Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial

Andrew Zolopa, Janet Andersen, William Powderly, Alejandro Sanchez, Ian Sanne, Carol Suckow, Evelyn Hogg, Lauren Komarow, Andrew Zolopa, Janet Andersen, William Powderly, Alejandro Sanchez, Ian Sanne, Carol Suckow, Evelyn Hogg, Lauren Komarow

Abstract

Background: Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined.

Methods and findings: A5164 was a randomized strategy trial of "early ART"--given within 14 days of starting acute OI treatment versus "deferred ART"--given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) >or=50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. THE DIFFERENCE IN THE PRIMARY ENDPOINT DID NOT REACH STATISTICAL SIGNIFICANCE: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27-0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30-0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events.

Conclusions: Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.

Trial registration: ClinicalTrials.gov NCT00055120.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Study Subject Enrollment and Discontinuation.
Figure 1. Study Subject Enrollment and Discontinuation.
Figure 2. Time to ART initiation from…
Figure 2. Time to ART initiation from the start of OI/BI treatment.
Early arm median 12 days [IQR 9–13 days]; Deferred arm median 45 days [IQR 41–55 days].
Figure 3. Time to AIDS progression or…
Figure 3. Time to AIDS progression or death.
HR = 0.53 Early versus Deferred ART [95%CI 0.30–0.92 p = 0.023].
Figure 4. AIDS Progression/Death by entry diagnoses…
Figure 4. AIDS Progression/Death by entry diagnoses given as log Odds ratios (with 95%CI) with OR
Total, fungal and CD4

