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Title: What ARV regimen to start with in children older than or equal to three years of age? Contents 1. PICO question ....................................................................................................................................... 1 2. 3. 4. 4.1. 4.2. Search strategy ...................................................................................................................................... 1 Flow diagram of screening process ....................................................................................................... 2 Evidence summaries ............................................................................................................................. 2 Nucleoside reverse-transcriptase inhibitor comparisons ................................................................. 3 Non-nucleoside reverse-transcriptase inhibitor comparisons .......................................................... 3
4.3. Nucleoside reverse-transcriptase inhibitor and non-nucleoside reverse-transcriptase inhibitor comparisons .................................................................................................................................................. 4 4.4. Nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse-transcriptase inhibitor and protease inhibitor comparisons .................................................................................................................... 5 4.5. 5. 6. 7. Non-nucleoside reverse-transcriptase inhibitor and protease inhibitor comparisons ..................... 5 Quality of evidence ............................................................................................................................... 8 Bibliography of included studies .......................................................................................................... 9 Excluded studies with reasons ............................................................................................................ 10
1. PICO question What ARV regimen to start (in children ≥3 years) Children ≥3 years living with HIV 3 NRTI; or 2 NRTI + NNRTI; or 2 NRTI + PI/r (or PI, but only LPV and DRV) As above Mortality, morbidity, severe adverse events, viral response, CD4 response, adherence, switching rate, care retention, tolerability, TB incidence
P I C O
2. Search strategy Search Query #4 Search ((#1) AND #2) AND #3 #3 Search "TDF+3TC/FTC+EFV"[tiab] OR "TDF + FTC + EFV"[tiab] OR "TDF+FTC+EFV"[tiab] OR "TDF + 3TC + EFV"[tiab] OR "TDF+3TC+EFV"[tiab] OR (tenofovir[tiab] AND (lamivudine[tiab] OR emtricitabine[tiab]) AND efavirenz[tiab]) OR (TDF[tiab] AND (3TC[tiab] OR FTC[tiab]) AND EFV[tiab]) OR (TDF[tiab] AND FTC[tiab]) OR truvada[tiab] OR atripla[tiab] OR (epivir[tiab] AND emtriva[tiab] AND viread[tiab]) #2 Search "HIV Infections"[MeSH] OR HIV[MeSH] OR HIV[tiab] OR hiv-1*[tiab] OR hiv2*[tiab] OR hiv1[tiab] OR hiv2[tiab] OR HIV infect*[tiab] OR human immunodeficiency virus[tiab] OR human immunedeficiency virus[tiab] OR human immuno-deficiency This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 1
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Search Query virus[tiab] OR human immunedeficiency virus[tiab] OR ((human immun*) AND (deficiency virus[tiab])) OR acquired immunodeficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR acquired immuno-deficiency syndrome[tiab] OR acquired immunedeficiency syndrome[tiab] OR ((acquired immun*) AND (deficiency syndrome[tiab])) #1 Search randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [MeSH] OR random allocation [MeSH] OR double-blind method [MeSH] OR single-blind method [MeSH] OR clinical trial [pt] OR clinical trials [MeSH] OR ("clinical trial" [tiab]) OR ((singl* [tiab] OR doubl* [tiab] OR trebl* [tiab] OR tripl* [tiab]) AND (mask* [tiab] OR blind* [tiab])) OR (placebos [MeSH] OR placebo* [tiab] OR random* [tiab] OR research design [mh:noexp] OR follow-up studies [MeSH] OR prospective studies [MeSH] OR control*[tiab] OR prospectiv* [tiab]) OR nonrandomi*[tiab] OR before after study[tiab] OR time series[tiab] OR case control[tiab] OR prospective cohort[tiab] OR cohort*[tiab] OR cross-section*[tiab] OR prospective[tiab] OR retrospective[tiab] OR research design[mh:noexp] OR follow-up studies[MeSH] OR prospective studies[MeSH] OR control*[tiab] OR prospectiv*[tiab]) NOT (animals [MeSH] NOT human [MeSH]) 3. Flow diagram of screening process 4655 records identified through database searching 1117 duplicates removed
