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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. 2020 05; 17(5):e1003110.PM

Abstract

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.

Authors+Show Affiliations

Maternal and Child Health and Nutrition Department, Global Health, Population, and Nutrition, Durham, North Carolina, United States of America.Department of Epidemiology and Biostatistics, City University of New York School of Public Health, New York, New York, United States of America.Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Observatory, Cape Town, South Africa.Department of Statistics and Institute for Health Care Policy and Aging Research, Rutgers University, Piscataway, New Jersey, United States of America.Global Population and Health Research Department, Global Health, Population, and Nutrition, Durham, North Carolina, United States of America.Department of Obstetrics and Gynaecology, University of Cape Town, Observatory, Cape Town, South Africa. New Somerset Hospital, Cape Town, South Africa.Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Observatory, Cape Town, South Africa. 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.

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

32442189

Citation

Todd, Catherine S., et al. "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 Medicine, vol. 17, no. 5, 2020, pp. e1003110.
Todd CS, Jones HE, Langwenya N, et al. 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. 2020;17(5):e1003110.
Todd, C. S., Jones, H. E., Langwenya, N., Hoover, D. R., Chen, P. L., Petro, G., & Myer, L. (2020). 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 Medicine, 17(5), e1003110. https://doi.org/10.1371/journal.pmed.1003110
Todd CS, et al. 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. 2020;17(5):e1003110. PubMed PMID: 32442189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Todd,Catherine S, AU - Jones,Heidi E, AU - Langwenya,Nontokozo, AU - Hoover,Donald R, AU - Chen,Pai-Lien, AU - Petro,Gregory, AU - Myer,Landon, Y1 - 2020/05/22/ PY - 2019/11/15/received PY - 2020/04/13/accepted PY - 2020/5/23/entrez PY - 2020/5/23/pubmed PY - 2020/7/25/medline SP - e1003110 EP - e1003110 JF - PLoS medicine JO - PLoS Med VL - 17 IS - 5 N2 - 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. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/32442189/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_ L2 - https://dx.plos.org/10.1371/journal.pmed.1003110 DB - PRIME DP - Unbound Medicine ER -