Figure 5. Time to CD4>50 cells/mm3;…

Figure 5. Time to CD4>50 cells/mm3; Early ART median time 4.0 weeks (IQR 0–5.0…

Figure 5. Time to CD4>50 cells/mm3; Early ART median time 4.0 weeks (IQR 0–5.0 weeks) versus deferred ART median time 8.1 weeks (IQR 0–12.7 weeks).
Right side graph: Time to CD4>100 cells/mm3; Early ART median time 4.3 weeks (IQR 4.0–23.6 weeks) versus Deferred ART median time 12.1 weeks (IQR 8.6–28.1 weeks) (p
Similar articles
Immediate versus deferred antiretroviral therapy in HIV-infected patients presenting with acute AIDS-defining events (toxoplasmosis, Pneumocystis jirovecii-pneumonia): a prospective, randomized, open-label multicenter study (IDEAL-study).
Schäfer G, Hoffmann C, Arasteh K, Schürmann D, Stephan C, Jensen B, Stoll M, Bogner JR, Faetkenheuer G, Rockstroh J, Klinker H, Härter G, Stöhr A, Degen O, Freiwald E, Hüfner A, Jordan S, Schulze Zur Wiesch J, Addo M, Lohse AW, van Lunzen J, Schmiedel S; IDEAL study group. Schäfer G, et al. AIDS Res Ther. 2019 Nov 15;16(1):34. doi: 10.1186/s12981-019-0250-2. AIDS Res Ther. 2019. PMID: 31729999 Free PMC article. Clinical Trial.
Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study.
Babiker AG, Emery S, Fätkenheuer G, Gordin FM, Grund B, Lundgren JD, Neaton JD, Pett SL, Phillips A, Touloumi G, Vjechaj MJ; INSIGHT START Study Group. Babiker AG, et al. Clin Trials. 2013;10(1 Suppl):S5-S36. doi: 10.1177/1740774512440342. Epub 2012 Apr 30. Clin Trials. 2013. PMID: 22547421 Free PMC article. Clinical Trial.
BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial.
Butler K, Inshaw J, Ford D, Bernays S, Scott K, Kenny J, Klein N, Turkova A, Harper L, Nastouli E, Paparini S, Choudhury R, Rhodes T, Babiker A, Gibb D. Butler K, et al. Health Technol Assess. 2016 Jun;20(49):1-108. doi: 10.3310/hta20490. Health Technol Assess. 2016. PMID: 27377073 Free PMC article. Clinical Trial.
Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age.
Penazzato M, Prendergast A, Tierney J, Cotton M, Gibb D. Penazzato M, et al. Cochrane Database Syst Rev. 2012 Jul 11;(7):CD004772. doi: 10.1002/14651858.CD004772.pub3. Cochrane Database Syst Rev. 2012. PMID: 22786492 Updated. Review.
Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection.
Grant PM, Komarow L, Andersen J, Sereti I, Pahwa S, Lederman MM, Eron J, Sanne I, Powderly W, Hogg E, Suckow C, Zolopa A. Grant PM, et al. PLoS One. 2010 Jul 1;5(7):e11416. doi: 10.1371/journal.pone.0011416. PLoS One. 2010. PMID: 20617176 Free PMC article. Clinical Trial.
Cited by
Outcomes in critically Ill HIV-infected patients between 1997 and 2020: analysis of the OUTCOMEREA multicenter cohort.
Gaillet A, Azoulay E, de Montmollin E, Garrouste-Orgeas M, Cohen Y, Dupuis C, Schwebel C, Reignier J, Siami S, Argaud L, Adrie C, Mourvillier B, Ruckly S, Forel JM, Timsit JF. Gaillet A, et al. Crit Care. 2023 Mar 13;27(1):108. doi: 10.1186/s13054-023-04325-9. Crit Care. 2023. PMID: 36915207 Free PMC article.
Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.
Zeng YM, Li Y, Lu YQ, Liu M, Nie JM, Yuan J, Harypursat V, Zhou YH, Qin YY, Chen XH, Zhang YL, Zhang DF, Wang N, Chen H, Tian Q, Zhou Y, Qin YM, Yang XP, Chen YK. Zeng YM, et al. BMC Pulm Med. 2022 Aug 25;22(1):323. doi: 10.1186/s12890-022-02118-4. BMC Pulm Med. 2022. PMID: 36008855 Free PMC article.
Antiretroviral therapy initiation and outcomes of hospitalized HIV-infected patients in Uganda-An evaluation of the HIV test and treat strategy.
Katende A, Nakiyingi L, Andia-Biraro I, Katairo T, Muhumuza R, Ssemata AS, Nsereko C, Semitala FC, Meya DB. Katende A, et al. PLoS One. 2022 Aug 19;17(8):e0268122. doi: 10.1371/journal.pone.0268122. eCollection 2022. PLoS One. 2022. PMID: 35984779 Free PMC article.
Influence of Combination Antiretroviral Therapy on HIV-1 Serological Responses and Their Implications: A Systematic Review and Meta-Analysis.
Liang Y, Lin H, Dzakah EE, Tang S. Liang Y, et al. Front Immunol. 2022 Mar 30;13:844023. doi: 10.3389/fimmu.2022.844023. eCollection 2022. Front Immunol. 2022. PMID: 35432309 Free PMC article.
Early Antiretroviral Therapy in AIDS Patients Presenting With Toxoplasma gondii Encephalitis Is Associated With More Sequelae but Not Increased Mortality.
Cubas-Vega N, López Del-Tejo P, Baia-da-Silva DC, Sampaio VS, Jardim BA, Santana MF, Lima Ferreira LC, Safe IP, Alexandre MAA, Lacerda MVG, Monteiro WM, Val F. Cubas-Vega N, et al. Front Med (Lausanne). 2022 Feb 25;9:759091. doi: 10.3389/fmed.2022.759091. eCollection 2022. Front Med (Lausanne). 2022. PMID: 35280886 Free PMC article.
References
Palella FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, et al. Mortality in the highly active antiretroviral therapy era. J Acquir Immune Defic Syndr. 2006;43(1):27–34. - PubMed Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. The Lancet. 2003;362 (9377):2–29. - PubMed Lewden C, Chene G, Morlat P, Raffi F, Dupon M, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46(1):72–77. - PubMed Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med. 1997;337(11):725–33. - PubMed Hirsch M, Steigbigel R, Staszewski S, Scerpella E, Hirschel B, et al. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced immunodeficiency virus type 1 infection and prior antiretroviral therapy. JID. 1999;180(3):659–665. - PubMed
Show all 20 references
Publication types
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
MeSH terms
Acquired Immunodeficiency Syndrome / drug therapy*
Anti-Retroviral Agents / administration & dosage
Anti-Retroviral Agents / adverse effects
Anti-Retroviral Agents / therapeutic use*
Drug Administration Schedule
HIV Infections / drug therapy*
Substances
Associated data
ClinicalTrials.gov/NCT00055120
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 5. Time to CD4>50 cells/mm3;…
Figure 5. Time to CD4>50 cells/mm3; Early ART median time 4.0 weeks (IQR 0–5.0 weeks) versus deferred ART median time 8.1 weeks (IQR 0–12.7 weeks).
Right side graph: Time to CD4>100 cells/mm3; Early ART median time 4.3 weeks (IQR 4.0–23.6 weeks) versus Deferred ART median time 12.1 weeks (IQR 8.6–28.1 weeks) (p

