WHO/HIV/2013.16
© World Health Organization 2013
Title: When to start ART in pregnant women living with HIV?
Contents 1. 2. 3. 4. 4.1. 4.2. 5. PICO question ....................................................................................................................................... 1 Search strategy ...................................................................................................................................... 1 Flow diagram of screening process ....................................................................................................... 2 Evidence summaries ............................................................................................................................. 3 Randomized controlled trials ............................................................................................................ 3 Observational studies ........................................................................................................................ 4 Bibliography of included studies .......................................................................................................... 8
1. PICO question When to start: pregnant women living with HIV (may include women with childbearing potential) Pregnant women living with HIV: a) breastfeeding settings; b) non-breastfeeding settings ART initiation at CD4 >350 cells/mm3 or irrespective of CD4 cell count Defer ART initiation until CD4 cell count ≤350 cells/mm3 or symptomatic HIV disease (WHO stages 3 and 4); provide ARV prophylaxis Vertical transmission, sexual transmission, individual health benefit (HIV mortality and morbidity), non-HIV morbidity and mortality, child survival, severe adverse events, retention, adherence, HIV drug resistance, TB incidence
P I C O
2. Search strategy 15 June 2009–27 Aug 2012
Search Query #5 #4 Search (((#1) AND #2) AND #3) AND #4 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 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 immune-deficiency syndrome[tiab] OR ((acquired immun*) AND (deficiency syndrome[tiab])) 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]
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Search Query 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 non-randomi*[tiab] OR before after study[tiab] OR time series[tiab] OR case control[tiab] OR prospective cohort[tiab] OR cohort*[tiab] OR crosssection*[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]) #2 Search (pregnan*[tiab] OR "Pregnancy"[MeSH]) OR (childbearing[tiab] AND potential[tiab]) OR (childbearing[tiab] AND age[tiab]) OR (child-bearing[tiab] AND potential[tiab]) OR (childbearing [tiab] AND age[tiab]) OR (reproductive[tiab] AND age[tiab]) OR (nonpregnant[tiab] OR nonpregnant[tiab] OR “not pregnant”[tiab])) Search (HAART[tiab] OR ART[tiab] OR antiretroviral[tiab] OR anti-retroviral[tiab] OR "AntiHIV Agents/therapeutic use"[MeSH] OR "Drug Therapy, Combination/methods"[MeSH] OR Antiretroviral Therapy, Highly Active[MeSH] OR efavirenz[tiab] OR EFV[tiab] OR sustiva[tiab] OR stocrin[tiab]) AND (start*[tiab] OR initia*[tiab] OR begin*[tiab] OR timing[tiab] OR early[tiab] OR earli*[tiab] OR (CD4[tiab] AND (irrespective[tiab] OR above 350 [tiab] OR 350[tiab] OR >350[tiab]))
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3. Flow diagram of screening process 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
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3.1. When to start ART among pregnant women 308 records identified through database searching 116 duplicates removed
192 records screened
302 total records excluded 20 full-text articles assessed for eligibility
6 studies included in review
4. Evidence summaries 4.1. Randomized controlled trials Outcome: Severe adverse events and lab abnormalities. The quality of evidence is high from one RCT (Cohen 2011) with no observed study limitations. • One study (Cohen 2011) in Africa, South America and Europe found no significant difference in severe adverse events comparing early and deferred treatment cohorts (RR=1.06, 95% CI 0.84– 1.33). Outcome: serious non-AIDS defining illness and non-opportunistic disease–related death. The quality of evidence for this outcome is very low and comes from one randomized study (SMART 2008) that studied the risk of serious non-AIDS-defining diagnoses and non-opportunistic disease–related deaths among patients treated early compared to patients who deferred treatment. For this outcome, the evidence was downgraded due to very serious imprecision and serious indirectness because ART in the delayed group was actually initiated when CD4 fell below 250 cells/mm3, not 350. • In one United States study (SMART 2008), the risk of developing a non-AIDS-defining illness or non-opportunistic disease-related death was lower among patients who started ART early when compared to patients who started ART later (RR=0.14, 95% CI 0.03–0.64).
