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.

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.

RCT Entities:   Population Interventions Outcomes

Introduction

Across sub-Saharan Africa, many women acquire HIV early in their reproductive years. Subsequently, women living with HIV (WLHIV) must balance contraceptive decision-making with the potential impact of HIV infection on pregnancy outcomes and timing, risk of transmission to partners or infants, and appropriate method choice for prevention of pregnancy and sexually transmitted infections [1,2]. WLHIV discontinue hormonal methods more frequently and may have higher rates of unmet contraceptive need than their uninfected peers [3-5].

Intrauterine contraceptives (IUCs) have some of the longest effective durations among long-acting reversible contraceptive (LARC) methods but are not widely used in countries with both high total fertility rates and high HIV prevalence [6,7]. The copper T-380 intrauterine device (C-IUD) is a highly effective contraceptive method that appears to be safe for WLHIV; a Kenyan study among 156 WLHIV not using antiretroviral therapy (ART) found a low incidence of ascending reproductive tract infection (RTI) and no measurable impact on HIV progression [8,9]. However, less is known about levonorgestrel intrauterine system (LNG-IUS) safety for WLHIV.

Systematic reviews and analysis from a large observational cohort suggest that some hormonal contraceptives may be associated with increased HIV progression among or transmission to sexual partners of WLHIV [10,11]. Genital tract viral load (gVL) has been implicated in HIV transmission to male partners and a host of factors are noted to impact gVL, potentially including exogenous progestins [12-14]. LNG-IUS users experience sustained low serum LNG concentrations and relatively higher local LNG tissue concentrations [15,16], but few studies have evaluated genital tract HIV RNA shedding among WLHIV using the LNG-IUS. One small case series evaluated 12 WLHIV, 10 of whom were receiving ART in Finland for 12 months post-LNG-IUS insertion [17], and another followed 25 WLHIV not using ART in Kenya for 6 months [18]. In these studies, women served as their own controls, and the presence or quantity of plasma and genital tract HIV RNA was compared over time, with no significant change noted in either study. Similarly, for the C-IUD, Richardson and colleagues compared samples from 96 WLHIV not using ART immediately prior to and 6 months after C-IUD placement and found no significant change in cervical HIV RNA detection [19]. Although these studies are notable for relatively high IUC continuation rates, most were of short duration, had small sample sizes, and lacked a comparator group, relying on a crossover design. A systematic review including these and other smaller studies concluded that genital tract shedding likely does not increase with IUC use among WLHIV but that supporting evidence quality regarding shedding is fair to poor [20].

Data for whether IUCs are safe for use among WLHIV and, specifically, whether IUCs impact gVL is germane given expanded global ART use and findings of persistent detectable gVL among WLHIV virally suppressed with very low to undetectable plasma viral load (pVL) [21-23]. There are emerging concerns that HIV acquisition and transmission risk may increase in the presence of RTIs, non-Lactobacillus dominant microbiota, and hormonal contraceptives because of local interaction with ART agents [24-26]. Thus, evidence regarding gVL change with exposure to hormonal and nonhormonal IUC use among WLHIV with typical ART use patterns in a context with high background RTI prevalence is timely and may help inform this debate. The purpose of this study was to compare the LNG-IUS with the C-IUD among WLHIV to assess safety concerning HIV transmission and disease progression using the proxy measures of gVL (primary outcome) and pVL (secondary outcome) and by adverse events (AEs) and to assess acceptability as measured by IUC continuation (secondary outcomes). Our hypothesis was that the LNG-IUS was no different from C-IUD regarding change in rates of detectable gVL (noninferiority trial).

