Early Initiation of Antiretroviral Therapy in Asymptomatic HIV-infected, Treatmentnaive Adults and Adolescents: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

 LINYi-xiao ^1,2 , WANGMing ^1,2 , TIANSi-jia ³ , TONGAn ⁴ ,  TANGHong ^1,2

1. Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China;
2. Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China;
3. Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, China;
4. Department of Obstetric and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

TANGHong, Email: htang6198@hotmail.com

Keywords：

Antiretroviral therapy; Early initiation; HIV/AIDS; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.20160174

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Objective To systematically evaluate the efficacy and safety of early initiation of antiretroviral therapy (ART) in asymptomatic HIV-infected, treatment-naive adults and adolescents. To assess the evidence for the optimal time to initiate ART. Methods Databases including PubMed, EMbase, The Cochrane Library (Issue 4, 2016), CBM, CNKI, VIP and WanFang Data were searched to collect randomized controlled trials (RCTs) about early initiation and optimal time to initiate ART in asymptomatic, treatment-naive HIV-infected patients from January 1996 to April 2016. Two review authors independently assessed study eligibility, extracted data and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. We meta-analysed dichotomous outcomes using the risk ratio (RR) and report the 95% confidence intervals (95% CIs) by using RevMan 5.3 software. Results A total of 4 RCTs involving 8 751 patients were included. The results of meta-analysis showed that initiating ART at CD4⁺ T-cell counts (CD4 counts) ≥350 cells/μL or 500 cells/μL, comparing to deferring initiation of ART to CD4 counts <350 cells/μL, would benefit patients more: (1) Risk of AIDS-defining illnesses which representing disease progression, reduced significantly when starting ART at higher CD4 counts (no less than 350 cells/μL) (RR=0.49, 95%CI 0.38 to 0.64, P<0.001). The reduction of risk was even more significant when initiating ART at CD4 counts of not less than 500 cells/μL (RR=0.38, 95%CI 0.24 to 0.59, P<0.001). (2) When initiating ART at CD4 counts of not less than 350 cells/μL, the risk of serious non-AIDS related events was significantly reduced by 42% (RR=0.58, 95%CI 0.40 to 0.83, P=0.003). When initiating ART at CD4 counts of not less than 500 cells/μL, according to START 2015, the risk of serious non-AIDS related events could be reduced by 39% (RR=0.61, P=0.04). (3) However, when initiating ART at CD4 counts of not less than 350 cells/μL or 500 cells/μL, comparing to deferring initiation, there were no statistically significant differences in death (RR=0.70, 95%CI 0.48 to 1.02, P=0.06) and serious adverse events (RR=0.67, 95%CI 0.38 to 1.20, P=0.18). Conclusion Our findings contribute to the evidence base for recommending initiating ART at CD4 counts of 350-500 cells/μL compared to initiating it later when CD4 counts fall below 350 cells/μL. As for patients with CD4 counts of not less than 500 cells/μL, initiation of ART is also recommended.

Citation： LINYi-xiao, WANGMing, TIANSi-jia, TONGAn, TANGHong. Early Initiation of Antiretroviral Therapy in Asymptomatic HIV-infected, Treatmentnaive Adults and Adolescents: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2016, 16(10): 1137-1147. doi: 10.7507/1672-2531.20160174 Copy

