ARV Consolidated Guidelines 2015

Transcription

1 ARV Consolidated Guidelines 2015 This document outlines the draft list of PICO questions to support systematic review process for the 2015 ARV guidelines process. PICO questions are grouped by clinical and operational issues and further subdivided according to relevant topics. All PICO questions are displayed with a short reference title and research question. A1 Adults, adolescents and pregnant women 6 When to start A2 Adults, adolescents and pregnant women 5 What ART regimen to start A3 Adults, adolescents and pregnant women 8 What ART regimen to switch to B1 Paediatrics 1 When to start B2 Paediatrics 4 What ART regimen to start B3 Paediatrics 4 What ART regiment to switch to C1 Laboratory diagnosis 4 C2 Laboratory testing before and after initiation of ART 2 C3 Laboratory testing treatment response and failure 6 D Drug toxicity 5 E HIV testing and counselling 5 F1 Service delivery: care package 3 F2 Service delivery: adherence to ART 5 F3 Service delivery: linkage to HIV care 3 F4 Service delivery: human resources 2 F5 Service delivery: service quality 6 Total 69 Placeholders: (subgroups or questions to be added): o Cash transfer adolescents Non communicable diseases Infant feeding 1

2 GROUP A: CLINICAL: ART drug regimens (Adults, adolescents and pregnant women) A1. When to start ART When to start ART in adults and adolescents ( 10 yrs) Existing recommendations As a priority, ART should be initiated in all individuals with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and individuals with CD4 count 350 cells/mm 3 should start ART as a priority. (Strong recommendation, moderate quality evidence). ART should be initiated in all individuals with HIV with a CD4 count > 350 cells and 500 cells/mm 3, regardless of WHO clinical stage. (Strong recommendation, moderate quality evidence). ART should be initiated in all individuals with HIV regardless of WHO clinical stage or CD4 count in the following situations: Individuals with HIV and active TB disease (strong recommendation, low-quality evidence). Individuals coinfected with HIV and HBV with evidence of severe chronic liver disease (strong recommendation, low quality evidence). Partners with HIV in serodiscordant couples should be offered ART to reduce HIV transmission to uninfected partners (strong recommendation, high-quality evidence). Pregnant and breastfeeding women with HIV - section All pregnant and breastfeeding women with HIV should initiate triple ARVs (ART), which should be maintained at least for the duration of mother to child transmission risk. Women meeting treatment eligibility criteria should continue lifelong ART (strong recommendation, moderate quality evidence). For programmatic and operational reasons, particularly in generalized epidemics, all pregnant women and breastfeeding women with HIV should initiate ART as lifelong treatment (conditional recommendation, low quality evidence). In some countries, for women who are not eligible for ART for their own health, consideration can be given to stopping the ARV regimen after the period of mother to child transmission risk has ceased (conditional recommendation, low-quality evidence. A1.1 When to start in asymptomatic HIV+ individuals with CD4 greater than 500 When to start in HIV+ individuals >50 yrs In adults and adolescents with HIV is ART initiated at above CD4 500 cells/ul compared to below 500 cells/ul more effective? Population Adults and adolescents with HIV Intervention ART initiated above CD4 500 cells/ul 2

3 Comparator Outcome(s) ART initiated CD4 500 cells/ul Death, AIDS, tuberculosis, non-aids events 1, uptake, retention, viral suppression, severe treatment-related adverse events, transmission 10-19yrs Adults <50yrs Adults > 50yrs All adults >19yrs A1.2 When to start in asymptomatic HIV+ key populations with CD4 greater than 500 In HIV positive asymptomatic adults and adolescents with high risk of transmission (key populations) is ART initiated ART CD4 500 cells/ul compared to below CD4 500 cells/ul more effective? Population Key populations adults and adolescents with HIV. Intervention ART initiated above CD4 500 cells/ul Comparator ART initiated CD4 500 cells/ul Outcome(s) Death, AIDS, tuberculosis, non-aids events 1, uptake, retention, viral suppression, severe treatment-related adverse events, transmission People who inject drugs Men who have sex with men Transgender people Sex workers A1.3 When to start in HIV/HCV coinfection (irrespective of liver disease) In adults and adolescents with HIV and Hepatitis C is ART initiated at above CD4 500 cells/ul compared to below 500 cells/ul more effective? Population Adults and adolescents with HIV and HCV Intervention ART initiated above CD4 500 cells/ul Comparator ART initiated CD4 500 cells/ul Outcome(s) Death (HIV and hepatitis-related), AIDS, tuberculosis, retention, viral suppression, severe treatment-related adverse events, degree of fibrosis (including cirrhosis), hepatocellular carcinoma A1.4 When to start in HIV/HBV co infection (irrespective of liver disease) In adults and adolescents with HIV and hepatitis B is ART initiated at above CD4 500 cells/ul compared to below 500 cells/ul more effective? Population Adults and adolescents with HIV and hepatitis B (irrespective of liver disease) Intervention ART initiated above CD4 500 cells/ul Comparator ART initiated CD4 500 cells/ul Outcome(s) Death (HIV and hepatitis-related), AIDS, tuberculosis, retention, viral suppression, severe treatment-related adverse events, degree of fibrosis (including cirrhosis), hepatocellular carcinoma A1.5 Timing of ART initiation in TB/HIV In adults and adolescents with HIV and active tuberculosis on tuberculosis treatment is ART initiated after 8 weeks of TB treatment compared to within 8 weeks of TB treatment more effective? Population Adults and adolescents with HIV and active TB Intervention ART initiated after 8 weeks of TB treatment Comparator ART initiated within 8 weeks of TB treatment Outcome(s) Death, other AIDS defining events, incidence of IRIS, retention, severe treatmentrelated adverse events 1 non-aids events include non-aids cancers, cardiovascular disease, diabetes mellitus, renal disease, neurological disease, and liver disease 3

