Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: An open-label randomized controlled trial in Lesotho


Autoři: Alain Amstutz aff001;  Bienvenu Lengo Nsakala aff004;  Fiona Vanobberghen aff001;  Josephine Muhairwe aff004;  Tracy Renée Glass aff001;  Tilo Namane aff005;  Tlali Mpholo aff006;  Manuel Battegay aff002;  Thomas Klimkait aff007;  Niklaus Daniel Labhardt aff001
Působiště autorů: Swiss Tropical and Public Health Institute, Basel, Switzerland aff001;  University of Basel, Basel, Switzerland aff002;  Department of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland aff003;  SolidarMed, Partnerships for Health, Maseru, Lesotho aff004;  Motebang Government Hospital, Leribe, Lesotho aff005;  Senkatana HIV Clinic, Maseru, Lesotho aff006;  Molecular Virology, Department of Biomedicine, University of Basel, Basel, Switzerland aff007
Vyšlo v časopise: Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: An open-label randomized controlled trial in Lesotho. PLoS Med 17(9): e1003325. doi:10.1371/journal.pmed.1003325
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003325

Souhrn

Background

Current World Health Organization (WHO) antiretroviral therapy (ART) guidelines define virologic failure as two consecutive viral load (VL) measurements ≥1,000 copies/mL, triggering empiric switch to next-line ART. This trial assessed if patients with sustained low-level HIV-1 viremia on first-line ART benefit from a switch to second-line treatment.

Methods and findings

This multicenter, parallel-group, open-label, superiority, randomized controlled trial enrolled patients on first-line ART containing non-nucleoside reverse transcriptase inhibitors (NNRTI) with two consecutive VLs ≥100 copies/mL, with the second VL between 100–999 copies/mL, from eight clinics in Lesotho. Consenting participants were randomly assigned (1:1), stratified by facility, demographic group, and baseline VL, to either switch to second-line ART (switch group) or continued first-line ART (control group; WHO guidelines). The primary endpoint was viral suppression (<50 copies/mL) at 36 weeks. Analyses were by intention to treat, using logistic regression models, adjusted for demographic group and baseline VL. Between August 1, 2017, and August 7, 2019, 137 individuals were screened, of whom 80 were eligible and randomly assigned to switch (n = 40) or control group (n = 40). The majority of participants were female (54 [68%]) with a median age of 42 y (interquartile range [IQR] 35–51), taking tenofovir disoproxil fumarate/lamivudine/efavirenz (49 [61%]) and on ART for a median of 5.9 y (IQR 3.3–8.6). At 36 weeks, 22/40 (55%) participants in the switch versus 10/40 (25%) in the control group achieved viral suppression (adjusted difference 29%, 95% CI 8%–50%, p = 0.009). The switch group had significantly higher probability of viral suppression across different VL thresholds (<20, <100, <200, <400, and <600 copies/mL) but not for <1,000 copies/mL. Thirty-four (85%) participants in switch group and 21 (53%) in control group experienced at least one adverse event (AE) (p = 0.002). No hospitalization or death or other serious adverse events were observed. Study limitations include a follow-up period too short to observe differences in clinical outcomes, missing values in CD4 cell counts due to national stockout of reagents during the study, and limited generalizability of findings to other than NNRTI-based first-line ART regimens.

Conclusions

In this study, switching to second-line ART among patients with sustained low-level HIV-1 viremia resulted in a higher proportion of participants with viral suppression. These results endorse lowering the threshold for virologic failure in future WHO guidelines.

Trial registration

The trial is registered at ClinicalTrials.gov, NCT03088241.

Klíčová slova:

Antiretroviral therapy – Hemoglobin – HIV – Cholesterol – Medical risk factors – Randomized controlled trials – Viral load – Viremia


Zdroje

1. European AIDS Clinical Society (EACS). https://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html; Guidelines Version 10.0—November 2019.

2. Cutrell J, Jodlowski T, Bedimo R. The management of treatment-experienced HIV patients (including virologic failure and switches). Ther Adv Infect Dis. 2020 Dec;7:2049936120901395.

3. Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, Degen O, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. The Lancet. 2019 15;393(10189):2428–38.

4. Saag MS, Benson CA, Gandhi RT, Hoy JF, Landovitz RJ, Mugavero MJ, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2018 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2018 24;320(4):379–96. doi: 10.1001/jama.2018.8431 30043070

5. BHIVA guidelines for the routine investigation and monitoring of adult HIV-1-positive individuals 2016 (2019 interim update) [Internet]. [cited 2020 May 8]. Available from: https://www.bhiva.org/monitoring-guidelines

6. UNAIDS data 2019 | UNAIDS [Internet]. [cited 2020 Mar 8]. Available from: https://www.unaids.org/en/resources/documents/2019/2019-UNAIDS-data

7. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection; Recommendations for a public health approach—Second edition June 2016 [Internet]. 2016 [cited 2016 Oct 3]. Available from: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1

8. Swenson LC, Min JE, Woods CK, Cai E, Li JZ, Montaner JS, et al. HIV Drug Resistance Detected During Low-Level Viremia Is Associated with Subsequent Virologic Failure. AIDS Lond Engl. 2014 May 15;28(8):1125–34.