1.	Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med, 1998, 338(13): 853-860.
2.	Palella Jr FJ, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Dific Syndr, 2006, 43(1): 27-34.
3.	Loubiere S, El Filal K M, Sodqi M, et al. When to initiate highly active antiretroviral therapy in low-resource settings: the Moroccan experience. Antivir ther, 2008, 13(2): 241-251.
4.	Lundgren JD, Babiker AG, Gordin FM, et al. When to start antiretroviral therapy: the need for an evidence base during early HIV infection. BMC Med, 2013, 11: 148.
5.	Franco RA, Saag MS. When to start antiretroviral therapy: as soon as possible. BMC Med, 2013, 11: 147.
6.	Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis, 2014, 14(4): 281-290.
7.	Insight Start Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med, 2015, 2015(373): 795-807.
8.	Günthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA, 2014, 312(4): 410-425.
9.	Panel on Antiretroviral Guidelines for Adults and Adolescents, Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://www.aidsinfo.nih.gov/contenfiles/lvguidelines/adultandadolescentgl.pdf..
10.	Churchill D, Waters L, Ahmed N, et al. BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. London: British HIV Association (BHIVA), 2015.
11.	Ryom L, Boesecke C, Gisler V, et al. Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV‐positive persons. HIV Med, 2016, 17(2): 83-88.
12.	WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015.
13.	Carr A, Cooper DA. Adverse effects of antiretroviral therapy. The Lancet, 2000, 356(9239): 1423-1430.
14.	Reisler RB, Han C, Burman WJ, et al. Grade 4 events are as important as AIDS events in the era of HAART. J Acquiv Immune Dific Syndr, 2003, 34(4): 379-386.
15.	Rhame FS. When to start antiretroviral therapy. Curr Infect Dis Rep, 2011, 13(1): 60-67.
16.	Sigaloff CE, Lange MA, Montaner J. Global response to HIV: treatment as prevention, or treatment for treatment? Clin Infect Dis, 2014, 59(suppl 1): 7-11.
17.	中华医学会感染病学分会艾滋病学组.艾滋病诊疗指南第三版(2015版). 中华临床感染病杂志, 2015, 8(5): 385-401.
18.	Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org..
19.	Severe P, Jean MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med, 2010, 363(3): 257-265.
20.	卢瑞朝, 张勇, 李虹如, 等. 人类免疫缺陷病毒/丙型肝炎病毒合并感染抗反转录病毒治疗时机选择. 中华传染病杂志, 2013, 31(6): 342-346.
21.	Holtedahl K, Salpou D, Braaten T, et al. Optimal starting point for antiretroviral HIV treatment in a town in Cameroon: a randomised controlled study. BMC Public Health, 2014, 14(1): 1.
22.	Strategies for Management of Antiretroviral Therapy (SMART) Study Group. 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.
23.	Temprano ANRS 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med, 2015, 2015(373): 808-822.
24.	Buehler MD, Berkelman RL. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep, 1992, 41(RR-17): 1-19.
25.	Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med, 2006(355): 2283-2296.
26.	El-Sadr WM, Cohen CJ, Emery S, et al. Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy. Ann Intern Med, 2008, 149(5): 289-299.
27.	Volberding PA, Lagakos SW, Grimes JM, et al. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. N Engl J Med, 1995, 333(7): 401-407.
28.	Ho DD. Time to hit HIV, early and hard. N Engl J Med, 1995. 333(7): 450-451.
29.	Carpenter CJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society-USA Panel. JAMA, 1997, 277(24): 1962-1969.
30.	Yeni PG, Hammer SM, Carpenter CJ, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA, 2002, 288(2): 222-235.
31.	Baker JV, Henry K. If we can't get what we want, can we get what we need? optimizing use of antiretroviral therapy in the current Era. Ann Intern Med, 2011, 154(8): 563-565.
32.	Murphy RL, da Silva BA, Hicks CB, et al. Seven-year efficacy of a lopinavir/ritonavir-based regimen in antiretroviral-naïve HIV-1-infected patients. HIV Clin Trials, 2008, 9(1): 1-10.
33.	Anglemyer A, Rutherford GW, Baggaley RC, et al. Antiretroviral therapy for prevention of HIV transmission in HIV‐discordant couples. Cochrane Database Syst Rev, 2013, (4): CD009153.
34.	Siegfried N, Uthman OA, Rutherford GW. Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV‐infected, treatment‐naive adults. Cochrane Database Syst Rev, 2010, (3): CD008272.
35.	Anglemyer A, Rutherford GW, Easterbrook PJ, et al. Early initiation of antiretroviral therapy in HIV-infected adults and adolescents: a systematic review. AIDS, 2014, 28 (Suppl 2): 105-118.
36.	Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med, 2003, (349): 1993-2003.
37.	Ryom L, Mocroft A, Kirk O, et al. Association Between Antiretroviral Exposure and Renal Impairment Among HIV-Positive Persons With Normal Baseline Renal Function: the D: A: D Studya. J Infect Dis, 2013, 207(9): 1359-1369.
38.	李健健, 杨绍敏, 张米, 等. 云南省 2007-2012 年 HIV/AIDS 高效联合抗病毒治疗效果及药物不良反应分析. 中华流行病学杂志, 2013, 34(10): 1045-1046.
39.	覃川, 蒋忠胜, 温小凤. 214 例 HIV/AIDS 病人的 HAART 不良反应及换药原因分析. 中国艾滋病性病, 2014, 4(12): 901-904.
40.	魏秀青, 张园园, 贺健梅, 等. 湖南省 6558 例 HIV/AIDS 病人 HAART 疗效及不良反应分析. 中国艾滋病性病, 2014, 4(8): 3.
41.	Deeks SG, Barbour JD, Grant RM, et al. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS, 2002, 16(2): 201-207.
42.	Rawizza HE, Chaplin B, Meloni ST, et al. Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings. Clin Infect Dis, 2011, 53(12): 1283-1290.
43.	Gupta RK, Jordan MR, Sultan BJ, et al. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. The Lancet, 2012, 380(9849): 1250-1258.
44.	Hosseinipour MC, Gupta RK, Van Zyl G, et al. Emergence of HIV drug resistance during first-and second-line antiretroviral therapy in resource-limited settings. J Infect Dis, 2013, 207(suppl 2): 49-56.
45.	Zhang F J, Jennifer P, Lan Y, et al. Current progress of China's free ART program. Cell Res, 2005, 15(11): 877-882.