4 Subgroup analyses CD4<200 CD CD4>350 When to start ART in pregnant and breastfeeding women. A1.6 When to start lifelong ART in HIV+ pregnant and breastfeeding women Or -- When to stop in HIV+ pregnant and BF women who have been initiated on ART In pregnant and breastfeeding women with HIV meeting treatment eligibility criteria is alternative criteria more effective than Option B+ to assess whether ART should continue beyond the PMTCT period? Population HIV+ pregnant and breastfeeding women Intervention continue lifelong ART beyond PMTCT period in those meeting other eligibility criteria (e.g. CD4<500) Comparator continue lifelong ART beyond PMTCT period in all (Option B+) Outcome(s) mortality, morbidity, adverse events, adherence, prevention of sexual transmission, HIVDR, retention, stopping and re-starting ART (Option B Epidemiologic settings or specific settings (generalized epidemics, high fertility) 4

5 A2. What ART regimen to start with (first line ART) Existing recommendations First line ART for adults First line ART should consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a nonnucleoside reverse transcriptase inhibitor (NNRTI). TDF+3TC (or FTC) + EFV as a fixed dose combination is recommended as the preferred option to initiate ART (strong recommendation, moderate-quality evidence). If TDF+3TC(of FTC) +EFV is contraindicated or not available, one of the following options is recommended: AZT+3TC+EFV, AZT+3TC+NVP, TDF+3TC(or FTC) +NVP (Strong recommendation, moderate quality evidence). Countries should discontinue d4t use in first-line regimens because of its well-recognized metabolic toxicities. (Strong recommendation, moderate quality evidence). First line ART for pregnant and breastfeeding women and ARV drugs for their infants A once daily fixed dose combination of TDF+3TC (or FTC) +EFV is recommended as first line ART in pregnant and breastfeeding women, including pregnant women in the first trimester of pregnancy and women of childbearing age. The recommendation applies to lifelong treatment and to ART initiated for PMTCT and then stopped (strong recommendation, low to moderate quality evidence: moderate quality evidence for adults in general but low quality evidence for the specific population of pregnant and breastfeeding women and infants). Infants of mothers who are receiving ART and are breastfeeding should receive six weeks of infant prophylaxis with daily NVP. If infants are receiving replacement feeding, they should be given four to six weeks of infant prophylaxis with daily NVP (or twice daily AZT). Infant prophylaxis should begin at birth or when HIV exposure is recognized postpartum (strong recommendation, moderate quality evidence for breastfeeding infants; strong recommendation, low quality evidence for infants only replacement feeding). Proposed PICOs A2.1 What ART regimen to start (EFV vs INSTI) In treatment naive adults and adolescents with HIV is using NRTI with INSTI compared to NRTI and efavirenz as first line ART more effective? Population Adults and adolescents with HIV Intervention NRTI backbone +integrase inhibitor (DTG, RAL or EVG/COBI) Comparator NRTI backbone (same as intervention) + efavirenz Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults Pregnant and breastfeeding women 5

6 PLHIV and TB HBV coinfection A2.2 What ART regimen to start (EFV standard vs EFV low dose) In treatment naive adults and adolescents with HIV is using NRTI with efavirenz 400mg daily compared to NRTI and efavirenz 600mg daily as first line ART more effective? Population Adults and adolescents with HIV Intervention NRTI backbone + efavirenz 400mg daily Comparator NRTI backbone (same as intervention) + efavirenz 600mg daily Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults Pregnant and breastfeeding women PLHIV and TB HBV coinfection A2.3 What ART to start (OD FDC vs OD separate tablets) In treatment naive adults and adolescents with HIV is once daily fixed dose combination compared to once daily separate tables as first line ART more effective? Population Treatment naive adults and adolescents with HIV Intervention At least three ARVs dosed once daily as more than one tablet Comparator Same ARVs dosed once daily as a single tablet (fixed dose) Outcome(s) Death, AIDS, tuberculosis, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults Pregnant and breastfeeding women PLHIV and TB HBV coinfection A2.4 What ART regimen to start in HIV 2 (integrase inhibitors vs bpis vs 3NRTIs) In treatment naive adults and adolescents with HIV-2 is a NRTI backbone and PI LPV/r ATV/r compared to NRTI and DTG or other 3 rd NRTI more effective? Population Treatment naive adults and adolescents with HIV 2 Intervention NRTI backbone (same as intervention) + INSI (DTG or RAL or EVG/COBI) Comparator a) NRTI backbone + (LPV/r or ATV/r) b) NRTI backbone (same as intervention) + 3 rd NRTI Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults Pregnant and breastfeeding women PLHIV and TB PLHIV and Hepatitis B A2.5 What infant prophylaxis to use for HIV-exposed infants In HIV exposed infants is prophylaxis with triple ARV compared to monotherapy more effective? Population HIV exposed infants Intervention Comparator Outcome(s) Triple ARV prophylaxis monotherapy (NVP or AZT for 4-6 weeks) mortality, morbidity, adverse events, adherence, HIVDR, retention, stopping and 6

7 re-starting ART (Option B) infants whose mothers had antenatal prophylaxis infant whose mothers not receive antenatal prophylaxis or insufficient for VL suppression infants who were identified as HIV exposed during BF Settings: Epidemiological and specific Regimen of triple ARV Duration of triple ARV 7