3538 records screened 3525 total records excluded 31 full-text articles assessed for eligibility
13 studies included in review
4. Evidence summaries We identified five randomized controlled trials that examined 10 different regimens and reported 7 critical or important outcomes. The regimens compared LPV/r to EFV (Viganò 2005), TDF + EFV to d4T + PI/r (Viganò 2007), LPV/r to NVP (PROMOTE 2012), LPV/r or nelfinavir to NVP or EFV (PENPACT-1 2011) and continuous 3TC+ABC+NVP/EFV versus induction with AZT + 3TC + ABC + NVP/EFV for 36 weeks followed by maintenance 3TC + ABC + NVP/EFV versus This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 2
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induction AZT + 3TC + ABC + NVP/EFV for 36 weeks followed by maintenance AZT + 3TC + ABC (ARROW 2012). We identified four observational studies that compared five different regimens and reported findings for three critical outcomes. One study compared NRTI backbones (Bolton-Moore 2007) and three examined NNRTI or PI/r (Castro 2011, Charpentier 2012, Davies 2011). Treatment regimens included AZT versus d4T (Bolton-Moore 2007), NVP versus EFV (Davies 2011), LPV/r versus NVP (Charpentier 2012, Davies 2011), LPV/r versus EFV (Davies 2011) and LPV/r versus an NNRTI (NVP or EFV) plus two NRTI (Castro 2011). Summaries are arranged below as: • • • nucleoside reverse-transcriptase inhibitor comparisons (AZT versus d4T); non-nucleoside reverse-transcriptase inhibitor comparisons (NVP versus EFV); nucleoside reverse-transcriptase inhibitor and non-nucleoside reverse-transcriptase inhibitor comparisons (continuous 3TC + ABC + NVP/EFV versus induction AZT + 3TC + ABC + NVP/EFV with maintenance 3TC + ABC + NVP/EFV versus induction AZT + 3TC + ABC + NVP/EFV with maintenance AZT + 3TC + ABC); nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse-transcriptase inhibitor and protease inhibitor comparisons (TDF + EFV versus d4T + PI); non-nucleoside reverse-transcriptase inhibitor and protease inhibitor comparisons (LPV/r versus NVP; LPV/r versus EFV; LPV/r versus NVP or EFV; LPV/r or nelfinavir versus EFV or NVP).
• •
4.1. Nucleoside reverse-transcriptase inhibitor comparisons AZT versus d4T Observational studies (Bolton-Moore 2007) Outcome: mortality One study reporting on mortality provides low quality (Bolton-Moore 2007). No specific reasons were identified for upgrading the evidence, though due to the results originating from observational data, the evidence was low quality. The data did not exclude a potential superiority or inferiority of AZT compared with d4T (RR=0.90, 95% CI 0.64–1.27). 4.2. Non-nucleoside reverse-transcriptase inhibitor comparisons
NPV versus EFV Observational studies (Davies 2011) Outcome: viral failure
This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 3
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Davies et al. (2011) estimated the effect of NVP versus EFV on viral failure and found a significantly higher risk of viral failure in the NVP-treated group compared to the EFV-treated group (RR=1.77; 95% CI 1.11–2.83). The evidence from this single observational study is of low quality. 