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Outcome: mortality or survival outcomes. The one RCT (Cohen 2011) reporting on mortality provides low-quality evidence. The quality of evidence was downgraded because of very serious imprecision due to few events. • One study (Cohen 2011) in Africa, South America and Europe found no significant difference in risk of death comparing early and deferred treatment cohorts (RR=0.77, 95% CI 0.34–1.75).
Outcome: HIV disease progression. The one RCT (SMART 2008) reporting on progression to AIDS provides very-low-quality evidence. The quality of evidence was downgraded because of very serious imprecision due to few events and serious indirectness (ART in the delayed group was initiated when CD4 fell below 250 cells/mm3, not 350). • One study (SMART 2008) in the United States found a significantly lower risk of progression to AIDS among patients initiating ART treatment early when compared to patients who deferred treatment (RR=0.31, 95% CI 0.10–0.96).
Outcome: combined outcomes of progression to AIDS and/or mortality or AIDS-free survival. The two randomized studies (SMART 2008 and Cohen 2011) reporting on progression to AIDS or mortality provide low-quality evidence. The evidence was downgraded because of serious imprecision and serious indirectness (in the SMART study, ART in the delayed group was actually initiated when CD4 fell below 250 cells/mm3, not 350). Both studies reporting AIDS progression and mortality outcomes consistently found a statistically significant reduced risk among patients treated early versus patients treated later. • Two RCTs (SMART 2008 and Cohen 2011) in North America, South America and Africa found a significantly lower risk of progression to AIDS or death among patients initiating ART treatment early when compared to patients who deferred treatment (RR=0.48, 95% CI 0.26–0.91).
Outcome: viral failure. The one RCT (Grant 2011) reporting on time to viral failure provides lowquality evidence. The quality of evidence was downgraded because of very serious imprecision due to few events. • One study (GRANT 2011) in the United States found a nonsignificantly higher risk of viral failure among patients initiating different ART treatment regimens early when compared to patients who deferred treatment (ABC/3TC: RR=1.54, 95% CI 0.92–2.56 and TDF/FTC: RR=1.30, 95% CI 0.77–2.20, respectively).
4.2. Observational studies Outcome: HIV disease progression. The quality of evidence is very low in the four observational studies, given the possible confounding and serious imprecision in the estimates. Only one study (Opravil 2002) adjusted for other factors influencing the timing of ART initiation. All but one (ART Cohort Collaboration 2009) of these studies are consistent in reporting decreases in the risk of progression to AIDS. When the results are restricted to only patients who were immunologically improving six months after ART initiation, one study (ART Cohort Collaboration 2009) found no significant effect of early versus deferred treatment. The quality of evidence from this study for all considered outcomes describing HIV 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
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disease progression is very low. None of the estimates was adjusted for potential confounding, and one estimate was at risk for serious imprecision. Considering only the clinical categories for determining the progression of HIV disease, Opravil et al. found a decreased risk of progression to Category B or C disease among patients treated early when compared to deferred-treatment patients. The quality of evidence for this outcome was very low due to a serious risk of imprecision resulting from very few cases. • Three studies (Ahdieh-Grant 2003, Opravil 2002, Plettenberg 2011) using observational cohort data found a lower risk of progression to AIDS among patients who initiated ART early (CD4 count ≥350 cells/mm3) compared to patients who initiated ART late (<350 cells/mm3). AhdiehGrant (United States) found an RR of 0.95 (95% CI 0.47–1.93) comparing early versus late ART initiators. Similarly, Opravil (Switzerland) and Plettenberg (Germany) found an RR of 0.23 (95% CI 0.08–0.67) and 0.57 (95% CI 0.24–1.36), respectively, comparing similar ART initiation groups. One study (ART Cohort Collaboration 2009) using multiple observational cohorts from the United States and Europe found no difference of risk for progression to AIDS comparing early and delayed cohorts (RR 1.06, 95% CI 0.85–1.34). The pooled risk across all four studies comparing early versus delayed treated patients on progression to AIDS is RR=0.70 (95% CI 0.40–1.24). One study (ART Cohort Collaboration 2009) using multiple observational cohorts from the United States and Europe found no difference in the risk for progression to AIDS comparing early and delayed cohorts (RR 1.15, 95% CI 0.89–1.49) when restricted to patients whose CD4 increased six months post-initiation. One study (Opravil 2002) using an observational cohort in Switzerland found no difference in the risk of progression to B or C disease comparing early and delayed cohorts (RR 0.19, 95% CI 0.11–0.33).