8 A3. What ART regimen to switch to (second and third line ART) Second line ART Existing recommendations Second line ART for adults should consist of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) + a ritonavir boosted protease inhibitor (PI). The following sequence of second line NRTI options is recommended: After failure on TDF+3TC (or FTC) based first line regimen use AZT+3TC as the NRTI backbone in second line regimens After failure on an AZT or d4t+3tc based first line regimen, use TDF +3TC (or FTC) as the NRTI backbone in second line regimens. Use of NRTI backbone as a fixed dose combination is recommended as the preferred approach (strong recommendation, moderate quality evidence). Heat stable fixed dose combinations of ATV/r and LPV/r are the preferred boosted PI options for second line ART (strong recommendation, moderate quality evidence). Proposed PICOs A3.1 What to switch to bpi In adults and adolescents with HIV failing NRTI-based regimen is switching to a boosted PI (ATV/r or DRV/r more effective than LPR/r? Population Adults and adolescents with HIV failing NRTI based regimen Intervention NRTI backbone (as intervention) +DRV/r Comparator NRTI backbone +LPV/r or ATV/r Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Boosted PI ATV/r LPV/r Adults PLHIV and TB A3.2 What to switch to (bpi vs INSTI) In adults and adolescents with HIV failing NNRTI based regimen is switching to a INSTI compared to bpi more effective? Population Adults and adolescents with HIV failing NRTI based regimen Intervention NRTI backbone (same as intervention) + integrase inhibitors (dolutegravir, raltegravir or elvitegravir/cobicistat) Comparator NRTI backbone + bpi (LPV/r, ATV/r, or DRV/r) Outcome(s) Death, AIDS, retention, 8

9 viral suppression, severe treatment-related adverse events, regimen substitutions hepatitis- degree of fibrosis (including cirrhosis) hepatocellular carcinoma Adults PLHIV and TB PLHIV and Hepatitis B PLHIV and hepatitis C A3.3 What to switch to NRTI backbone or nuke sparing regimen In adults and adolescents with HIV failing a first line regimen is switching to bpi +INSTI more effective than bpi +2 NRTIs? Population Adults and adolescents with HIV and failing 1st line regimen Intervention bpi + integrase inhibitors (dolutegravir, raltegravir or elvitegravir/cobicistat) Comparator bpi + 2 NRTIs Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults PLHIV and TB A3.4 What to switch to daily versus twice daily DRV/r dosing In adults and adolescents with HIV failing 1 st line regimen is switching to DRV/r 600mg compared to DRV/r 800mg more effective? Population Adults and adolescents with HIV and failing 1 st line regimen Intervention NRTI backbone + DRV/r 600mg twice daily Comparator NRTI backbone (same as intervention) + DRV/r 800mg once daily Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults PLHIV and TB A3.5 What to switch to DRV dosing In adults and adolescents with HIV failing NRTI based regimen is switching to a NRTI +DRV/r twice daily compared to DRV/r +once daily more effective? Population Adults and adolescents with HIV failing NRTI based regimen Intervention NRTI backbone + DRV/r 800mg once daily Comparator NRTI backbone (same as intervention) + DRV/r 400mg once daily or DRV/r 600mg once daily Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions DRV/r dose PLHIV and TB 9

10 Third line ART National programmes should develop policies for third line ART (conditional recommendation, low-quality evidence) Third-line regimens should include new drugs with minimal risk of cross resistance to previously used regimens, such as integrase inhibitors and second generation NNRTIS and PIs (conditional recommendation, low quality evidence) Patients on a failing second line regimen with non-new ARV options should continue with a tolerated regimen (conditional recommendation, very low quality evidence) Proposed PICOs A3.4 What to switch to (role of NRTI backbone) In adults and adolescents with HIV who have failed NNRTI and bpi regimen is switching to DRV/r +RAL +NRTI backbone compared to DRV/r +RAL more effective? Population Adults and adolescents with HIV who have failed NNRTI and bpi regimen Intervention DRV/r + RAL Comparator DRV/r + RAL+ NRTI backbone Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults A3.5 What to switch to (role of ETR) In adults and adolescents with HIV who have failed NNRTI and bpi regimens is switching to DRV/r +RAL +ETR compared to DRV/r +RAL more effective? Population Adults and adolescents with HIV who have failed NNRTI and bpi regimen Intervention DRV/r + RAL + ETR Comparator DRV/r + RAL Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, regimen substitutions Adults 10

11 Group B: Clinical ART drug regimens (Paediatrics) B1. When to start ART in children Existing recommendations ART should be initiated in all children infected with HIV below five years of age, regardless of WHO clinical stage or CD4 cell count. Infants diagnosed in the first year of life (strong recommendation, moderate quality of evidence). Children infected with HIV one year to less than five years of age (conditional recommendation, very low quality of evidence). ART should be initiated in all HIV infected children five years of age and older with CD4 cell count <=500cells/mm3, regardless of clinical stage. CD4 count <= 350 cells/mm3 (strong recommendation, moderate quality of evidence). CD4 count between 350 and 500 cells/mm3 (conditional recommendation, very low quality of evidence). ART should be initiated in all children infected with HIV with severe or advanced symptomatic disease (WHO clinical stage 3 or 4)regardless of age and CD4 cell count (strong recommendation, moderate quality evidence). ART should be initiated in any child younger than 18 months of age who has been given presumptive clinical diagnosis of HIV infection (strong recommendation, low quality of evidence). Proposed PICOs B1.1 When to start in children 5 to 15 yrs. In children aged 5-15 years who are asymptomatic and have CD4 above 500 is initiating ART compared to not initiating ART more effective? Population children 5-15 years who are asymptomatic and have CD4 above 500 Intervention ART initiation Comparator no ART initiation Outcome(s) mortality, morbidity, VL suppression, immunological recovery, adverse events, adherence, HIVDR, retention 11

12 B2 What ART regimen to start (first line ART) Existing recommendations A LPV/r based regimen should be used as first-line ART for all children infected with HIV younger than three years (36 months) of age, regardless of NNRTI exposure. If LPV/r is not feasible, treatment should be initiated with a NCP-based regimen (strong recommendation, moderate quality evidence). Where viral load monitoring is available, consideration can be given to substituting LPV/r with a NNRTI after virological supression is sustained (conditional recommendation, low quality evidence). For infants and children infected with HIV younger than three years, ABC+3TC +AZT is recommended as an option for children who develop TB while on an ART containing NVP or LPV/r. Once TB therapy has been completed, this regimen should be stopped and the initial regimen should be restarted (strong recommendation, moderate quality evidence). For infants and children infected with HIV younger than three years, the NRTI backbone for an ART regimen should be ABC or AZT +3TC (strong recommendation, low-quality evidence). For children infected with HIV three years and older (including adolescents). EFV is the preferred NNRTI for first line treatment and NVP is the alternative (strong recommendation, low quality evidence). For children infected with HIV three years to less than 10 years old (or adolescents less than 35 kg), the NRTI backbone for an ART regimen should be one of the following, in preferential order: ABC+3TC, AZT or TDF +3TC (or FTC). (Conditional recommendation, low quality evidence). For adolescents infected with HIV (10 to 19 years) weighing 35kg or more, the NRTI backbone for an ART regimen should align with that of adults and be one of the following, in preferential order: TDF+3TC (or FTC), AZT +3TC, ABC+3TC. (strong recommendation, low quality evidence). Proposed PICOs B2.1 Which NRTI backbone to start In children below 3yrs with HIV is initiating ART with ABC +3TC compared to AZT +3TC more effective? Population Children with HIV below 3 years Intervention ABC plus 3TC Comparator AZT plus 3TC Outcome(s) mortality, morbidity, virological suppression, immunological response, HIVDR, adverse events, adherence LPV-based regimen NVP-based regimen B2.2 Which NRTI backbone to start 12

13 In children aged 3-10 years with HIV is initiating ART with AZT +3TC or TDF+3TC compared to ABC +3TC more effective? Population Children with HIV 3-10 years Intervention AZT plus 3TC or TDF plus 3TC Comparator ABC plus 3TC Outcome(s) mortality, morbidity, virological suppression, immunological response, HIVDR, adverse events, adherence AZT plus 3TC TDF plus 3TC B2.3 Which NRTI backbone to start Hep B coinfected In children <15 years old with HIV and HBV infection is initiating ART with TDF+XTC compared to XTC without TDF more effective? Population Children <15 years old with HBV-HIV infection Intervention TDF-XTC containing ART Comparator XTC-containing ART without TDF Outcome(s) HBV VL, HBV eag positivity, ALT, liver dysfunction B2.4 Simplification strategy In children 3 years and older with HIV successfully treated with PI based first line therapy is substituting LPV with EFV more effective compared to remaining on LPV/r? Population Children 3 years and older successfully treated with PI-based first line therapy Intervention Substitute LPV with EFV Comparator Stay on LPV/r Outcome(s) mortality, morbidity, virological suppression, immunological response, HIVDR, adverse events, adherence 13

14 B3. What to switch to (2 nd line and 3 rd line ART) Second line ART for children (including adolescents) After failure of a first line NNRTI based regimen m, a boosted PI plus two NRTIS are recommended for second-line ART, LPV/r is the preferred boosted PI. (strong recommendation, moderate quality evidence) After failure of a first line LPV/r based regimen, children younger than 3 years should remain on their first-line regimen, and measure to improve adherence should be undertaken. (conditional recommendation, very low quality evidence) After failure of a first-line LPV/r based regimen, children 3 years or older should switch to a second line regimen containing an NNRTI plus 2 NRTIs: EFV is the preferred NNRTI (conditional recommendation, low quality evidence) After failure of a first line regimen of ABC or TDF +3TC (or FTC) the preferred NRTI backbone option for second line ART is AZT +3TC (strong recommendation, low quality evidence) After failure of a first line regimen containing AZT or d4t +3TC (or FTC), the preferred NRTI backbone option for second line ART Is ABC or TDF +3TC (or FTC) (strong recommendation, low quality evidence) Proposed PICOs B3.1 Second line in children younger than 3 years and failing LPV/r In children younger than 3 years failing on LPV/r is switching to NNRTI based or RAL based second line more effective than remaining on LPV based 1 st line? Population Children younger than 3 years failing PI-based first line therapy Intervention Switch to NNRTI (NVP or EFV)- based or RAL-based 2 nd line Comparator Stay on LPV-based 1 st line Outcome(s) mortality, morbidity, virological suppression, immunological response, HIVDR, adverse events, adherence B3.2 Second line in children older than 3 years failing LPV/r In children older than 3 years with HIV failing LPV/r based first line therapy is DRV based or RAL based second line more effective than EFV based second line ART? Population Children older than 3 years failing LPV/r-based first line therapy Intervention DRV-based or RAL-based second line Comparator EFV-based second line Outcome(s) mortality, morbidity, virological suppression, immunological response, HIVDR, adverse events, adherence B3.3 Second line in children 3 years and older failing NNRTI In children 3 years and over with HIV failing on NNRTI is DRV or ATV compared to LPV/r more effective? Population Children 3 years and older failing NNRTI-based first line therapy Intervention DRV or ATV Comparator LPVr 14

15 Outcome(s) mortality, morbidity, virological suppression, immunological response, HIVDR, adverse events, adherence Third line ART National programmes should develop policies for third line ART (conditional recommendation, low-quality evidence) Third-line regimens should include new drugs with minimal risk of cross resistance to previously used regimens, such as integrase inhibitors and second generation NNRTIS and PIs (conditional recommendation, low quality evidence) Patients on a failing second line regimen with non new ARV options should continue with a tolerated regimen (conditional recommendation, very low quality evidence) B3.4 Third line In children with HIV failing second line therapy is DRV+/- ETR compared to Integrase inhibitor (RAL or DTG) more effective? Population children failing second line therapy (i.e., an NNRTI-based regimen and a LPVrbased regimen) Intervention DRV +/- ETR Comparator Integrase Inhibitor (RAL or DTG) Outcome(s) mortality, morbidity, virological suppression, immunological response, HIVDR, adverse events, adherence 15

16 GROUP C Diagnostics and monitoring C1. HIV diagnosis Proposed PICOs E1.1 Should perinatal HIV infection in infants exposed to peri/ postnatal ART be diagnosed performing a Nucleic acid amplification test (RNA or DNA or TNA) compared to HIV DNA PCR at 6 weeks on DBS specimen? Population infants exposed to HIV (i.e. infants born to an HIV positive mother) and to maternal ART and or postnatal prophylaxis Intervention HIV NAT (venous blood) Comparator HIV DNA PCR at 6 weeks on whole blood Outcome(s) Sensitivity, Specificity, PPV, NPV Timing of HIV NAT (at birth, 6 weeks) C1.2 Should infants who have a negative NAT at birth receive a Nucleic acid amplification test (RNA or DNA or TNA) at weeks to identify peripartum infections? Population infants exposed to HIV ( infants born to an HIV positive mother) with exposure to maternal ART and/or neonatal prophylaxis Intervention HIV NAT at weeks on DBS Comparator HIV NAT at 6 weeks on DBS Outcome(s) Sensitivity, Specificity, PPV, NPV C1.3 Should HIV infection acquired with breastfeeding be diagnosed performing an HIV NAT test at 9 months? Population infants exposed to HIV ( i.e.<18 months infants born to an HIV positive mother) with positive Ab test Intervention HIV NAT at 9 months Comparator ELISA at 18 months? Or at the end of breastfeeding? Outcome(s) sensitivity, Specificity, PPV, NPV C1.4 Should HIV serologic tests (rapid antibody tests) be used to exclude HIV infection in children? In infants exposed to HIV is HIV serological testing with RDT(ab) at 9 months compared to ELISA more effective to diagnose HIV? In infants with unknown HIV exposure if RDT (ab) testing between birth and 18 months compared to ELISA more effective to diagnose HIV? In children over 18 months is HIV serological testing with RDT (ab) at 18 months compared to ELISA more effective at diagnosing HIV? Population infants exposed to HIV ( i.e.<18 months infants born to an HIV positive mother) with negative PCR and not breastfed infants less than 18 months with unknown HIV exposure status children with known or unknown exposure to HIV Intervention RDT (Ab) testing Comparator ELISA Outcome(s) Sensitivity, Specificity, PPV, NPV Time of RDT (AB) testing (9 months, birth to 18 months, after 18 months) 16

17 C2 Laboratory monitoring before and after initiating ART Proposed PICOs C2.1 Should baseline (set point) HIV VL be used for predicting treatment response? In individuals with HIV commencing HIV is baseline viral load testing compared to no viral load testing more effective? Population Individuals with HIV soon to commence ART Intervention Baseline HIV viral load Comparator No baseline HIV viral load Outcome(s) Patient retention, adherence, correlation (set point and post ART 3 month HIV VL) Age C2.2 Should viral load testing be carried out 3 months after ART initiation? In individuals with HIV receiving ART is viral load testing at 3 months more effective than at 6 months? Population HIV positive adults initiated on ART Intervention HIV viral load testing at 3 months after ART initiation Comparator HIV viral load testing at 6 months after ART initiation Outcome(s) Proportion of adherent patients achieving viral suppression Age 17

18 Group C3. Lab monitoring the response to ART and the diagnosis of treatment failure. Existing recommendations Proposed PICOs Viral load is recommended as the preferred monitoring approach to diagnose and confirm ARV treatment failure (strong recommendation, low quality evidence). If viral load is not routinely available, CD4 cell count and clinical monitoring should be used to diagnose treatment failure (strong recommendation, moderate quality evidence). Special notes: Special notes: treatment failure is defined by a persistently detectable viral load exceeding 1000 copies/ml (two consecutive viral load measurements within a 3 month interval, with adherence support between measurements) after at least six months of using ARV drugs. Viral load testing is usually performed in plasma, however certain technologies that use whole blood as a sample type, such as laboratory based tests using dried blood spots and point of care tests are unreliable at this lower threshold and where these are used a higher threshold should be adopted. Viral load should be tested early after initiating ART (6 months) and then at least every 12 months to detect treatment failure. If viral load testing is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failure, with targeted viral load testing to confirm virological failure where possible. C3.1 Should second viral load test on failing patients i.e. initial VL) > 1000cpm) be done at 3 months after initial VL count? In individuals with HIV who are failing (initial VL> 1000cpm) is repeat testing 3 months after initial viral load testing more effective than 6 months after initial viral load? Population Individuals with HIV on ART with initial VL >1000cpm Intervention Follow up VL test within 3 months of initial test (same initial testing point) Comparator Follow up VL test within 6 months of initial test (same initial testing point) Outcome(s) Proportion of co-morbidities, mortality, mean CD4, drug resistance incidence, transmission to partners. Time from initiation to initial viral load testing Age C3.2 Should viral load test on patients switched to second line therapy be tested within 3 months after switch? In individuals with HIV who have recently switched to 2 nd line therapy is viral load testing at 3 months more effective than at 12 months? Population Individuals with HIV recently switched to 2 nd line therapy Intervention HIV viral load testing at 3 months after 2 nd line switch Comparator HIV viral load testing at 12 months after 2 nd line switch Outcome(s) Proportion of patients that fail 2 nd line therapy (VL > 1000cpm, mortality, drug resistance, mean cd4/proportion >350cells/ul) Age C3.3 How to monitor (VL vs. CD4 and VL) In individuals with HIV who have achieved viral suppression on ART with a CD4 count> 350 is CD4 18