Methods

We conducted a double-masked randomized controlled trial with one-to-one allocation comparing the C-IUD (SMB Copper T-380A IUD; SMB Corporation of India, Mumbai, India, or Nova-T Copper T-380 IUD; Bayer Pharmaceuticals, Germany) to the LNG-IUS (Mirena; Bayer Health Care Pharmaceuticals, Montville, NJ) among WLHIV, stratified by enrollment ART status (ART and non-ART users) in Gugulethu, Cape Town, South Africa (clinicaltrials.gov NCT01721798) (please see S1 CONSORT checklist). Women were recruited from surrounding healthcare facilities, community events promoting reproductive health, and radio and newspaper advertisements.

Ethical review

The University of Cape Town Human Research Ethics Committee (#283/2012) and FHI 360 Protection of Human Subjects Committee (#10369/398733) approved the study prior to study activity initiation, and all participants provided written informed consent prior to screening and trial participation.

Eligibility

Eligible women were ages 18–40 years; confirmed as HIV-infected; not pregnant or desiring pregnancy for the next 30 months; at least 6 months postpartum; not planning relocation within 30 months; screened with cervical cytology within the last year (women without a documented cervical cytology report within the last year were offered cytology smear during the pelvic examination at the screening visit in an opt-out fashion to ensure appropriate triage for evidence of neoplasia and eligibility at enrollment visit); without history of ectopic pregnancy, tubal sterilization, or other conditions contraindicating IUC use; and interested in IUC use for contraception. Eligible women using ART had documented pVL < 1,000 copies/mL in the last 6 months, and non-ART women were ART-ineligible at enrollment by CD4 lymphocyte count per local guidelines. As guidelines changed during the trial period, the non-ART arm criteria also changed; when guidelines changed to immediate ART initiation, non-ART women were screened and enrolled and referred for ART at these visits.

Visit procedures

The visit schedule comprised screening, enrollment, and follow-up at 3, 6, 12, 18, and 24 months. All visits were conducted at the study clinic on site at the Gugulethu Community Health Centre in Gugulethu, Cape Town, South Africa. At screening, consenting women were tested for RTIs (Neisseria gonorrhea [NG], Chlamydia trachomatis [CT], Trichomonas vaginalis [TV], Treponema pallidum [TP], and sialidase-positive bacterial vaginosis [BV]) and treated for reactive test results. At enrollment, women had either nonreactive results for all pathogens within 30 days or were 2 to 4 weeks posttreatment for reactive tests; women could be screened up to 3 times. Women were encouraged to continue their current contraceptive method until enrollment; for those reporting injectable progestin contraceptive (IPC) use (depot medroxyprogesterone acetate [DMPA] or norethisterone enanthate), enrollment was scheduled synchronously with the next IPC dose to mitigate potential residual hormonal effect on gVL measures while sustaining contraception [10]. Staff scheduled visits to avoid menstrual bleeding, with visits rescheduled for reported or clinically observed bleeding, and asked participants to avoid vaginal intercourse or douching 48 hours prior to visits.

At enrollment, participants completed an interview-administered baseline questionnaire on sociodemographic characteristics, reproductive and sexual history, menstrual bleeding, and pelvic symptoms; follow-up visit questionnaires also queried IUC acceptability and changes in partnership status and HIV care. At all visits, women inserted menstrual cups (Instead Softcup; Evofem, San Diego, CA, United States of America) for genital tract sample collection, provided urine specimens for pregnancy testing, and provided blood for pVL. At all visits except 3 months, full blood count and CD4 testing (non-ART group) were also conducted. A study nurse certified in IUC insertion provided the LNG-IUS or C-IUD at the end of the enrollment visit based on randomized allocation. Each visit included pelvic examination to collect swabs for RTI testing, bimanual exam, and, at follow-up visits, string visualization to confirm IUC placement. If strings were not visible, immediate onsite ultrasound was used to confirm IUC presence and intrauterine placement. During visits, the study nurse inquired regarding bleeding or other symptoms, which were tracked within an AE register.

Participants were counseled about possible bleeding pattern changes, how to check strings, and notifying the clinic immediately if the IUC was expelled, heavy or abnormal bleeding occurred, or symptoms concerning for RTI or pregnancy occurred. Women were further counseled they could have the IUC removed at any time and a new method provided. Women requesting IUC removal and agreeing to continue with the study were retained through the 24-month visit but excluded from all as-treated (AT) analyses; the only participants terminated from the study were those with diagnosed pregnancy. Women presenting within 72 hours of complete IUC expulsion or with recognized partial expulsion on examination were offered replacement with the allocated IUC if a pregnancy test was negative. Women with clinically diagnosed pelvic inflammatory disease (PID) were offered IUC removal and treated according to national protocols [27]; these women received close follow-up.

Laboratory testing

Plasma and genital tract specimens were tested for HIV RNA at the South African National Health Laboratory Service (NHLS) using the Abbott M2000SP/RT VL assay (Abbott Diagnostics, IL, USA) until June 2015, then subsequently with Roche COBAS TaqMan HIV-1 v2·0 assay (Roche Diagnostics, Mannheim, Germany) with lower limits of detection (LoDs) of 40 and 20 copies/mL, respectively [28]. RTI testing comprised NG and CT nucleic acid amplification testing with NG/CT Xpert (Cepheid Diagnostics, Sunnyvale, CA, USA), TV and BV rapid diagnostic tests (RDTs) for genital tract specimens with OSOM Trichomonas and BV Blue (Sekisui Diagnostics, Lexington, MA, USA), and TP with Alere Determine Syphilis (Alere Diagnostics, San Diego, CA, USA) RDT for whole blood with reflex Rapid Plasma Reagin titer testing of plasma, according to package instructions. Hematological testing comprised CD4 lymphocyte count (non-ART group) using Beckman Coulter XL flow cytometry and complete blood count tests, including hemoglobin, all processed on automated platforms per NHLS procedures.

Outcome measures

The primary trial outcome was change in proportions of WLHIV with detectable gVL from baseline across 6 and 24 months of follow-up. At study initiation in 2013, the original primary outcome was change in pVL, and enrollment into the study was originally restricted to non-ART users. With changes in South African guidelines to ART initiation at diagnosis in 2014 [29], we amended the primary outcome to genital HIV shedding, as a proxy for transmission (originally a secondary outcome), and enrollment to include virally suppressed (pVL<1,000 copies/mL) ART-using WLHIV. Secondary outcomes were changes in pVL; other side effects and safety issues related to IUC use, including hemoglobin, overall and related AEs, and serious AEs (SAEs); and acceptability via IUC continuation.

Sample size rationale and adjustment with outcome change

The original sample size and assumptions are presented in S1 Text. With the change in primary outcome in 2014, the original evaluable sample size of 288 was divided into ART and non-ART groups, and power estimates were calculated for change in proportion of WLHIV with detectable gVL between study arms using a 2-sample exact test with enrollment and 6-month visit measures, using a 2-sided α = 0.05. We further assumed a 15% IUC discontinuation rate and a 5% loss to follow-up rate at 6 months. For ART-using women, we estimated that 54 evaluable women in each arm gave 80% power to exclude a difference of at least 27.7% in proportion of women with detectable gVL between arms at 6 months, assuming 22% of ART-using women had detectable gVL [30]. For non-ART women, we estimated that 62 evaluable women in each arm would provide 80% power to measure a 23.7% difference in detectable gVL between arms at 6 months, informed by shedding rates of 61% of the first 36 non-ART participants [22]. For the pooled sample, we estimated 80% power to detect at least a 19.1% difference in detectable gVL with 116 evaluable women in each arm, assuming a pooled baseline gVL of 42.8%. The pooled gVL value was calculated by using non-ART gVL of 61% * 62/116 + estimated ART-user gVL of 22% * 54/116; this was calculated in 2015 at the time of primary outcome change and ART group addition with available evidence [22].