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Outcome: immune recovery. The quality of evidence in these observational studies is low to very low for several reasons. Several observational studies explored the impact of early versus delayed ART initiation with multiple outcomes, to include CD4 increase at specified thresholds (at least 50, 100, 150 and 200 cells/mm3), CD4 reaching ≥800 cells/mm3 after ART initiation and viral suppression. All studies exploring the impact of early initiation of ART on CD4 were consistent and found increased CD4 counts among patients who were treated early versus the patients who were treated later (Althoff 2010, CASCADE 2003, Gras 2007). It should be noted, however, that the results of all but one study (Gras 2007) were not statistically significant. Due to a lack of confounder adjustment, most evidence from these outcomes was downgraded to very-low quality. However, both Althoff and Gras reported adjusted estimates and were therefore downgraded only for their observational design. Two studies (Althoff 2010, Phillips 2001) estimated the impact of early versus delayed treatment on viral suppression and found very similar results: a reduced likelihood of viral suppression among patients treated early when compared to patients with delayed treatment. The quality of evidence for viral suppression is low. No specific reasons were noted for downgrading the evidence other than the observational study design. To explore the converse of immune recovery, we also included viral failure and viral rebound outcomes. One observational study (Cozzi Lepri 2001) estimated the effect of early versus deferred treatment on viral failure and found no difference between cohorts. The quality of evidence for this outcome is low due to the source being observational study data. No other reasons were noted for downgrading evidence of viral failure. Additionally, one observational study estimated the effect of early versus deferred treatment on 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
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viral rebound (Phillips 2001) and found no difference between cohorts. Similarly, the quality of evidence for this outcome is low due to the source being observational study data, although no other reasons were noted for downgrading evidence of viral rebound. • One study (CASCADE 2003) in Europe found an increased likelihood of CD4 increase six months after HAART among patients who were treated early compared to patients who were treated late. Though none of the rate ratios are statistically significant, the point estimates are all increased for increases of at least 50, 100, 150 and 200 cells/mm3 (RR=1.09, 95% CI 0.97–1.22; RR=1.07, 95% CI 0.91–1.25; RR=1.02, 95% CI 0.83–1.26; and RR=1.18, 95% CI 0.89–1.57, respectively). In one study (Gras 2007) in the Netherlands, the likelihood of reaching ≥800 CD4 cells/mm3 after initiating ART was increased among patients who were treated early when compared to patients treated later (RR=2.83, 95% CI 2.44–3.28). In one study (Althoff 2010) in North America, patients who initiated ART early were no more likely to have an increase of 100 CD4 cells/mm3 than patients who initiated ART later (RR=1.05; 95% CI 0.98–1.12). In two studies (Althoff 2010, Phillips 2001) in North America and Europe, the likelihood of viral suppression (<500 copies/ml) was lower among patients treated early when compared to patients whose treatment was delayed (RR=0.94; 95% CI 0.89–0.99). Specifically, Althoff estimated the risk of viral suppression among patients treated early was adjusted hazard odds ratio=0.94 (95% CI 0.89–1.00) when compared to patients treated later. Similarly, Phillips et al. found that the risk of viral suppression among patients treated early versus patients treated later was RR=0.93 (95% CI 0.83–1.03). In one study (Cozzi Lepri) in Italy, the risk of viral failure after initiating ART was not different among patients who were treated early when compared to patients treated later (RR=1.01; 95% CI 0.79–1.29). In one study (Phillips) in Europe, among patients with baseline viral suppression, patients who initiated ART early were no more likely to suffer a viral rebound than patients who initiated ART later (RR=1.16; 95% CI 0.94–1.44).