4.3. Nucleoside reverse-transcriptase inhibitor and non-nucleoside reverse-transcriptase inhibitor comparisons Continuous 3TC + ABC + NVP/EFV versus induction AZT + 3TC + ABC + NVP/EFV with maintenance 3TC + ABC + NVP/EFV versus induction AZT + 3TC + ABC + NVP/EFV with maintenance AZT + 3TC + ABC (ARROW 2012) Experimental studies Outcome: mortality The ARROW trial compared mortality among children in Uganda and Zimbabwe who were continuously treated with 3TC + ABC + NVP/EFV (Arm A) to those initially treated for 36 weeks with AZT + 3TC + ABC + NVP/EFV and subsequently with 3TC + ABC + NVP/EFV (Arm B) to those initially treated for 36 weeks with AZT + 3TC + ABC + NVP/EFV and subsequently with AZT + 3TC + ABC (Arm C) (ARROW 2012). Study data do not exclude the potential superiority or inferiority of the initial four-drug induction and maintenance 3TC + ABC + NVP/EFV regimen compared with the continuous 3TC + ABC + NVP/EFV regimen (RR=0.69; 95% CI 0.35–1.34) or the initial fourdrug induction and maintenance AZT + 3TC + NVP/EFV regimen to the continuous 3TC + ABC + NVP/EFV regimen (RR=0.98; 95% CI 0.54–1.79). The quality of these outcomes was downgraded to low due to very serious imprecision because of few events. Outcome: combined outcomes of progression to AIDS, viral failure and/or mortality Data from the ARROW trial do not exclude the potential superiority or inferiority of the initial four-drug induction and maintenance 3TC + ABC + NVP/EFV regimen compared with the continuous 3TC + ABC + NVP/EFV regimen or the initial four-drug induction and maintenance AZT + 3TC + NVP/EFV regimen to the continuous 3TC + ABC + NVP/EFV regimen with respect to new WHO category 4 disease or death (arm A versus arm B, RR=0.76; 95% CI 0.49–1.19; arm A versus arm C, RR=0.78; 95% CI 0.50–1.22) or with respect to new WHO category 3 disease or death (arm A versus arm B, RR=0.81; 95% CI 0.59–1.10; arm A versus arm C, RR=0.73; 95% CI 0.52–1.00). The quality of these outcomes was downgraded to moderate due to serious imprecision because of few events. Outcome: treatment switch and ART failure Data from the ARROW trial do not exclude the potential superiority or inferiority of the initial four-drug induction and maintenance 3TC + ABC + NVP/EFV regimen compared with the continuous 3TC + ABC + NVP/EFV regimen (RR=0.64; 95% CI 0.35–1.17) or the initial four-drug induction and maintenance AZT + 3TC + NVP/EFV regimen to the continuous 3TC + ABC + NVP/EFV regimen (RR=0.75; 95% CI 0.43–1.33) with respect to switching to second-line therapy. The quality of these outcomes was downgraded to moderate due to serious imprecision because of few events. This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 4
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4.4. Nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse-transcriptase inhibitor and protease inhibitor comparisons TDF + EFV versus d4T + PI Experimental studies (Viganò 2007) Outcome: HIV disease progression One randomized controlled trial (Viganò 2007) examined the effect of switching stable patients with undetectable viral loads from d4T to TDF and an unboosted PI (indinavir, nelfinavir or ritonavir) to EFV on HIV progression. Study data at 96 weeks do not exclude the potential superiority or inferiority of TDF + EFV compared with d4T + PI with respect to mean CD4% (mean difference=1.8%; 95% CI 1.99% lower to 5.59% higher) or mean CD4 count (mean difference=1 cell/mm3; 95% CI 171.01 lower to 173.01 higher). The quality of evidence was downgraded to low due to very serious imprecision. Outcome: other metabolic measures Viganò (2007) also studied the effect of switching from a PI to EFV and from d4T to TDF on mean body mass index in children at week 96. The data do not exclude the potential superiority or inferiority of TDF + EFV compared to d4T + PI with respect to this outcome (mean difference=0.7 kg/m2 higher, 95% CI 1.03 lower to 2.43 higher). The quality of evidence was downgraded to low due to very serious imprecision. 4.5. Non-nucleoside reverse-transcriptase inhibitor and protease inhibitor comparisons LPV/r versus NVP Experimental studies (PROMOTE 2012) Outcome: mortality Data from a subanalysis of PROMOTE (2012) study data restricted to participants ≥36 months old do not exclude the potential superiority or inferiority of LPV/r compared to NVP with respect to mortality (RR=1.02; 95% CI 0.27–3.89). The quality of evidence for this outcome was downgraded to low due to very serious imprecision. Outcome: HIV disease progression In a subanalysis of children ≥36 months old, PROMOTE researchers estimated the mean CD4% between LPV/r and NNRTI (NVP or EFV)-treated children in Uganda and found that the data do not exclude the potential superiority or inferiority of LPV/r compared to NVP with respect to CD4% (mean difference=3.30% lower; 95% CI 6.88% lower to 0.28% higher). The quality of evidence for this outcome is low and downgraded due to very serious imprecision because of few events. Outcome: treatment interruption or viral failure This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 5