Randomization and masking

We used 1:1 permuted block randomization with block sizes of 4 to 6 stratified by ART use, age (18–23, 24–31, 32–40), and recent IPC exposure. An external data manager generated the randomization scheme and provided the study site with sequentially numbered, sealed envelopes by stratification arm. The study manager or nurse provided each eligible participant the next sequential envelope in their stratum during the enrollment visit, specifying either “Treatment A” or “Treatment B.” Only study nurses conducting insertions and a site manager were unmasked to specific IUC corresponding to arm; all investigators and outcomes assessors were masked. Participants were unmasked at exit visits.

Statistical analysis

Participant baseline demographic and health history data by study arm were summarized using means (± standard deviations), medians (with interquartile ranges), and proportions. IUC expulsions presenting beyond 72 hours or women declining IUC replacement were censored from VL-associated analysis at that time point for AT analyses. Women with positive pregnancy tests had immediate ultrasound and referral as appropriate with IUC removal for cases with partial expulsion; these women were censored from all analyses following pregnancy diagnosis.

For primary and secondary HIV viral load outcomes, we analyzed differences between arms both by AT and intent-to-treat (ITT) using generalized linear models (GLMs) with generalized estimating equations (GEEs) via combined and stratified analysis by ART group. We preferentially selected AT analyses for the primary (gVL) and 2 secondary outcomes (pVL and AEs); ITT analyses are also presented. We selected AT analysis during study design and analysis planning, as the VL outcomes, pVL and gVL (the latter becoming the primary outcome measure), are both safety measures reflective of potential accelerated disease progression and transmission to partners, respectively. As safety outcomes, we believed it was essential to reflect actual exposure to IUCs with the AT approach rather than the more conservative ITT. To compare the primary outcome, change in proportion of women with detectable gVL from baseline pooled across 6 and 24 months, we used GEE with logistic link and exchangeable working correlation structure to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). All models were adjusted for baseline gVL, as the primary outcome was change in gVL, post-IUC insertion, and adjusted for age and ART group, given stratified randomization. In sensitivity analysis, we further adjusted AT models for prespecified hypothesized confounders of concurrent RTI and baseline pVL. Because of differential IUC discontinuation rates between arms, sensitivity analyses using inverse probability-of-discontinuation weights were applied to primary and secondary HIV-related safety outcomes [31], as were sensitivity analyses testing visit month effect and independent working correlation structure.

For analysis of changes in pVL, 2 approaches were used. For ART users, we used GEE to generate ORs with 95% CIs to evaluate detectable pVL rates between arms from baseline pooled across 6 and 24 months. For non-ART women, we used GLM with identical link to estimate mean change in log10 pVL between arms from baseline pooled across 6 months; we did not analyze across 24 months, as many non-ART women initiated ART during that period. The adjusted models for both ART groups included the previously prespecified confounders and baseline VL measures. For analyses of VL as a continuous measure with log10 values, participants with “undetectable” or lower than LoD results were assigned the value of 20 copies/mL, representing the lowest LoD of the 2 commercial assays used for VL measures and the midpoint between 0 and LoD of the assay with the higher LoD. Previous studies have used either approach (the manufacturer’s LoD to quantify undetectable measures [18,32-34] or the value between 0 and the LoD for undetectable values [35-37]). As VL tests were run through NHLS and assays were changed midway through the study, we believe using the value of 20 copies/mL represents the best assigned value for undetectable VL measures.

For the secondary acceptability outcome of discontinuation, we used Kaplan-Meier models with log-rank tests to estimate and compare cumulative discontinuation probabilities between arms, both overall and stratified by ART group. We also estimated crude and adjusted hazard ratios (aHRs) of discontinuation, adjusting for prespecified covariates of age, ART status, and concurrent RTI, using Cox proportional hazards models. The proportional hazard assumptions of Cox models were examined using Schoenfeld residuals, which do not reject that assumption with p = 0.134. AEs were summarized by those considered related to IUC use and by system organ class, pooled across study arms. Percentages of participants experiencing each AE (1 or more times) were calculated, and we analyzed differences between arms using chi-squared or, for comparisons with 5 or fewer individuals in 1 group, Fisher’s exact tests. We describe SAEs deemed related to IUC use by arm and with rates based on time contributed in an AT model. We compared mean absolute change in hemoglobin (g/dL) between arms across 6 and 24 months in pooled and ART group-stratified analysis using the same approach as for non-ART group pVL analysis. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). For further details on analytic approach and rationale, please see S1 Text for the study protocol and S2 Text for the statistical analysis plan.

Results

Participant characteristics and baseline measures

Of 205 women enrolled from October 2013 to December 2016, 199 contributed data for analysis through study closure in July 2018 (Fig 1).

Fig 1

Trial recruitment and study activity flow chart.

ART, antiretroviral therapy; C-IUD, copper intrauterine device; LNG-IUS, levonorgestrel intrauterine system; LTFU, loss to follow-up; TB, tuberculosis.

More than 85% of participants continued through the 6-month and end-of-study visits. Because of clinical activity closure in July 2018, 17 women (16 ART users, 1 non-ART user) were not eligible for the 24-month visit; as such, we did not conduct a 24-month visit with VL and RTI measures for these participants. Instead, to ensure informed contraceptive decision-making, we conducted exit visits to unmask these participants and ask whether they wished to retain their IUC. We also did telephone follow-up with these participants at the time of 24-month visit eligibility to assess IUC retention in women who elected to continue their allocated IUC at exit visit.

Most participants had been pregnant at least once and had a mean age of 31.4 years (Table 1). Only one-fifth had completed secondary education, and more than 80% reported having 1 partner over the last 12 months. At screening, RTIs were common, diagnosed among approximately 40% of women, particularly in the non-ART group, with BV, TV, and CT being the most frequent RTIs detected. At enrollment, more than 10% of ART users and 55% of non-ART women had detectable gVL; there were no significant differences in proportion of women with detectable gVL between study arms within each ART group.

Table 1

Participant baseline sociodemographic and health characteristics at enrollment by arm and ART status (n = 199).