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Outcome: mortality or survival outcomes. The 13 studies reporting on mortality provide low-quality evidence. No specific reasons were identified for upgrading the evidence, although the evidence was low quality due to the results originating from observational data. All 13 studies reporting mortality outcomes consistently found a reduced risk of mortality among patients treated early versus patients treated later, although only four studies found a statistically significant effect. When results are restricted to only patients who were immunologically improving six months after ART initiation, one study found no significant effect of early versus deferred treatment (ART Cohort Collaboration 2009) on mortality. The quality of evidence from all of these outcomes was very low due to the lack of confounder adjustment, resulting in a risk of bias from the results. One observational study estimated the effect of early ART treatment on survival compared to deferred treatment (CASCADE 2011). After two years and four years of follow-up, the authors found a significantly increased likelihood of survival among the early treatment cohort compared to the deferred cohort, although the quality of evidence from these two outcomes was also very low – downgraded for a lack of adjustment for potential confounders. • In 13 studies conducted in Europe, North America, South America and Africa (ART Cohort Collaboration 2003, ART Cohort Collaboration 2009, CASCADE 2011, Egger 2002, Gallant 2011, HIV CAUSAL 2010, HIV CAUSAL 2011, Kitahata 2009, Opravil 2002, Palella 2003,
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Phillips 2001, Plettenberg 2011, Sterne 2009), early initiation of ART when compared to delayed ART initiation was found to significantly reduce the risk of death (RR=0.66, 95% CI 0.55–0.79). All studies found a reduced risk, although only 4 of the 13 included studies found significantly reduced risks. In one study (ART Cohort Collaboration 2009) in North America and Europe, researchers also restricted results to only patients who were immunologically improving six months after ART initiation and found no significant effect of early versus deferred treatment on mortality (RR=0.99; 95% CI 0.74–1.31). Further, if the study was restricted to only patients with a CD4 increase of at least 50 cells/mm3 6 months after ART initiation, there was no significant difference between treatment arms (RR=0.94; 95% CI 0.88–1.29). In one study in Europe (CASCADE 2011), researchers estimated the effect of early ART treatment on survival compared to deferred treatment. After two years and four years of followup, the authors found a significantly increased likelihood of survival among the early treatment cohort compared to the deferred cohort (HR=1.01, 95% CI 1.00–1.02 and HR=1.02, 95% CI 1.00–1.03, respectively).
Outcome: combined outcomes of progression to AIDS and/or mortality or AIDS-free survival. The nine studies (ART Cohort Collaboration 2003, CASCADE 2011, Egger 2002, Garcia 2004, HIV CAUSAL 2011, Merito 2006, Opravil 2002, Phillips 2001, Sterne 2009) reporting on progression to AIDS or mortality provide low-quality evidence. No specific reasons were identified for upgrading the evidence, although the evidence was low quality due to the results originating from observational data. All nine studies reporting AIDS progression and mortality outcomes consistently found a reduced risk among patients treated early versus patients treated later, although only four studies found a statistically significant effect. The quality of evidence for AIDS-free survival was very low. One observational study estimated the effect of early ART treatment on AIDS-free survival compared to deferred treatment (CASCADE 2011), and the evidence from this study was downgraded due to a lack of confounder adjustment. • In nine studies conducted in Europe, North America, South America and Africa (ART Cohort Collaboration 2003, CASCADE 2011, Egger 2002, Garcia 2004, HIV CAUSAL 2011, Merito 2006, Opravil 2002, Phillips 2001, Sterne 2009), early initiation of ART when compared to delayed ART initiation was found to significantly reduce the risk of progression to AIDS or death (RR=0.72, 95% CI 0.65–0.81). All studies found a reduced risk, although only 4 of the 11 included studies found significantly reduced risks. In one observational study in Europe (CASCADE 2011), researchers estimated the effect of early ART treatment on AIDS-free survival at two and four years of follow-up compared to deferred treatment and found borderline significant effects suggesting an increased rate of AIDS-free HR=1.10, 95% CI 1.00–1.03, HR=1.01, 95% CI 0.98-1.04, respectively). survival (H
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Outcome: serious non-AIDS-defining illness and non-opportunistic disease–related death. The quality of evidence for this outcome is very low and comes from one observational study (Krishnan 2011) that studied the risk of non-AIDS-defining cancer diagnoses among patients treated early compared to patients who deferred treatment. For this outcome, the evidence was downgraded due to very serious imprecision.