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Researchers from PROMOTE (2012) conducted a subanalysis of children >12 months old and found that study data do not exclude the potential superiority or inferiority of LPV/r compared to NVP with respect to viral failure or treatment discontinuation among patients (RR=0.82; 95% CI 0.41–1.64) (PROMOTE 2012). This study provides low-quality evidence and was downgraded for very serious imprecision. Outcome: combined outcomes of progression to AIDS, viral failure and/or mortality PROMOTE (2012) researchers estimated the effect of LPV/r on mortality or viral failure in children ≥36 months old. The data do not exclude the potential superiority or inferiority of LPV/r compared to NVP (RR=0.95; 95% CI 0.38–2.35). The quality of evidence for this outcome was downgraded to very low due to very serious imprecision because of few events. Observational studies (Charpentier 2012; Davies 2011) Outcome: viral failure Two observational studies estimated the effect of LPV/r versus NVP on viral failure and found that pooled study data did not exclude a potential superiority or inferiority of LPV/r compared with NVP (RR=0.83; 95% CI 0.47–1.19) (Charpentier 2012; Davies 2011). The quality of evidence from these observational studies is very low and downgraded as a result of the inconsistency in point estimates. Specifically, Charpentier found a non-significant, unadjusted, increased risk of viral failure in the LPV/r arm (RR=1.17; 95% CI 0.60–1.74), while Davies found a non-significant, adjusted, decreased risk of viral failure in the LPV/r arm compared to the NVP arm (RR=0.60; 95% CI 0.13–1.07). Outcome: resistance and viral mutation Observational evidence for this outcome comes from one study (Charpentier 2012), which examined the incidence of antiretroviral resistance among patients treated with LPV/r compared to patients who were treated with NVP. Study data do not exclude the potential superiority or inferiority of LPV/r compared with NVP (RR=1.06; 95% CI 0.84–1.34). For this outcome, the evidence was downgraded due to serious imprecision and a lack of confounder adjustment. LPV/r versus EFV Experimental studies (Viganò 2005) Outcome: other metabolic measures LPV/r versus EFV. In a randomised controlled trial, Viganò (2005) found significantly higher risks for cholesterol >95th percentile for age, sex and race at week 12 in children treated with LPV/r compared to children treated with EFV (RR=7.54; 95% CI 1.07–53.23). The quality of evidence for this outcome was downgraded due to very serious imprecision. Observational studies (Davies 2011) Outcome: viral failure This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 6
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Davies et al. also compared the effect of LPV/r and EFV with respect to viral failure (HR=1.07; 95% CI 0.76–1.51) (Davies 2011). Study data did not exclude a potential superiority or inferiority of LPV/r compared with EFV. The evidence from this observational study is low