9. Taiwo B, Gallien S, Aga E, Ribaudo H, Haubrich R, Kuritzkes DR, et al. Antiretroviral Drug Resistance in HIV-1–Infected Patients Experiencing Persistent Low-Level Viremia During First-Line Therapy. J Infect Dis. 2011 Aug 15;204(4):515–20. doi: 10.1093/infdis/jir353 21791652

10. Boillat-Blanco N, Darling KEA, Schoni-Affolter F, Vuichard D, Rougemont M, Fulchini R, et al. Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study. Antivir Ther. 2015;20(2):165–75. doi: 10.3851/IMP2815 24964403

11. Laprise C, de Pokomandy A, Baril J-G, Dufresne S, Trottier H. Virologic Failure Following Persistent Low-level Viremia in a Cohort of HIV-Positive Patients: Results From 12 Years of Observation. Clin Infect Dis. 2013 Nov 15;57(10):1489–96. doi: 10.1093/cid/cit529 23946221

12. Antiretroviral Therapy Cohort Collaboration (ART-CC), Vandenhende M-A, Ingle S, May M, Chene G, Zangerle R, et al. Impact of low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients. AIDS Lond Engl. 2015 Jan 28;29(3):373–83.

13. Joya C, Won SH, Schofield C, Lalani T, Maves RC, Kronmann K, et al. Persistent Low-level Viremia While on Antiretroviral Therapy Is an Independent Risk Factor for Virologic Failure. Clin Infect Dis Off Publ Infect Dis Soc Am. 2019 Nov 27;69(12):2145–52.

14. Fleming J, Mathews WC, Rutstein RM, Aberg J, Somboonwit C, Cheever LW, et al. Low-level viremia and virologic failure in persons with HIV infection treated with antiretroviral therapy. AIDS Lond Engl. 2019 01;33(13):2005–12.

15. Esber A, Polyak C, Kiweewa F, Maswai J, Owuoth J, Maganga L, et al. Persistent Low-level Viremia Predicts Subsequent Virologic Failure: Is It Time to Change the Third 90? Clin Infect Dis Off Publ Infect Dis Soc Am. 2019 16;69(5):805–12.

16. Bernal E, Gómez JM, Jarrín I, Cano A, Muñoz A, Alcaraz A, et al. Low-Level Viremia Is Associated With Clinical Progression in HIV-Infected Patients Receiving Antiretroviral Treatment. J Acquir Immune Defic Syndr 1999. 2018 01;78(3):329–37.

17. Elvstam O, Marrone G, Medstrand P, Treutiger CJ, Sönnerborg A, Gisslén M, et al. All-Cause Mortality and Serious Non-AIDS Events in Adults with Low-Level HIV Viremia during Combination Antiretroviral Therapy: Results from a Swedish Nationwide Observational Study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2020 Apr 9;

18. Hermans LE, Moorhouse M, Carmona S, Grobbee DE, Hofstra LM, Richman DD, et al. Effect of HIV-1 low-level viraemia during antiretroviral therapy on treatment outcomes in WHO-guided South African treatment programmes: a multicentre cohort study. The Lancet Infect Dis. 2018;18(2):188–97. doi: 10.1016/S1473-3099(17)30681-3 29158101

19. Castagna A, Galli L. Stepping up HIV-1 low-level viraemia surveillance in South Africa. The Lancet Infect Dis. 2018;18(2):130–1. doi: 10.1016/S1473-3099(17)30680-1 29158100

20. Poveda E, Crespo M. Hot News: Impact of Low-level Viremia on Treatment Outcomes During ART—Is it Time to Revise the Definition of Virological Failure? AIDS Rev. 2018 Mar;20(1):71–2.

21. Amstutz A, Nsakala BL, Vanobberghen F, Muhairwe J, Glass TR, Achieng B, et al. SESOTHO trial (“Switch Either near Suppression Or THOusand”)–switch to second-line versus WHO-guided standard of care for unsuppressed patients on first-line ART with viremia below 1000 copies/mL: protocol of a multicenter, parallel-group, open-label, randomized clinical trial in Lesotho, Southern Africa. BMC infectious diseases. 2018 Dec 1;18(1):76. doi: 10.1186/s12879-018-2979-y 29433430

22. Lesotho 2016 National ART Guidelines. [Internet]. [cited 2016 Sept 15]. Available from: http://www.hivpolicywatch.org/duremaps/data/guidelines/LesothoARTGuidelinesAllChaptersandAnnex2016.pdf.

23. Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP [Internet]. [cited 2020 May 10]. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

24. Localio AR, Margolis DJ, Berlin JA. Relative risks and confidence intervals were easily computed indirectly from multivariable logistic regression. J Clin Epidemiol. 2007 Sep;60(9):874–82. doi: 10.1016/j.jclinepi.2006.12.001 17689803

25. Glass TR, Sterne JAC, Schneider M-P, De Geest S, Nicca D, Furrer H, et al. Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality. AIDS Lond Engl. 2015 Oct 23;29(16):2195–200.

26. Paton NI, Kityo C, Hoppe A, Reid A, Kambugu A, Lugemwa A, et al. Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa. N Engl J Med. 2014 Jul 17;371(3):234–47. doi: 10.1056/NEJMoa1311274 25014688

27. Cheng C-Y, Luo Y-Z, Wu P-Y, Liu W-C, Yang S-P, Zhang J-Y, et al. Antiretroviral therapy (ART) management of Low-Level Viremia in Taiwan (ALLEVIATE). J Int AIDS Soc. 2014;17(4 Suppl 3):19785.

28. Pham T, Alrabaa S, Somboonwit C, Le Hung null, Montero J. The HIV Virologic Outcomes of Different Interventions Among Treatment-Experienced Patients With 2 Consecutive Detectable Low-Level Viremia. J Int Assoc Physicians AIDS Care Chic Ill 2002. 2011 Feb;10(1):54–6.

29. Taramasso L, Magnasco L, Bruzzone B, Caligiuri P, Bozzi G, Mora S, et al. How relevant is the HIV low level viremia and how is its management changing in the era of modern ART? A large cohort analysis. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2020 Feb 1;123:104255.

30. Labhardt ND, Bader J, Lejone TI, Ringera I, Hobbins MA, Fritz C, et al. Should viral load thresholds be lowered?: Revisiting the WHO definition for virologic failure in patients on antiretroviral therapy in resource-limited settings. Medicine. 2016 Jul;95(28):e3985. doi: 10.1097/MD.0000000000003985 27428189

31. Paton NI, Kityo C, Thompson J, Nankya I, Bagenda L, Hoppe A, et al. Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. The Lancet HIV. 2017 Aug;4(8):e341–8. doi: 10.1016/S2352-3018(17)30065-6 28495562

32. Aboud M, Kaplan R, Lombaard J, Zhang F, Hidalgo JA, Mamedova E, et al. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial. The Lancet Infect Dis. 2019 Mar 1;19(3):253–64. doi: 10.1016/S1473-3099(19)30036-2 30732940

33. Smit PW, Sollis KA, Fiscus S, Ford N, Vitoria M, Essajee S, et al. Systematic review of the use of dried blood spots for monitoring HIV viral load and for early infant diagnosis. PLoS ONE. 2014;9(3):e86461. doi: 10.1371/journal.pone.0086461 24603442

34. Kerschberger B, Ntshalintshali N, Mpala Q, Díaz Uribe PA, Maphalala G, Kalombola S, et al. Field Suitability and Diagnostic Accuracy of the Biocentric Open Real-Time PCR Platform for Dried Blood Spot-Based HIV Viral Load Quantification in Eswatini. Journal of Acquired Immune Deficiency Syndromes (1999). 2019 Sep 1;82(1):96–104.

35. Pham MD, Haile BA, Azwa I, Kamarulzaman A, Raman N, Saeidi A, et al. Performance of a Novel Low-Cost, Instrument-Free Plasma Separation Device for HIV Viral Load Quantification and Determination of Treatment Failure in People Living with HIV in Malaysia: a Diagnostic Accuracy Study. J Clin Microbiol. 2019 Apr 1;57(4):e01683–18. doi: 10.1128/JCM.01683-18 30700508

36. Hermans LE, Carmona S, Nijhuis M, Tempelman HA, Richman DD, Moorhouse M, et al. Virological suppression and clinical management in response to viremia in South African HIV treatment program: A multicenter cohort study. PLoS Med. 2020;17(2):e1003037. doi: 10.1371/journal.pmed.1003037 32097428

37. Etoori D, Ciglenecki I, Ndlangamandla M, Edwards CG, Jobanputra K, Pasipamire M, et al. Successes and challenges in optimizing the viral load cascade to improve antiretroviral therapy adherence and rationalize second-line switches in Swaziland. J Int AIDS Soc. 2018;21(10):e25194. doi: 10.1002/jia2.25194 30350392

38. WHO | Update of recommendations on first- and second-line antiretroviral regimens [Internet]. WHO. World Health Organization; [cited 2020 May 10]. Available from: http://www.who.int/hiv/pub/arv/arv-update-2019-policy/en/


Článek vyšel v časopise

PLOS Medicine


2020 Číslo 9

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se