References

    1. Palella FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, et al. Mortality in the highly active antiretroviral therapy era. J Acquir Immune Defic Syndr. 2006;43(1):27–34.
    1. Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. The Lancet. 2003;362 (9377):2–29.
    1. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46(1):72–77.
    1. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med. 1997;337(11):725–33.
    1. Hirsch M, Steigbigel R, Staszewski S, Scerpella E, Hirschel B, et al. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced immunodeficiency virus type 1 infection and prior antiretroviral therapy. JID. 1999;180(3):659–665.
    1. Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, et al. Randomized placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Lancet. 1998;351(9102):543–549.
    1. Center of Disease Control and Prevention Website. .
    1. Giardi E, Sabin CA, Monforte AA. Late diagnosis of HIV infection: epidemiological features, consequences and strategies to encourage earlier testing. J Acquir Immune Defic Syndr. 2007;46(Suppl 11):S3–S8.
    1. Sabin CA, Smith CJ, Gumley H, Murphy G, Lampe FC, et al. Late presenters in era of highly active antiretroviral therapy: uptake of and responses to antiretroviral therapy. AIDS. 2004;18(16):2145–2151.
    1. Schwarcz S, Hsu L, Dilley JW, Loeb L, Nelson K, et al. Late diagnosis of HIV infection: trends, prevalence, and characteristics of persons whose HIV diagnosis occurred within 12 months of developing AIDS. J Acquir Immune Defic Syndr. 2006;43(4):491–494.
    1. Castilla J, Sobrino P, de la Fuente L, Noguer I, Guerra L, et al. Late diagnosis or HIV infection in the era of highly active antiretroviral therapy: consequences for AIDS incidence. AIDS. 2002;16(14):1945–51.
    1. Antiretroviral Therapy Cohort Collaboration. Importance of baseline prognostic factors with increasing time since initiation of highly active antiretroviral therapy: collaborative analysis of cohorts of HIV-1-infected patients. J Acquir Immune Defic Syndr. 2007;46(5):607–15.
    1. MMWR March 12, 1999. .
    1. Manabe YC, Campbell JD, Sydnor E, Moore RD. Immune reconstitution inflammatory syndrome: risk factors and treatment implications. J Acquir Immune Defic Syndr. 2007;46(4):456–462.
    1. French MA, Price P, Stone SF. Immune restoration diseases after antiretroviral therapy. AIDS. 2004;18(12):1615–27.
    1. Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers more questions. J Antimicrob Chemother. 2006;57(2):167–170.
    1. Jevtovic DJ, Salemovic D, Ranin J, Pesic I, Zerjav S, et al. The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy. HIV Med. 2005;6(2):140–143.
    1. Breton G, Duval X, Estellat C, Polaletti X, Bonnet D, et al. Determinates of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis. 2004;39(11):1709–1712.
    1. Shelburne SA, Visnegarwala F, Darcourt J, Graviss E, Giordano TP, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005;19(4):399–406.
    1. Murdoch DM, Venter WDF, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS. 2008;22(5):601–610.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere