Safety and continued use of the levonorgestrel intrauterine system as compared with the copper intrauterine device among women living with HIV in South Africa: A randomized controlled trial
Autoři:
Catherine S. Todd aff001; Heidi E. Jones aff002; Nontokozo Langwenya aff003; Donald R. Hoover aff004; Pai-Lien Chen aff005; Gregory Petro aff006; Landon Myer aff003
Působiště autorů:
Maternal and Child Health and Nutrition Department, Global Health, Population, and Nutrition, Durham, North Carolina, United States of America
aff001; Department of Epidemiology and Biostatistics, City University of New York School of Public Health, New York, New York, United States of America
aff002; Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Observatory, Cape Town, South Africa
aff003; Department of Statistics and Institute for Health Care Policy and Aging Research, Rutgers University, Piscataway, New Jersey, United States of America
aff004; Global Population and Health Research Department, Global Health, Population, and Nutrition, Durham, North Carolina, United States of America
aff005; Department of Obstetrics and Gynaecology, University of Cape Town, Observatory, Cape Town, South Africa
aff006; New Somerset Hospital, Cape Town, South Africa
aff007; Division of Epidemiology and Biostatistics, Centre for Infectious Diseases Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town Observatory, Cape Town, South Africa
aff008
Vyšlo v časopise:
Safety and continued use of the levonorgestrel intrauterine system as compared with the copper intrauterine device among women living with HIV in South Africa: A randomized controlled trial. PLoS Med 17(5): e32767. doi:10.1371/journal.pmed.1003110
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pmed.1003110
Souhrn
Background
Women living with HIV (WLHIV) have lower rates of contraceptive use than noninfected peers, yet concerns regarding contraceptive efficacy and interaction with antiretroviral therapy (ART) complicate counseling. Hormonal contraceptives may increase genital tract HIV viral load (gVL) and sexual transmission risk to male partners. We compared gVL, plasma VL (pVL), and intrauterine contraceptive (IUC) continuation between the levonorgestrel intrauterine system (LNG-IUS) and copper intrauterine device (C-IUD) in Cape Town, South Africa.
Methods and findings
In this double-masked, randomized controlled noninferiority trial, eligible WLHIV were ages 18–40, not pregnant or desiring pregnancy within 30 months, screened and treated (as indicated) for reproductive tract infections (RTIs) within 1 month of enrollment, and virologically suppressed using ART or above treatment threshold at enrollment (non-ART). Between October 2013, and December 2016, we randomized consenting women within ART groups, using 1:1 permuted block randomization stratified by ART use, age (18–23, 24–31, 32–40), and recent injectable progestin contraceptive (IPC) exposure, and provided the allocated IUC. At all visits, participants provided specimens for gVL (primary outcome), pVL, RTI, and pregnancy testing. We assessed gVL and pVL across 6 and 24 months controlling for enrollment measures, ART group, age, and RTI using generalized estimating equation and generalized linear models (non-ART group pVL and hemoglobin) in as-treated analyses. We measured IUC discontinuation rates with Kaplan-Meier estimates and Cox proportional hazards models. We enrolled 71 non-ART (36 LNG-IUS, 31 C-IUD; 2 declined and 2 were ineligible) and 134 ART-using (65 LNG-IUS, 67 C-IUD; 1 declined and 1 could not complete IUC insertion) women. Participant median age was 31 years, and 95% had 1 or more prior pregnancies. Proportions of women with detectable gVL were not significantly different comparing LNG-IUS to C-IUD across 6 (adjusted odds ratio [AOR]: 0.78, 95% confidence interval [CI] 0.44–1.38, p = 0.39) and 24 months (AOR: 1.03, 95% CI: 0.68–1.57, p = 0.88). Among ART users, proportions with detectable pVL were not significantly different at 6 (AOR = 0.83, 95% CI 0.37–1.86, p = 0.65) and 24 months (AOR = 0.94, 95% CI 0.49–1.81, p = 0.85), whereas among non-ART women, mean pVL was not significantly different at 6 months (−0.10 log10 copies/mL, 95% CI −0.29 to 0.10, p = 0.50) between LNG-IUS and C-IUD users. IUC continuation was 78% overall; C-IUD users experienced significantly higher expulsion (8% versus 1%, p = 0.02) and elective discontinuation (adjusted hazard ratio: 8.75, 95% CI 3.08–24.8, p < 0.001) rates. Sensitivity analysis adjusted for differential IUC discontinuation found similar gVL results. There were 39 serious adverse events (SAEs); SAEs believed to be directly related to IUC use (n = 7) comprised 3 pelvic inflammatory disease (PID) cases and 4 pregnancies with IUC in place with no discernible trend by IUC arm. Mean hemoglobin change was significantly higher among LNG-IUS users across 6 (0.57 g/dL, 95% CI 0.24–0.90; p < 0.001) and 24 months (0.71 g/dL, 95% CI 0.47–0.95; p < 0.001). Limitations included not achieving non-ART group sample size following change in ART treatment guidelines and truncated 24 months’ outcome data, as 17 women were not yet eligible for their 24-month visit at study closure. Also, a change in VL assay during the study may have caused some discrepancy in VL values because of different limits of detection.
Conclusions
In this study, we found that the LNG-IUS did not increase gVL or pVL and had low levels of contraceptive failure and associated PID compared with the C-IUD among WLHIV. LNG-IUS users were significantly more likely to continue IUC use and had higher hemoglobin levels over time. The LNG-IUS appears to be a safe contraceptive with regard to HIV disease and may be a highly acceptable option for WLHIV.
Trial registration
ClinicalTrials.gov NCT01721798.
Klíčová slova:
Antiretroviral therapy – Assisted reproductive technology – Female contraception – Hemoglobin – Hemorrhage – HIV – Pregnancy – Viral load
Zdroje
1. Harrison A, Colvin CJ, Kuo C, Swartz A, Lurie M. Sustained high HIV incidence in young women in Southern Africa: social, behavioral, and structural factors and emerging intervention approaches. Curr HIV/AIDS Rep. 2015;12: 207–215. doi: 10.1007/s11904-015-0261-0 25855338
2. Pollock LC, Weber S, Kaida A, Matthews LT, Seidman DL. HIV-affected couples and individuals who desire children should be offered options for safer conception. J Int AIDS Soc. 2017;20: 22155. doi: 10.7448/IAS.20.1.22155 28741333
3. Rucinski KB, Powers KA, Schwartz SR, Pence BW, Chi BH, Black V, et al. Longitudinal patterns of unmet need for contraception among women living with HIV on antiretroviral therapy in South Africa. PLoS ONE. 2018;13: e0209114. doi: 10.1371/journal.pone.0209114 30571702
4. Adeniyi OV, Ajayi AI, Moyaki MG, Goon DT, Avramovic G, Lambert J. High rate of unplanned pregnancy in the context of integrated family planning and HIV care services in South Africa. BMC Health Serv Res. 2018;18: 140. doi: 10.1186/s12913-018-2942-z 29482587
5. Todd CS, Anderman TC, Long S, Myer L, Bekker L-G, Petro GA, et al. A systematic review of contraceptive continuation among women living with HIV. Contraception. 2018;98: 8–24. doi: 10.1016/j.contraception.2018.02.002 29432719
6. Cleland J, Ali M, Benova L, Daniele M. The promotion of intrauterine contraception in low- and middle-income countries: a narrative review. Contraception. 2017;95: 519–528. doi: 10.1016/j.contraception.2017.03.009 28365165
7. Morse J, Chipato T, Blanchard K, Nhemachena T, Ramjee G, McCulloch C, et al. Provision of long-acting reversible contraception in HIV-prevalent countries: results from nationally representative surveys in southern Africa. BJOG. 2013;120: 1386–1394. doi: 10.1111/1471-0528.12290 23721413
8. Sinei SK, Morrison CS, Sekadde-Kigondu C, Allen M, Kokonya D. Complications of use of intrauterine devices among HIV-1-infected women. Lancet. 1998;351: 238–41. doi: 10.1016/S0140-6736(97)10319-1
9. World Health Organization. Medical eligibility criteria for contraceptive use. 5th ed. Geneva: World Health Organization; 2015.
10. Heffron R, Donnell D, Rees H, Celum C, Mugo N, Were E, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12: 19–26. doi: 10.1016/S1473-3099(11)70247-X 21975269
11. Phillips SJ, Polis CB, Curtis KM. The safety of hormonal contraceptives for women living with HIV and their sexual partners. Contraception. 2016;93: 11–16. doi: 10.1016/j.contraception.2015.10.002 26515194
12. Baeten JM, Kahle E, Lingappa JR, Coombs RW, Delany-Moretlwe S, Nakku-Joloba E, et al.; Partners in Prevention HSV/HIV Transmission Study Team. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Sci Transl Med. 2011;3: 77ra29. doi: 10.1126/scitranslmed.3001888 21471433
13. Mugo NR, Heffron R, Donnell D, Wald A, Were EO, Rees H, et al.; Partners in Prevention HSV/HIV Transmission Study Team. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1-serodiscordant couples. AIDS. 2011;25: 1887–1895. doi: 10.1097/QAD.0b013e32834a9338 21785321
14. Haddad LB, Polis CB, Sheth AN, Brown J, Kourtis AP, King C, et al. Contraceptive methods and risk of HIV acquisition or female-to-male transmission. Curr HIV/AIDS Rep. 2014;11: 447–458. doi: 10.1007/s11904-014-0236-6 25297973
15. Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol (Oxf). 1982;17: 529–536. doi: 10.1111/j.1365-2265.1982.tb01625.x 6819901
16. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception. 1994;49: 56–72. doi: 10.1016/0010-7824(94)90109-0 8137626
17. Heikinheimo O, Lehtovirta P, Suni J, Paavonen J. The levonorgestrel-releasing intrauterine system (LNG-IUS) in HIV-infected women—effects on bleeding patterns, ovarian function and genital shedding of HIV. Hum Reprod. 2006;21: 2857–2861. doi: 10.1093/humrep/del264 16880227
18. Coleman JS, Mwachari C, Balkus J, Sanguli L, Muliro A, Agnew K, et al. Effect of the levonorgestrel intrauterine device on genital HIV-1 RNA shedding among HIV-1-infected women not taking antiretroviral therapy in Nairobi, Kenya. J Acquir Immune Defic Syndr. 2013;63: 245–248. doi: 10.1097/QAI.0b013e31828decf8 23446496
19. Richardson BA, Morrison CS, Sekadde-Kigondu C, Sinei SK, Overbaugh J, Panteleeff DD, et al. Effect of intrauterine device use on cervical shedding of HIV-1 DNA. AIDS. 1999;13: 2091–2097. doi: 10.1097/00002030-199910220-00012 10546862
20. Tepper NK, Curtis KM, Nanda K, Jamieson DJ. Safety of intrauterine devices among women with HIV: a systematic review. Contraception. 2016;94: 713–724. doi: 10.1016/j.contraception.2016.06.011 27343750
21. Venkatesh KK, DeLong AK, Kantor R, Chapman S, Ingersoll J, Kurpewski J, et al. Persistent genital tract HIV-1 RNA shedding after change in treatment regimens in antiretroviral-experienced women with detectable plasma viral load. J Womens Health (Larchmt). 2013;22: 330–308. doi: 10.1089/jwh.2012.3849 23531097
22. Low AJ, Konate I, Nagot N, Weiss HA, Kania D, Vickerman P, et al; Yerelon Study Group. Cervicovaginal HIV-1 shedding in women taking antiretroviral therapy in Burkina Faso: a longitudinal study. J Acquir Immune Defic Syndr. 2014;65: 237–245. doi: 10.1097/QAI.0000000000000049 24226060
23. Cu-Uvin S, DeLong AK, Venkatesh KK, Hogan JW, Ingersoll J, Kurpewski J, et al. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS. 2010;24: 2489–2497. doi: 10.1097/QAD.0b013e32833e5043 20736815
24. Nicol MR, Eneh P, Nakalega R, Kaiser T, Kabwigu S, Isingel E, et al. Depot medroxyprogesterone acetate and the vaginal microbiome as modifiers of tenofovir diphosphate and lamivudine triphosphate concentrations in the female genital tract of Ugandan women: Implications for TDF/3TC in pre-exposure prophylaxis. Clin Infect Dis. 2019 May 25;70(8):1717–1724. pii: ciz443. doi: 10.1093/cid/ciz443 31131846
25. Cohen MS, Council OD, Chen JS. Sexually transmitted infections and HIV in the era of antiretroviral treatment and prevention: the biologic basis for epidemiologic synergy. J Int AIDS Soc. 2019;22(Suppl 6): e25355. doi: 10.1002/jia2.25355 31468737
26. McKinnon LR, Achilles SL, Bradshaw CS, Burgener A, Crucitti T, Fredricks DN, et al. The Evolving Facets of Bacterial Vaginosis: Implications for HIV Transmission. AIDS Res Hum Retroviruses. 2019;35: 219–228. doi: 10.1089/AID.2018.0304 30638028
27. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64: 924. 26042815
28. Stevens WS, Marshall TM. Challenges in implementing HIV load testing in South Africa. J Infect Dis. 2010;201(Suppl 1): S78–84. doi: 10.1086/650383 20225952
29. Provincial Government of the Western Cape-Department of Health, HIV/AIDS/STI/TB (HAST) Directorate. The Western Cape consolidated guidelines for HIV treatment: prevention of mother-to-child transmission of HIV (PMTCT), children, adolescents and adults 2018 (amended version). Cape Town, South Africa: Western Cape Government Health; 2018.
30. Jaumdally SZ, Jones HE, Hoover DR, Gamieldien H, Kriek JM, Langwenya N, et al. Comparison of sampling methods to measure HIV RNA viral load in female genital tract secretions. Am J Reprod Immunol. 2017;77: e12619. doi: 10.1111/aji.12619 28111861
31. Cain LE, Cole SR. Inverse probability-of-censoring weights for the correction of time-varying noncompliance in the effect of randomized highly active antiretroviral therapy on incident AIDS or death. Stat Med. 2009;28: 1725–1738. doi: 10.1002/sim.3585 19347843
32. Masese LN, Graham SM, Gitau R, Peshu N, Jaoko W, Ndinya-Achola JO, et al. A prospective study of vaginal trichomoniasis and HIV-1 shedding in women on antiretroviral therapy. BMC Infect Dis. 2011;11: 307. doi: 10.1186/1471-2334-11-307 22047086
33. Murphy K, Keller MJ, Anastos K, Sinclair S, Devlin JC, Shi Q, et al. Impact of reproductive aging on the vaginal microbiome and soluble immune mediators in women living with and at-risk for HIV infection. PLoS ONE. 2019;14(4): e0216049. doi: 10.1371/journal.pone.0216049 31026271
34. Day S, Graham SM, Masese LN, Richardson BA, Kiarie JN, Jaoko W, et al. A prospective cohort study of the effect of depot medroxyprogesterone acetate on detection of plasma and cervical HIV-1 in women initiating and continuing antiretroviral therapy. J Acquir Immune Defic Syndr. 2014;66: 452–456. doi: 10.1097/QAI.0000000000000187 24798764
35. Greene SA, McGrath CJ, Lehman DA, Marson KG, Trinh TT, Yatich N, et al. Increased Cervical Human Immunodeficiency Virus (HIV) RNA Shedding Among HIV-Infected Women Randomized to Loop Electrosurgical Excision Procedure Compared to Cryotherapy for Cervical Intraepithelial Neoplasia 2/3. Clin Infect Dis. 2018;66: 1778–1784. doi: 10.1093/cid/cix1096 29272368
36. Blish CA, McClelland RS, Richardson BA, Jaoko W, Mandaliya K, Baeten JM, et al. Genital Inflammation Predicts HIV-1 Shedding Independent of Plasma Viral Load and Systemic Inflammation. J Acquir Immune Defic Syndr. 2012;61: 436–440. doi: 10.1097/QAI.0b013e31826c2edd 22878424
37. Kourtis AP, Wiener J, Hurst S, Nelson JAE, Cottrell ML, Corbett A, et al. Brief Report: HIV Shedding in the Female Genital Tract of Women on ART and Progestin Contraception: Extended Follow-up Results of a Randomized Clinical Trial. J Acquir Immune Defic Syndr. 2019;81: 163–165. doi: 10.1097/QAI.0000000000002011 31095006
38. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, Meehan MO, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. 2000;342: 921–929. doi: 10.1056/NEJM200003303421303 10738050
39. Attia S, Egger M, Müller M, Zwahlen M, Low N. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS. 2009;23: 1397–1404. doi: 10.1097/QAD.0b013e32832b7dca 19381076
40. Chinula L, Nelson JAE, Wiener J, Tang JH, Hurst S, Tegha G, et al. Effect of the depot medroxyprogesterone acetate injectable and levonorgestrel implant on HIV genital shedding: a randomized trial. Contraception. 2018;98: 193–198. doi: 10.1016/j.contraception.2018.05.001 29746813
41. Buckner LR, Drobnis EZ, Augustine MS, Rogers LK, Akers J, Mott PD, et al. Cervical and systemic concentrations of long acting hormonal contraceptive (LARC) progestins depend on delivery method: Implications for the study of HIV transmission. PLoS ONE. 2019; 14:e0214152. doi: 10.1371/journal.pone.0214152 31095572
42. Myer L, Dunning L, Lesosky M, Hsiao NY, Phillips T, Petro G, et al. Frequency of Viremic Episodes in HIV-Infected Women Initiating Antiretroviral Therapy During Pregnancy: A Cohort Study. Clin Infect Dis. 2017;64: 422–427. doi: 10.1093/cid/ciw792 27927852
43. Bahamondes L, Brache V, Meirik O, Ali M, Habib N, Landoulsi S; WHO Study Group on Contraceptive Implants for Women. A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls. Hum Reprod. 2015;30: 2527–2538. doi: 10.1093/humrep/dev221 26409014