1. Palella Jr FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med, 1998, 338(13): 853-860.
2. Palella Jr FJ, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Dific Syndr, 2006, 43(1): 27-34.
3. Loubiere S, El Filal K M, Sodqi M, et al. When to initiate highly active antiretroviral therapy in low-resource settings: the Moroccan experience. Antivir ther, 2008, 13(2): 241-251.
4. Lundgren JD, Babiker AG, Gordin FM, et al. When to start antiretroviral therapy: the need for an evidence base during early HIV infection. BMC Med, 2013, 11: 148.
5. Franco RA, Saag MS. When to start antiretroviral therapy: as soon as possible. BMC Med, 2013, 11: 147.
6. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis, 2014, 14(4): 281-290.
7. Insight Start Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med, 2015, 2015(373): 795-807.
8. Günthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA, 2014, 312(4): 410-425.
9. Panel on Antiretroviral Guidelines for Adults and Adolescents, Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://www.aidsinfo.nih.gov/contenfiles/lvguidelines/adultandadolescentgl.pdf..
10. Churchill D, Waters L, Ahmed N, et al. BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015. London: British HIV Association (BHIVA), 2015.
11. Ryom L, Boesecke C, Gisler V, et al. Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV‐positive persons. HIV Med, 2016, 17(2): 83-88.
12. WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015.
13. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. The Lancet, 2000, 356(9239): 1423-1430.
14. Reisler RB, Han C, Burman WJ, et al. Grade 4 events are as important as AIDS events in the era of HAART. J Acquiv Immune Dific Syndr, 2003, 34(4): 379-386.
15. Rhame FS. When to start antiretroviral therapy. Curr Infect Dis Rep, 2011, 13(1): 60-67.
16. Sigaloff CE, Lange MA, Montaner J. Global response to HIV: treatment as prevention, or treatment for treatment? Clin Infect Dis, 2014, 59(suppl 1): 7-11.
17. 中华医学会感染病学分会艾滋病学组.艾滋病诊疗指南第三版(2015版). 中华临床感染病杂志, 2015, 8(5): 385-401.
18. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org..
19. Severe P, Jean MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med, 2010, 363(3): 257-265.
20. 卢瑞朝, 张勇, 李虹如, 等. 人类免疫缺陷病毒/丙型肝炎病毒合并感染抗反转录病毒治疗时机选择. 中华传染病杂志, 2013, 31(6): 342-346.
21. Holtedahl K, Salpou D, Braaten T, et al. Optimal starting point for antiretroviral HIV treatment in a town in Cameroon: a randomised controlled study. BMC Public Health, 2014, 14(1): 1.
22. Strategies for Management of Antiretroviral Therapy (SMART) Study Group. 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.
23. Temprano ANRS 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med, 2015, 2015(373): 808-822.
24. Buehler MD, Berkelman RL. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep, 1992, 41(RR-17): 1-19.
25. Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med, 2006(355): 2283-2296.
26. El-Sadr WM, Cohen CJ, Emery S, et al. Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy. Ann Intern Med, 2008, 149(5): 289-299.