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In one United States study (Krishnan 2011), the risk of developing a non-AIDS-defining cancer was lower among patients who started ART early when compared to patients who started ART later (RR 0.47, 95% CI 0.23–0.98).
5. Bibliography of included studies Peer-reviewed articles 1. Ahdieh-Grant L, Yamashita T, Phair J, et al. When to initiate highly active antiretroviral therapy: a cohort approach. Am J Epidemiol 2003; 157:738-46. 2. Althoff K, Justice A, Gange S, et al. Virologic and immunologic response to HAART, by age and regimen class. AIDS 2010; 24:2469-79. 3. Antiretroviral Therapy (ART) Cohort Collaboration. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet 2003; 362:679-86. 4. Antiretroviral Therapy (ART) Cohort Collaboration. Effect of baseline CD4 cell counts on the clinical significance of short-term immunologic response to antiretroviral therapy in individuals with virologic suppression. J Acquir Immune Defic Syndr; 2009: 52:357-63. 5. CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Arch Intern Med 2011; 171: 1560-69. 6. CASCADE Collaboration. Short-term CD4 cell response after highly active antiretroviral therapy initiated at different times from seroconversion in 1500 seroconverters. J Acquir Immune Defic Syndr 2003; 32:303-10. 7. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493-505. a. Supplementary annex to: Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011 365:6, 493-505 (http://www.nejm.org/doi/suppl/10.1056/NEJMoa1105243/suppl_file/nejmoa1105243_a ppendix.pdf). 8. Cozzi Lepri A, Phillips A, d’Arminio Monforte A, et al. When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from ICONA study. AIDS 2001; 15:98390. 9. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360:119-29. 10. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008;197(8):1133-1144. 11. Garcia F, de Lazzari E, Plana M, et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr 2004; 36:702-13. 12. Gras L, Kesselring A, Griffin J, et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr 2007; 45:183-92. 13. HIV-CAUSAL Collaboration. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 2010; 24:123-37. 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
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14. HIV-CAUSAL Collaboration. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries. Ann Intern Med 2011; 154:509-15. 15. Kitahata M, Gange S, Abraham A, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009; 360:1815-26. 16. Krishnan S, Schouten J, Jacobson D, et al. Incidence of non-AIDS-defining cancer in antiretroviral treatment-naïve subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis. Oncology 2011;80:42-9. 17. Merito M, Pezzotti P. Comparing costs and effectiveness of different starting points for highly active antiretroviral therapy in HIV-positive patients. Eur J Health Econ 2006; 7:30-6. 18. Opravil M, Ledergerber B, Hansjakob F, et al. Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count >350 106/l. AIDS 2002;16:1371-81. 19. Palella F, Deloria-Knoll M, Chmiel J, et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Ann Intern Med 2003; 138: 620-626. 20. Phillips A, Staszewski S, Weber R, et al. HIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load. JAMA 2001;286: 2560-67. 21. Plettenberg A, Brockmeyer NH, Haastert B, et al. Impact of earlier HAART initiation on the immune status and clinical course of treated patients on the basis of cohort data of the German Competence Network for HIV/AIDS. Infection 2011;39:3-12. 22. When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352-62.
Conference abstracts 1. Grant P, Tierney C, Katzenstein D, et al. Association of baseline viral load, CD4 count, and week 4 virologic response (VR) with virologic failure (VF) in ACTG Study A5202. CROI 2011. 2. Gallant JE, Hulbert E, Harley C. Health outcomes associated with the timing of antiretroviral therapy initiation. 6th IAS Conference on HIV Pathogenesis and Treatment: Abstract no. CDB320.
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
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