LPV/r versus NVP or EFV Observational studies (Castro 2011) Outcome: viral failure One observational study estimated the effect of LPV/r versus NNRTI + two NRTIs (NVP or EFV) on viral failure and found that the data did not exclude a potential superiority or inferiority of LPV/r compared with either NVP or EFV (HR=0.40; 95% CI 0.12–1.30) (Castro 2011). The evidence from this observational study is very low due to imprecision. LPV/r or nelfinavir versus EFV or NVP Experimental studies (PENPACT-1 2011) Outcome: HIV disease progression PENPACT-1 (2011), a trial conducted in North and South America and Europe, also estimated the effect of LPV/r or nelfinavir-based regimens on disease progression compared to EFV- or NVP-based regimens (PENPACT-1 2011). The data from this study did not exclude the potential superiority or inferiority of LPV/r compared to NVP with respect to continued viral suppression (RR=0.99; 95% CI 0.80–1.23), viral load <400 copies/ml at week 24 and year 4 (RR=0.91; 95% CI 0.80–1.04, RR=1.0; 95% CI 0.89–1.12, respectively), mean reduction of viral load (mean difference=0.15 log10 lower; 95% CI 0.41 lower to 0.11 higher) or mean change in CD4% (mean difference=1.5% higher; 95% CI 0.7% lower to 3.7% higher). The quality of evidence from all HIV disease progression outcomes from PENPACT-1 was high and not downgraded. Outcome: treatment interruption or viral failure Researchers with the PENPACT-1 trial found a significantly higher risk of second-line ART failure in children treated with LPV/r or nelfinavir compared to children treated with EFV or NVP (RR=1.26; 95% CI 0.51–3.09) (PENPACT-1 2011). The quality of this outcome was downgraded to low due to very serious imprecision due to few events. Outcome: resistance and viral mutation The PENPACT-1 (2011) study found significantly lower risk for a major NNRTI mutation among patients treated with LPV/r or nelfinavir when compared to children treated with EFV or NVP (RR=0.28; 95% CI 0.14–0.56). They also found significantly higher risk for a major PI mutation among patients treated with LPV/r or nelfinavir when compared to children treated with EFV or NVP (RR=4.48; 95% CI 1.31–15.32). The evidence was low and downgraded due to very serious imprecision.
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5. Quality of evidence For the mortality outcomes, the quality of evidence is low. One randomized controlled trial estimated the effect of LPV/r versus NVP on reducing the risk of death (PROMOTE 2012). The authors found no significant differences and the quality of evidence from these randomized controlled trials was low and was downgraded due to very serious imprecision. Similarly the ARROW (2012) trial showed no significant differences in mortality among the three arms, and the quality of the evidence from this study is similarly low because of very serious imprecision due to few events. One observational study estimated the effect of AZT versus d4T on mortality (Bolton-Moore 2007). The authors found no significant differences and the evidence from this observational study is low due to the study design. For HIV disease progression, the quality of the evidence is low for the TDF + EFV versus d4T + PI (Viganò 2007) and for the LPV/r versus NVP (PROMOTE 2012) comparison due to serious imprecision from few events but high for the LPV/r or nelfinavir versus EFV or NVP comparison (PENPACT-1 2011). Given the different regimens, data from these studies could not be combined. Data from the individual studies could exclude the neither potential superiority nor the inferiority of any arm. For viral failure, the quality of evidence is low to very low. One observational study estimated the effect of NVP versus EFV on viral failure (Davies 2011). The authors found a significantly higher risk of viral failure in the NVP-treated group compared to the EFV group, though the evidence from this observational study is low due to the study design (observational). The authors also estimated the risk of viral failure in the LPV/r-treated group compared to the EFV group and found no significant differences, although the evidence from this observational study is low due to the study design (observational). Two observational studies estimated the effect of LPV/r versus NVP on viral failure (Charpentier 2012; Davies 2011). Data from neither study could exclude the potential superiority or inferiority of either arm. One observational study estimated the effect of LPV/r versus NVP or EFV and two NRTIs on viral failure (Castro 2011). Study data could not exclude the potential superiority or inferiority of either arm, and the evidence from this observational study is very low due to imprecision. For treatment interruption or viral failure, the quality of evidence is low. One randomized controlled trial estimated the effect of LPV/r versus NVP on the risk of viral failure and/or treatment discontinuation (PROMOTE 2012). The study data were unable to exclude the potential superiority or inferiority of either arm. This study provides low-quality evidence and was downgraded for very serious imprecision due to few events. For treatment switch, the quality of evidence is low. One RCT estimated the effect of LPV/r or nelfinavir versus NVP or EFV on second-line ART failure (PENPACT-1 2011). The authors found no significant differences, but the evidence from this RCT is low due to very serious imprecision due to few events. ARROW (2012) estimated the effect of three different regimens on the risk of switching. Data from the study could not exclude the potential superiority or inferiority of any one of the three arms, and the quality of the evidence from this RCT is low due to serious imprecision. For the combined outcomes of progression to AIDS, viral failure or mortality, the quality of evidence is low to moderate. One randomized controlled trial estimated the effect of LPV/r versus NVP on the risk of viral failure or death (PROMOTE 2012). The data do not exclude the potential superiority or interiority This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 8
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of LPV/r compared to NVP, and the quality of evidence is low due to various serious imprecision due to few events. Data from the ARROW (2012) trial similarly do not exclude the potential superiority or interiority of any of the arms. The evidence from this RCT is moderate due to a serious imprecision. For resistance and viral mutations, the quality of evidence is low to very low. One RCT estimated the effect of LPV/r or nelfinavir versus EFV or NVP on the risk of a major NNRTI or PI mutation (PENPACT-1 2011). The authors found a significantly lower risk of a major NNRTI mutation in the LPV/r or nelfinavir arm and a significantly higher risk in the LPV/r or nelfinavir arm for a major PI mutation, though the evidence from this RCT is low due to very serious imprecision. One observational study estimated the effect of LPV/r versus NVP on the antiretroviral resistance (Charpentier 2012) and found no significant difference. The evidence from this observational study is very low due to a serious risk of bias (no adjusted estimates) and serious imprecision. For other metabolic measures, the quality of evidence is low. One RCT estimated the effect of TDF + EFV versus PI + d4T on the mean BMI at week 96 (Viganò 2007). The authors found no significant differences, and the quality of the evidence from this RCT is low due to very serious imprecision. Another RCT estimated the effect of LPV/r versus EFV on the risk of cholesterol greater than 95th percentile for age, sex and race at week 12 (Viganò 2005). The authors found a significantly higher risk among LPV/r-treated children when compared to the EFV-treated children, although the quality of evidence from this RCT is low due to very serious imprecision. 6. Bibliography of included studies Peer-Reviewed Articles 1. Aurpibul L, Puthanakit T, Lee B, Mangklabruks A, Sirisanthana T, Sirisanthana V. Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reversetranscriptase inhibitor-based antiretroviral therapy. Antivir Ther 2007; 12: 1247-54. 2. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, Chintu N, Stringer EM, Chi BH, Sinkala M, Kankasa C, Wilson CM, Wilfert CM, Mwango A, Levy J, Abrams EJ, Bulterys M, Stringer JS. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA 2007; 298:1888-99. 3. Castro H, Judd A, Gibb DM, Butler K, Lodwick RK, van Sighem A, Ramos JT, Warsawski J, Thorne C, Noguera-Julian A, Obel N, Costagliola D, Tookey PA, Colin C, Kjaer J, Grarup J, Chene G, Phillips A. Risk of triple-class virological failure in children with HIV: a retrospective cohort study. Lancet 2011; 377:1580-87. 4. Charpentier C, Gody JC, Mbitikon O, Moussa S, Matta M, Pere H, Fournier J, Longo JDD, Belec L. Virological response and resistance profiles after 18 to 30 months of first- or second-/third-line antiretroviral treatment: a cross-sectional evaluation in HIV type 1-infected children living in the Central African Republic. AIDS Res Hum Retrovirus 2012; 28:87-94. 5. Davies MA, Moultrie H, Eley B, Rabie H, Van Cutsem G, Giddy J, Wood R, Technau K, Keiser O, Egger M, Boulle A. Virologic failure and second-line antiretroviral therapy in children in South Africa-the IeDEA Southern Africa collaboration. J Acquir Immune Defic Syndr 2011; 56:270-78. This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 9
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6. European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS 2004; 18: 1443-51. 7. Patel K, Hernan MA, Williams PL, Seeger JD, McIntosh K, Dyke RB, Seage GR, 3rd. Long-term effects of highly active antiretroviral therapy on CD4+ cell evolution among children and adolescents infected with HIV: 5 years and counting. Clin Infect Dis 2008; 46:1751-60. 8. PENPACT-1 (PENTA 9/PACTG 390) Study Team, Babiker A, Castro nee Green H, Compagnucci A, Fiscus S, Giaquinto C, Gibb DM, Harper L, Harrison L, Hughes M, McKinney R, Melvin A, Mofenson L, Saidi Y, Smith ME, Tudor-Williams G, Walker AS. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse-transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infect Dis 2011; 11:273-83. 9. Tolle M, Howard L, Kirk B, Gomila A, Schwarzwald H, Anabwani G. Reverse-transcriptase genotypes in pediatric patients failing initial antiretroviral therapy in Gaborone, Botswana. J Int Assoc Physicians AIDS Care 2012; 11:260-68. 10. Viganò A, Brambilla P, Cafarelli L, Giacomet V, Borgonovo S, Zamproni I, Zuccotti G, Mora S. Normalization of fat accrual in lipoatrophic, HIV-infected children switched from stavudine to tenofovir and from protease inhibitor to efavirenz. Antivir Ther 2007; 12:297-302. 11. Viganò A, Aldrovandi GM, Giacomet V, Merlo M, Martelli L, Beretta S, Luraschi P, Rombolà G, Mora S. Improvement in dyslipidaemia after switching stavudine to tenofovir and replacing protease inhibitors with efavirenz in HIV-infected children. Antivir Ther 2005; 10:917-24. Unpublished Data 1. Anti-Retroviral Research for Watoto. The ARROW Trial. 2012. Unpublished data. 2. HIV protease inhibitors for the prevention of malaria in Ugandan children. The PROMOTEPEDS Trial. 2012. Unpublished data. Conference abstracts 1. Not done 7. Excluded studies with reasons Peer-reviewed publications Deeks ED. Atazanavir: In pediatric patients with HIV-1 infection. Pediatr Drugs 2012; 14: 131-141. Comment: Excluded because the study is actually a review Brewinski M, Megazzini K, Freimanis Hance L, Cruz MC, Pavia-Ruz N, Della Negra M, Ferreira FGF, Marques H, Hazra R. Dyslipidemia in a cohort of HIV-infected Latin American children receiving highly active antiretroviral therapy. J Trop Paediatr 2011; 57: 324-332. Comment: Excluded due to toxicity end-points (covered in other reviews)
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Coovadia A, Abrams EJ, Stehlau R, Meyers T, Martens L, Sherman G, Hunt G, Hu CC, Tsai WY, Morris L, Kuhn L. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial. JAMA 2010;10:1082-1090. Comment: Excluded because all children were <24 months old at enrolment Delaugerre C, Teglas JP, Treluyer JM, Vaz P, Jullien V, Veber F, Rouzioux C, Chaix ML, Blanche S. Predictive factors of virologic success in HIV-1-infected children treated with lopinavir/ritonavir. J Acquir Immune Defic Syndr 2004; 37: 1269-1275. Comment: Excluded due to absence of drug or therapy of interest comparisons. Giacomet V, Bedogni G, Vigano A, Mora S, Manfredini V, Stucchi S, Erba P, Penagini F, Di Nello F, Brambilla P, Zuccotti GV. Six-year changes of anthropometric, total and appendicular fat masses measures in HIV-infected children