27. Volberding PA, Lagakos SW, Grimes JM, et al. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. N Engl J Med, 1995, 333(7): 401-407.
28. Ho DD. Time to hit HIV, early and hard. N Engl J Med, 1995. 333(7): 450-451.
29. Carpenter CJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society-USA Panel. JAMA, 1997, 277(24): 1962-1969.
30. Yeni PG, Hammer SM, Carpenter CJ, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA, 2002, 288(2): 222-235.
31. Baker JV, Henry K. If we can't get what we want, can we get what we need? optimizing use of antiretroviral therapy in the current Era. Ann Intern Med, 2011, 154(8): 563-565.
32. Murphy RL, da Silva BA, Hicks CB, et al. Seven-year efficacy of a lopinavir/ritonavir-based regimen in antiretroviral-naïve HIV-1-infected patients. HIV Clin Trials, 2008, 9(1): 1-10.
33. Anglemyer A, Rutherford GW, Baggaley RC, et al. Antiretroviral therapy for prevention of HIV transmission in HIV‐discordant couples. Cochrane Database Syst Rev, 2013, (4): CD009153.
34. Siegfried N, Uthman OA, Rutherford GW. Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV‐infected, treatment‐naive adults. Cochrane Database Syst Rev, 2010, (3): CD008272.
35. Anglemyer A, Rutherford GW, Easterbrook PJ, et al. Early initiation of antiretroviral therapy in HIV-infected adults and adolescents: a systematic review. AIDS, 2014, 28 (Suppl 2): 105-118.
36. Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med, 2003, (349): 1993-2003.
37. Ryom L, Mocroft A, Kirk O, et al. Association Between Antiretroviral Exposure and Renal Impairment Among HIV-Positive Persons With Normal Baseline Renal Function: the D: A: D Studya. J Infect Dis, 2013, 207(9): 1359-1369.
38. 李健健, 杨绍敏, 张米, 等. 云南省 2007-2012 年 HIV/AIDS 高效联合抗病毒治疗效果及药物不良反应分析. 中华流行病学杂志, 2013, 34(10): 1045-1046.
39. 覃川, 蒋忠胜, 温小凤. 214 例 HIV/AIDS 病人的 HAART 不良反应及换药原因分析. 中国艾滋病性病, 2014, 4(12): 901-904.
40. 魏秀青, 张园园, 贺健梅, 等. 湖南省 6558 例 HIV/AIDS 病人 HAART 疗效及不良反应分析. 中国艾滋病性病, 2014, 4(8): 3.
41. Deeks SG, Barbour JD, Grant RM, et al. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS, 2002, 16(2): 201-207.
42. Rawizza HE, Chaplin B, Meloni ST, et al. Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings. Clin Infect Dis, 2011, 53(12): 1283-1290.
43. Gupta RK, Jordan MR, Sultan BJ, et al. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. The Lancet, 2012, 380(9849): 1250-1258.
44. Hosseinipour MC, Gupta RK, Van Zyl G, et al. Emergence of HIV drug resistance during first-and second-line antiretroviral therapy in resource-limited settings. J Infect Dis, 2013, 207(suppl 2): 49-56.
45. Zhang F J, Jennifer P, Lan Y, et al. Current progress of China's free ART program. Cell Res, 2005, 15(11): 877-882.

Chinese Journal of Evidence-Based Medicine

Early Initiation of Antiretroviral Therapy in Asymptomatic HIV-infected, Treatmentnaive Adults and Adolescents: A Systematic Review

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