	All participants (n = 199)		ART-using women (n = 132)		Non-ART women (n = 67)
Variable	C-IUD (n = 98)	LNG-IUS (n = 101)	C-IUD (n = 67)	LNG-IUS(n = 65)	C-IUD (n = 31)	LNG-IUS (n = 36)
Age in years, mean (SD)	31.4 (4.6)	31.4 (4.9)	31.8 (4.5)	32.1 (4.8)	30.6 (4.6)	30·2 (5.0)
Completed secondary education, n (%)	21 (21.4)	28 (27.7)	16 (23.9)	15 (23.1)	5 (16.1)	13 (36.1)
Currently employed, n (%)	29 (29.6)	38 (37.6)	18 (26.9)	22 (33.8)	11 (35.5)	16 (44.4)
Ever pregnant, n (%)	96 (98.0)	94 (93.1)	65 (97.0)	63 (96.9)	31 (100.0)	31 (86.1)
Number of pregnancies, median (IQR)	2 (1, 3)	2 (1, 3)	2 (1, 3)	2 (2, 3)	2 (1, 3)	2 (1, 2)
Number of sex partners in past 12 months, n (%)
0	6 (6.1)	4 (4.0)	5 (7.5)	3 (4.6)	1 (3.2)	1 (2.8)
1	82 (83.7)	87 (86.1)	55 (82.1)	57 (87.7)	27 (87.1)	30 (83.3)
2+	10 (10.2)	10 (9.9)	7 (10.4)	5 (7.7)	3 (9.7)	5 (13.9)
Sexual frequency, last 3 months, n (%)
Less than once per month	25 (25.8)	29 (28.7)	14 (21.2)	18 (27.7)	11 (35.5)	11 (30.6)
1–3 times per month	24 (24.7)	22 (21.8)	18 (27.3)	12 (18.5)	6 (19.4)	10 (27.8)
Once per week	16 (16.5)	24 (23.8)	9 (13.6)	18 (27.7)	7 (22.6)	6 (16.7)
More than once per week	32 (33.0)	26 (25.7)	25 (37.9)	17 (26.1)	7 (22.6)	9 (25.0)
Years since HIV diagnosis, median (IQR)	5.4 (2.0, 8.4)	5.0 (2.0, 8.4)	7.3 (3.3, 10.4)	6.2 (4.2, 9.0)	2.6 (1.1, 4.3)	3.8 (0.5, 5.9)
Detectable pVL, n (%)	44 (44.9)	46 (45.5)	14 (20.9)	12 (18.5)	30 (96.8)	34 (94.4)
pVL copies/mL, n (%)
<40	55 (56.1)	55 (54.5)	54 (80.6)	53 (81.5)	1 (3.2)	2 (5.6)
40–1,000	11 (11.2)	13 (12.9)	6 (9.0)	8 (12.3)	5 (16.1)	5 (13.9)
1,001–10,000	15 (15.3)	17 (16.8)	5 (7.5)	2 (3.1)	10 (32.3)	15 (41.7)
10,001–100,000	15 (15.3)	13 (12.9)	2 (3.0)	2 (3.1)	13 (41.9)	11 (30.6)
>100,000	2 (2.0)	3 (3.0)	0 (0.0)	0 (0.0)	2 (6.4)	3 (8.3)
pVL log10 copies/mL, median (IQR)a	3.7 (2.8, 4.5)	3.5 (2.9, 4.2)	3.2 (2.2, 3.6)	2.2 (1.9, 3.1)	4·0 (3.3, 4.5)	3.8 (3.1, 4.3)
CD4 lymphocyte count at last screening prior to enrollment, median (IQR)b	NA	NA	NA	NA	684 (551, 832)	568 (462, 732)
Detectable gVL, n (%)	28 (28.6)	30 (29.7)	10 (14.9)	7 (10.8)	18 (58.1)	23 (63.9)
gVL copies/mL, n (%)c
<40	71 (72.4)	71 (70.3)	57 (85.1)	58 (89.2)	14 (45.2)	13 (36.1)
40–1,000	8 (8.2)	13 (12.9)	7 (10.4)	5 (7.7)	1 (3.2)	8 (22.2)
1,001–10,000	12 (12.2)	9 (8.9)	2 (3.0)	1 (1.5)	10 (32.3)	8 (22.2)
10,001–100,000	7 (7.1)	7 (6.9)	1 (1.5)	1 (1.5)	6 (19.3)	6 (16.7)
>100,000	0 (0.0)	1 (1.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.8)
gVL log10 copies/mL, median (IQR)a	3.2 (2.8, 4.0)	3.4 (2.5, 4.0)	2.6 (2.3, 3.3)	2.5 (2.1, 3.6)	3.3 (3.1, 4.1)	3.6 (2.7, 4.2)
Reproductive tract infections at screening,d n (%)	30 (30.6)	40 (39.6)	17 (25.4)	22 (33.8)	13 (41.9)	18 (50.0)
Sialidase-positive bacterial vaginosis	11 (11.2)	18 (17.8)	5 (7.5)	9 (13.8)	6 (19.3)	9 (25.0)
N. gonorrhea	4 (4.1)	4 (4.0)	3 (4.5)	2 (3.1)	1 (3.2)	2 (5.6)
C. trachomatis	5 (5.1)	7 (6.9)	2 (3.0)	5 (7.7)	3 (9.7)	2 (5.6)
T. vaginalis	10 (10.2)	9 (8.9)	7 (10.4)	6 (9.2)	3 (9.7)	3 (8.3)
T. pallidum	0 (0.0)	2 (2.0)	0 (0.0)	0 (0.0)	0 (0.0)	2 (5.6)
Hemoglobin, mean (SD)e	12.4 (1.2)	12.4 (1.1)	12.2 (1.3)	12.4 (1.1)	12.8 (1.0)	12.4 (1.3)

aAmong women with detectable (>40 copies/mL) pVL or gVL.

bData not collected for ART-using women.

cThree cases imputed.

dEnrollment within 1 month of screening.

eOne case missing data in ART-using C-IUD arm.