19 count and VL annually more effective than VL annually? Population Individuals with HIV who have achieved viral suppression on ART and have CD4 count > 350 Intervention CD4 and VL annually Comparator VL annually Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events, adherence, coinfections Adults Children < 18 months PLHIV and TB C3.4 How frequently to monitor VL In individuals with HIV who have been on ART for 1 year and have achieved viral suppression is measuring viral load 6 monthly compared to annually more effective? Population Individuals who have been on ART for one year and achieved viral suppression Intervention Viral load 6 monthly Comparator VL annually Outcome(s) Death, AIDS, retention, viral suppression, severe treatment-related adverse events Adults Children PLHIV and TB C3.5 Which VL threshold to use in DBS In individuals with HIV on ART is dried blood spot testing at VL threshold> 1000cp/ml more effective than VL> 5000 cp/ml? Population Individuals with HIV on ART Intervention VL > 1,000 cp/ml Comparator VL > 5,000 cp/ml Outcome(s) Sensitivity compared to plasma Specificity compared to plasma Adults Children C3.6 Monitoring of HIV individuals on ART where VL monitoring is not available In individuals with HIV on ART where VL monitoring is not available is new criteria more effective than existing CD4 criteria? Population Individuals starting on ART where VL is not available, or not available according to current recommendations Intervention new set of criteria Comparator existing CD4 criteria Outcome(s) mortality, morbidity, unnecessary switch, HIVDR Adults and adolescents HIV+ pregnant breastfeeding women Children on first line ART PLHIV and TB C3.7 Should HIVDR testing be used to inform switch to 2 nd and 3 rd line? In individuals with HIV on ART is HIV drugs resistance testing an effective strategy to guide switching to 2 nd and 3 rd line compared to no testing? 19

20 Population Intervention Comparator Outcome(s) Individuals with HIV on ART Drug resistance testing No drug resistance testing Viral load, mortality, cost Switch to 2 nd line Switch to 3 rd line Age 20

21 GROUP D: CLINICAL: Monitoring and drug substitutions for ARV drug toxicities Proposed PICOs D1.1 TDF toxicity In individuals with HIV on ART is a non TDF based regimen compared to a TDF based regimen result in a lower incidence of adverse events? Population Individuals on TDF-containing ART Intervention Use of non TDF based regimen (same backbone) Comparator Use of TDF based regimen (same backbone) Outcome(s) Renal dysfunction, bone toxicity, growth delay, bone fracture and discontinuation Adults Adults>50yrs Children Pregnant and breastfeeding women Infants exposed to ART during pregnancy or breastfeeding (including HIV negative) Backbone regimens D1.2 Frequency of renal monitoring for TDF In individuals with HIV on ART does renal monitoring at baseline compared than no renal monitoring result in lower incidence of adverse events? Population Individuals on ART Intervention Baseline + regular urinalysis & creatinine testing/other tests in all individuals (or baseline + regular urinalysis in high risk groups) Comparator No lab monitoring (or baseline + regular urinalysis & creatinine testing/other tests in high risk groups) Outcome(s) renal dysfunction, monitoring children adolescents adults pregnant and breastfeeding women D1.3 Hepatic toxicity of new integrase inhibitors as ARV In individuals with HIV on ART do the use of INSTIs compared to EFV/boosted PI result in lower incidence of adverse events? Population Individuals on ART Intervention NRTI backbone + INSTI (DTG, RAL, EVG/cobi) Comparator NRTI backbone + EFV NRTI backbone + PI/r Outcome(s) Hepatic dysfunction, discontinuation children, adolescents adults pregnant and breastfeeding women HIV/Hep C, HIV/TB IDUs D1.4 EFV toxicity In individuals with HIV on ART does the use of EFV compared to non EFV regimens result in a lower 21

22 incidence of adverse events? Population Individuals with HIV on ART Intervention Use of non-efv containing regimens including INSTIs Comparator Use of EFV containing regimens Outcome(s) CNS toxicities, suicide, depression, sleep disturbance, dizziness, behavioural change, discontinuation Children adolescents adults pregnant and breastfeeding women D1.5 Abacavir toxicity In individuals with HIV does the use of ABC containing regimens compared to use of non ABC containing regimens lower the incidence of adverse events? Population Individuals with HIV Intervention Use of ABC containing regimens Comparator Use of non EBC containing regimens Outcome(s) Hypersensitivity reactions, rash, discontinuations 22

23 Group E HIV testing and counselling Existing recommendations HIV testing and counselling in health facilities In generalized epidemics, provider-initiated testing and counselling should be recommended to everyone (adults, adolescents and children) attending all health facilities, including medical and surgical services; sexually transmitted infection, hepatitis and TB clinics; public and private facilities; inpatient and outpatient settings; mobile or outreach medical services; services for pregnant women (antenatal care, family planning and maternal and child health settings); services for key populations; service for infants and children; reproductive health services. In concentrated and low level epidemics provider initiated testing and counselling should be recommended in all health facilities for: adults and adolescents or children who present in clinical settings with signs and symptoms or medical conditions that could indicate HIV infection, including TB and HIV exposed children, children born to women living with HIV and symptomatic infants and children. Provider initiated testing and counselling should be considered in sexually transmitted infection, hepatitis and TB services, antenatal care settings and services for key populations (notably men who have sex with men, transgender people, sex workers and people who inject drugs) Community-based HIV testing and counselling In generalized HIV epidemics, community based HIV testing and counselling with linkage to prevention, care and treatment services is recommended, in addition to provider initiated testing and counselling (strong recommendation, low quality evidence) In all HIV epidemic settings, community based HIV testing and counselling for key populations, with linkage to prevention, care and treatment services is recommended, in addition to provider initiated testing and counselling (strong recommendation, low quality evidence) Couples Couples and partners should be offered voluntary HIV testing and counselling with support for mutual disclosure (strong recommendation, low quality evidence) Couple and partners in antenatal care settings should be offered voluntary HIV testing and counselling with support for mutual disclosure (strong recommendation, low quality evidence) Couples and partners voluntary HIV testing and counselling with support for mutual disclosure should be offered to individuals with known HIV status and their partners (strong recommendation, low quality evidence for all people with HIV in all epidemic settings; conditional recommendation, low quality evidence for HIV negative people depending on the country specific HIV prevalence Pregnant and postpartum women Generalized epidemics: Provider initiated testing and counselling is recommended for women as a routine component of the package of care in all antenatal, childbirth, postpartum and paediatric care settings. Retesting is recommended in the third trimester, or during labour or shortly after delivery, because of the high risk of acquiring HIV infection during pregnancy. Low level and concentrated epidemics: Provider initiated testing and counselling should be 23

24 considered for pregnant women. Many countries prioritize provider initiated testing and counselling in antenatal care as a key component of their effort to eliminate the mother to child transmission of HIV and are effectively bundling HIV testing with syphilis screening, hepatitis testing and other key test relevant to the setting as well as strengthening the underlying maternal and child health system Infants and children It is strongly recommended that all infants with unknown or uncertain HIV exposure being seen in health care facilities at or around birth or at the first postnatal visit (usually 4-6 weeks) or other child health visit, have their HIV exposure status ascertained (strong recommendation, high quality evidence) It is strongly recommended that all HIV exposed infants have HIV virological testing at four to six weeks of age or at the earliest opportunity thereafter (strong recommendation, high quality evidence) For infants with an initial positive virological test result, it is strongly recommended that ART be started without delay, and at the same time, a second specimen be collected to confirm the initial positive virological result. Do not delay ART. Immediate initiation of ART saves lives and should not be delayed while waiting for the results of the confirmatory test (strong recommendation, high quality evidence) It is strongly recommended that infants with signs and symptoms suggestive of HIV infection undergo HIV serological testing and if positive (reactive) virological testing (strong recommendation - low quality evidence ) It is strongly recommended that well, HIV exposed infants undergo HIV serological testing at around nine months of age (or at the time of the last immunization visit). Infants who have reactive serological assays at nine months should have a virological test to identify HIV infected infants who need ART (strong recommendation, low quality evidence) It is strongly recommended that children 18 months of age or older with suspected HIV infection or HIV exposure, have HIV serological testing performed according to the standard diagnostic HIV serological testing algorithm used in adults (strong recommendation, high quality evidence) Children of school age should be told their HIV positive status and their parents or caregivers status; younger children should be told their status incrementally to accommodate their cognitive skills, and emotional maturity, in preparation for full disclosure (strong recommendation, low quality evidence) HIV testing and counselling with linkages to prevention, treatment and care is recommended for adolescents from key populations in all settings (generalized, low and concentrated epidemics) (strong recommendation, very low quality evidence) HIV testing and counselling with linkage to prevention, treatment and care is recommended for all adolescents in generalized epidemics (strong recommendation, very low quality evidence) We suggest that HIV testing and counselling with linkage to prevention, treatment and care be accessible to all adolescents in low and concentrated epidemics (conditional recommendation, 24

25 very low quality evidence) We suggest that adolescents be counselled about the potential benefits and risks of disclosure of their HIV status and empowered and supported to determine if, when, how and to whom to disclose (conditional recommendation, very low evidence) Proposed PICOs E1.1 Is dual HIV/Syphilis testing feasible? In pregnant women attending ANC is dual testing of HIV/syphilis at the first ANC visit compared to single testing or rapid testing more effective? Population Pregnant women attending ANC Intervention HIV/Syphilis dual testing in pregnant women at first ANC visit Comparator Single HIV and Syphilis laboratory or rapid testing in pregnant women at first ANC visit Outcome(s) Sensitivity, Specificity (HIV and Syphilis) Uptake of testing, access to treatment, ease of us and time to result. E1.2 Is POC EID feasible In infants less than 18 months is POC EID compared to laboratory EID more effective at diagnosis of HIV? Population Infants less than 18 months Intervention POC EID testing disaggregated by platform Comparator Laboratory based EID testing Outcome(s) laboratory and/or field/clinical sensitivity, specificity, PPV, NPV, error rate, ease of use ( steps), sample type, level of health facility, type of health care worker, turnaround time to result receipt, time to ART initiation, cost per test (fully loaded), cost for set up, E1.3 Should EID be delivered in immunisation clinics or Under-5 clinics? In infants less than 18 months is EID performed in immunisation clinics compared to under 5 clinics more effective at diagnosis of HIV? Population infants less than 18 months Intervention EID delivered at immunisation clinics Comparator EID delivered at PMTCT services/art clinics Outcome(s) proportion of children tested, proportion of HIV-infected children referred for care, proportion starting treatment E1.4 Should EID lab services be decentralized to lower level labs? In infants less than 18 months is lab decentralization compared to lab centralization more effective for HIV diagnosis? Population Infants less than 18 months receiving virological testing Intervention lab decentralisation Comparator lab centralisation Outcome(s) Time from test to result, proportion of results returned, retention in the cascade, time to referred to care, time to ART initiation, cost per test undertaken, cost per HIV-infected infant identified, quality of test results 25