switching from stavudine to tenofovir and from protease inhibitor to efavirenz. Infection 2011; 39:S52: Comment: Excluded due to toxicity end-points (covered in other reviews) Hunt GM, Coovadia A, Abrams EJ, Sherman G, Meyers T, Morris L, Kuhn L. HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine. AIDS 2011; 25: 1461-1469. Comment: Excluded due to drug resistance mutation end-points in children exposed to sdNVP. Judd A; European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Early antiretroviral therapy in HIV-1-infected infants, 1996-2008: treatment response and duration of first-line regimens. AIDS 2011; 25:2279-87. Comment: Excluded because all children were <12 months old at enrolment Kuhn L, Coovadia A, Strehlau R, Martens L, Hu CC, Meyers T, Sherman G, Hunt G, Persaud D, Morris L, Tsai WY, Abrams EJ. Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: Long-term follow-up of a randomised, open-label trial. Lancet Infect Dis 2012; 12: 521-530. Comment: Excluded because all children were <24 months old at enrolment Okomo U, Togun T, Oko F, Peterson K, Townend J, Peterson I, Jaye A. Treatment outcomes among HIV-1 and HIV-2 infected children initiating antiretroviral therapy in a concentrated low prevalence setting in west Africa. BMC Pediatr 2012; 12:95 Comment: Excluded due to absence of drug or therapy of interest comparisons. Pierre RB, Steel-Duncan JC, Evans-Gilbert T, Rodriguez B, Moore J, Palmer P, Smikle MF, Davis D, Figueroa JP, Christie CD. Effectiveness of antiretroviral therapy in treating paediatric HIV/AIDS in Jamaica. West Indian Med J 2008; 57: 223-230. Comment: Excluded due to absence of drug or therapy of interest comparisons. This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 11
WHO/HIV/2013.27
© World Health Organization 2013
Rosso R, Nasi M, Di Biagio A, Repetto E, Dentone C, Pinti M, Nemes E, Ferraresi R, Mussini C, Esposito R, Viscoli C, Cossarizza A. Effects of the change from stavudine to tenofovir in human immunodeficiency virus-infected children treated with highly active antiretroviral therapy: studies on mitochondrial toxicity and thymic function. Pediatr Infect Dis J 2008; 27:17-21. Comment: Excluded due to toxicity end-points (covered in other reviews) Saez-Llorens X, Nelson Jr RP, Emmanuel P, Wiznia A, Church J, Sleasman J, Van Dyke R, Richardson CG, Rosko C, Cutrell A, Hethrington SV. Ziagen (abacavir, ABC) combined with 3TC & ZDV is safe and effective through 48 weeks in HIV-1 infected antiretroviral therapy-experienced children (CNA3006). Pediatric Res 2000; 47:4, 275a. Comment: Excluded due to comparison of dual versus triple therapy drug exposure Strehlau R, Coovadia A, Abrams EJ, Martens L, Arpadi S, Meyers T, Kuhn L. Lipid profiles in young hiv-infected children initiating and changing antiretroviral therapy. JAIDS J Acquir Immune Defic Syndr 2012; 60:369-76. Comment: Excluded due to toxicity end-points (covered in other reviews) Violari A, Lindsey JC, Hughes mean difference, Mujuru HA, Barlow-Mosha L, Kamthunzi P, Chi BH, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med 2012; 366:2380-9. Comment: Excluded because all children were <36 months old at enrolment. Wamalwa DC, Farquhar C, Obimbo EM, Selig S, Mbori-Ngacha DA, Richardson BA, Overbaugh J, Emery S, Wariua G, Gichuhi C, Bosire R, John-Stewart G. Early response to highly active antiretroviral therapy in HIV-1-infected Kenyan children. J Acquir Immune Defic Syndr 2007; 45: 311-317. Comment: Excluded due to absence of drug or therapy of interest comparisons. Zhao Y, Mu W, Harwell J, Zhou H, Sun X, Cheng Y, Li C, Zhang F. Drug resistance profiles among HIV-1-infected children experiencing delayed switch and 12-month efficacy after using second-line antiretroviral therapy: an observational cohort study in rural China. J Acquir Immune Defic Syndr 2011; 58: 47-53. Comment: Excluded due to no clear comparison of first-line drugs
This work was commissioned by the World Health Organization and carried out by The University of California, San Francisco (UCSF), Cochrane Review Group on HIV/AIDS 12