et al. J Acquir Immune Defic Syndr 2015;69:138–144. 44. Taylor BS, et al. AIDS Res Hum Retroviruses 2011;27:945–956. 45. Pillay S, et al. AIDS Res Ther 2014;11:3. 46. Sebunya R, et al. AIDS Res Ther 2013;10:25.

46. Response to PI and NNRTI-Based Second-line Therapy in Children A retrospective cohort analysis of electronic medical records (McCord Hospital, South Africa), Aug 2003–Dec 2010 From 880 HIV-infected children who initiated ART 80 switched to second-line ART due to therapeutic failure of first-line ART* 70 (87.5%) received PI-based second-line ART (after failure of a NNRTI-based first-line regimen) 8 (10%) received NNRTI-based second-line ART (after failure of a PI-based first-line regimen) 82% achieved viral suppression at 6 months 29% achieved viral suppression at 6 months P=0.003 *2 received non-standard dual therapy as second-line ART NNRTI-based second-line ART carries a high risk of virologic failure compared to PI-based second-line ART Children have a good response to PI-based second-line ART after NNRTI-based first-line ART31(S90)

47. 6. SWITCHING TO THIRD LINE

48. Fewer Than 1% of People on ART Are Using Third-Line Therapy • WHO estimates that <1% of people taking ART globally are using third-line regimens, but the demand for third-line regimens will increase as access to VL monitoring and use of first- and second-line ART continue to expand • The cost of third-line drugs is either higher than first- and second-line regimens or has not been established, which may limit the adoption of third-line regimens in many countries with limited resources • Although developing a policy on access to third-line ART is desirable, it should not compromise access to first- and second-line ART • There have been limited studies on the use of many newer ARV drugs as part of third-line regimens in children and adolescents and during pregnancy and breastfeeding; pharmacokinetic and safety data are particularly lacking • Therefore, there is an urgent need for affordable access to third-line drugs for children in lower- to middle-income countries23(61) Successful third-line therapy of pediatric patients is hindered by the lack of pediatric formulations and high costs, with dosing especially problematic for children <6 years 3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016. 52. van Zyl GU, et al. J Int AIDS Soc 2011;14:55.

49. Summary of Sequencing Options 3. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second Edition, June 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf. Accessed December 2016.

50. Response to Third-Line ART in Children