26 E1.5 Should SMS printers be used to deliver EID results? In infants less than 18 months is returning results by SMS printer more effective than routine result retrieval? Population children less than 18 months receiving virological testing Intervention use of SMS printers to return results to laboratories or health facilities or parents/care givers Comparator no use of SMS printers (results delivered by courier to the health facility) Outcome(s) Time from test to result, proportion of results returned,, time to referred to care, time to ART initiation 26

27 Group F Service delivery: Care package Existing recommendations Delivering ART in antenatal care and maternal and child health settings In generalized epidemic settings, ART should be initiated and maintained in eligible pregnant and postpartum women and in infants at maternal and child health care settings, with linkage and referral to ongoing care and ART, where appropriate (strong recommendation, very low quality evidence) Delivering ART in TB treatment settings and TB treatment in HIV care settings In settings with a high burden of HIV and TB, ART should be initiated for an individual living with HIV in TB treatment settings, with linkage to ongoing HIV care and ART (strong recommendation, very low quality evidence) In settings with a high burden of HIV and TB, TB treatment may be provided for an individual living with HIV in HIV care settings where TB diagnosis has also been made (strong recommendation, very low quality evidence) ART in settings providing opioid substitution therapy ART should be initiated and maintained in eligible people living with HIV at care settings where opioid substitution (OST) is provided (strong recommendation, very low quality evidence) Decentralizing HIV treatment and care The following options should be considered for decentralisation of ART initiation and maintenance: Initiation of ART in hospitals with maintenance of ART in peripheral health facilities (strong recommendation, low quality evidence) Initiation and maintenance of ART in peripheral health facilities (strong recommendation, low quality evidence) Initiation of ART at peripheral health facilities with maintenance at the community level (that is outside health facilities in settings such as outreach sites, health posts, home based services or community based organizational between regular clinical visits (strong recommendation, moderate quality evidence) Proposed PICOs F1.1 What is the most effective and acceptable frequency of HIV clinic visits in adults, adolescents and children living with HIV? Population PLHIV Intervention Three monthly follow up clinic visit Comparator More frequent clinic visit Outcome(s) Mortality, morbidity, viral suppression, treatment adherence, retention, patient 27

28 acceptability. PLHIV adherent and stable on ART; PLHIV presenting late in the course of HIV infection; PLHIV who are failing first line ART PLHIV presenting early in generalized and concentrated epidemics Adults Children F1.2 For adults and adolescents living with HIV, does delivery of ART in STI clinics has comparable outcome to them receiving ART in HIV care clinic settings? Population For PLHIV in generalized and concentrated epidemics settings Intervention ART provided in STI care settings Comparator ART provided in HIV care settings Outcome(s) Comparable health and programmatic outcomes, mortality, morbidity, viral suppression, treatment adherence, retention, patient acceptability. Adults Settings F1.3 For HIV infected children in high MTCT settings, does receiving HIV care/art in child health care settings provide comparable outcome to referral to HIV care settings? Population HIV-infected children in high MTCT burden settings Intervention HIV treatment for children provided in child health clinics Comparator referral to HIV care clinic Outcome(s) Comparable health and programmatic outcomes: Mortality, morbidity, viral suppression, treatment adherence, retention, patient acceptability. 28

29 F2 ART Adherence Existing recommendations Interventions to optimize adherence to ART Mobile phone text messages could be considered as a reminder tool for promoting adherence to ART as part of a care package of adherence interventions (strong recommendation, moderate quality of evidence) Proposed PICOs F2.1. For HIV infected adults, adolescents, and children, does fixed dose combination ARV result better or comparable treatment adherence? Population For HIV-infected individuals on ART in generalised or concentrated epidemics Intervention ARV fixed dose combination regimen Comparator Non fixed dose ARV regimen Outcome(s) treatment adherence and viral suppression Adults Children F2.2 For adults and adolescents who inject drug and living with HIV, does substitution therapy result better ART adherence compared to those who are not on substitution therapy? Population For HIV-infected people who inject drugs and opt for substitutions therapy Intervention Opioid substitution therapy Comparator No opioid substitution therapy Outcome(s) treatment adherence, viral suppression, severe adverse events, quality of life, mortality, patient acceptability Adults F2.3. For adults, adolescents and children (i.e. their care providers) living with HIV does peer support and adherence counselling result better ART adherence? Population adults, adolescents, and children (i.e. their care providers) living with HIV Intervention peer support and adherence counselling Comparator no peer support and adherence counselling Outcome(s) treatment adherence, viral suppression, adverse events, quality of life, mortality patient and provider acceptability Adults Children F2.4. For adults, adolescents and children living with HIV does out of pocket payment at point of care result poor ART adherence? Population adults, adolescents, and children (i.e. their care providers) living with HIV Intervention No out of pocket payment at POC Comparator Out of pocket payment at POC Outcome(s) treatment adherence and viral suppression, adverse events, quality of life, mortality patient acceptability 29