44. Stringer EM, Kaseba C, Levy J, Sinkala M, Goldenberg RL, Chi BH, et al. A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol. 2007;197: 144.e1–8. doi: 10.1016/j.ajog.2007.03.031 17689627
45. Kakaire O, Byamugisha JK, Tumwesigye NM, Gemzell-Danielsson K. Intrauterine contraception among women living with human immunodeficiency virus: a randomized controlled trial. Obstet Gynecol 2015;126: 928–934. doi: 10.1097/AOG.0000000000001087 26444127
46. Jatlaoui TC, Simmons KB, Curtis KM. The safety of intrauterine contraception initiation among women with current asymptomatic cervical infections or at increased risk of sexually transmitted infections. Contraception. 2016;94: 701–712. doi: 10.1016/j.contraception.2016.05.013 27263041
47. Grimes DA. Intrauterine device and upper-genital-tract infection. Lancet. 2000;356: 1013–1019. doi: 10.1016/S0140-6736(00)02699-4 11041414
48. Langwenya N, Todd C, Jones H, Hoover DM, Ronan A, Myer L. Reproductive tract infection risk-based screening for IUD insertion in HIV+ women. Poster 1075. Proceedings of the 2018 Conference on Retroviruses and Opportunistic Infections (CROI); 2018 March 5; Boston, Massachusetts, US.
49. Hoke T, Harries J, Crede S, Green M, Constant D, Petruney T, et al. Expanding contraceptive options for PMTCT clients: a mixed methods implementation study in Cape Town, South Africa. Reprod Health. 2014;11: 3. doi: 10.1186/1742-4755-11-3 24410922
50. Heinemann K, Reed S, Moehner S, Minh TD. Comparative contraceptive effectiveness of levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices. Contraception. 2015;91: 280–283. doi: 10.1016/j.contraception.2015.01.011 25601350
51. Simonatto P, Bahamondes MV, Fernandes A, Silveira C, Bahamondes L. Comparison of two cohorts of women who expulsed either a copper-intrauterine device or a levonorgestrel-releasing intrauterine system. J Obstet Gynaecol Res. 2016;42: 554–559. doi: 10.1111/jog.12939 26817571
52. Lowe RF, Prata N. Hemoglobin and serum ferritin levels in women using copper-releasing or levonorgestrel-releasing intrauterine devices: a systematic review. Contraception 2013;87: 486–496. doi: 10.1016/j.contraception.2012.09.025 23122687
53. Application seeks to extend duration of use up to 5 years for LILETTA. San Francisco, CA: Medicines 360. 22 Feb 2018. [cited 2020 Mar 24]. Available from: http://www.medicines360.org/2018/02/22/fda-acceptance-of-medicines360s-filing-for-supplemental-new-drug-application-for-liletta-levonorgestrel-releasing-intrauterine-system-52-mg/
54. Rowlands S, Searle S. Contraceptive implants: current perspectives. Open Access J Contracept. 2014;5: 73–84. https://doi.org/10.2147/OAJC.S55968
55. Benova L, Cleland J, Daniele MAS, Ali M. Expanding Method Choice in Africa with Long-Acting Methods: IUDs, Implants or Both? Int Perspect Sex Reprod Health. 2017;43:183–191. doi: 10.1363/43e5217 29874164
Článek vyšel v časopise
PLOS Medicine
2020 Číslo 5
- Případ Bulovka: Jak postupují jiné nemocnice, aby podobným tragédiím zabránily?
- Jak často se u masových střelců vyskytují duševní choroby?
- FDA varuje před selfmonitoringem cukru pomocí chytrých hodinek. Jak je to v Česku?
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- Není statin jako statin aneb praktický přehled rozdílů jednotlivých molekul
Nejčtenější v tomto čísle
- National and regional prevalence of posttraumatic stress disorder in sub-Saharan Africa: A systematic review and meta-analysis
- Risk of severe maternal morbidity or death in relation to elevated hemoglobin A1c preconception, and in early pregnancy: A population-based cohort study
- Antibody-based therapies for COVID-19: Can Europe move faster?
- The association of innate and adaptive immunity, subclinical atherosclerosis, and cardiovascular disease in the Rotterdam Study: A prospective cohort study