ART, antiretroviral therapy; C-IUD, copper intrauterine device; gVL, genital viral load; IQR, interquartile range; LNG-IUS, levonorgestrel intrauterine system; NA, not available; pVL, plasma viral load; SD, standard deviation

Safety regarding genital tract and plasma HIV RNA

Detectable levels of genital tract HIV RNA were consistently present in at least 8% of participants at any time point, irrespective of ART status (Fig 2).

Fig 2

Trends in female gVL and pVL and IUC continuation by study arm and within ART use strata across the cohort period overall and with AT group.

ART, antiretroviral therapy; AT, as-treated; C-IUD, copper intrauterine device; gVL, genital viral load; IUC, intrauterine contraceptive; LNG-IUS, levonorgestrel intrauterine system; pVL, plasma viral load.

Approximately one-fifth of ART users had detectable pVL at enrollment, and this increased steadily within this group across the cohort period, mirrored by detectable gVL. Larger proportions of women in the non-ART group at enrollment had undetectable or suppressed pVL values starting from 18 months’ follow-up, with related trends in gVL.

There were no significant differences between study arms in proportions of women with detectable gVL in all models and by ART group (Table 2). In sensitivity analyses including censoring adjustment for differential IUC discontinuation, adjustment for visit month effect, and independent working correlation, we found no substantive change in odds of detectable gVL between arms (S1–S3 Tables).

Table 2

Detectable genital tract HIV RNA rates across 6 and 24 months by ART status.

	All participants (n = 199)	ART-using women (n = 132)	Non-ART women (n = 67)
Detectable gVL by study visit	AOR (95% CI) p-value	AOR (95% CI) p-value	AOR (95% CI) p-value
As-treated analysisa
Across 6 months	0.82 (0.46–1.47) 0.51	0.85 (0.39–1.84) 0.68	0.79 (0.33–1.90) 0.60
Across 24 months	0.96 (0.63–1.45) 0.84	0.79 (0.46–1.36) 0.40	1.20 (0.61–2.35) 0.60
Intent-to-treat analysisa
Across 6 months	0.87 (0.50–1.52) 0.62	0.76 (0.36–1.60) 0.47	1.04 (0.43–2.51) 0.94
Across 24 months	0.99 (0.66–1.48) 0.97	0.73 (0.44–1.24) 0.25	1.41 (0.74–2.67) 0.30
Adjusted as-treated analysis
Across 6 monthsb	0.78 (0.44–1.38) 0.39	0.82 (0.38–1.76) 0.61	0.70 (0.30–1.68) 0.43
Across 24 monthsb	0.95 (0.63–1.44) 0.81	0.79 (0.46–1.35) 0.39	1.19 (0.61–2.33) 0.61
Across 24 monthsc	1.03 (0.68–1.57) 0.88	0.80 (0.48–1.33) 0.40	1.31 (0.61–2.84) 0.49

Adjusted for baseline detectable gVL, age, and ART group (combined only).

bAdjusted for baseline detectable gVL, any RTI, age, and ART group (combined only).

cAdjusted for baseline detectable gVL, any RTI, age, baseline pVL (dichotomous), pVL (log10 continuous), and ART group (combined only).

AOR, adjusted odds ratio; ART, antiretroviral therapy; CI, confidence interval; gVL, genital viral load; pVL, plasma viral load; RTI, reproductive tract infection

We also detected no significant difference in detectable gVL between baseline compared with combined 3- and 6-month visit measures for each IUC (Table 3).

Table 3

Change in detectable genital tract HIV RNA viral load between baseline and pooled 3 and 6 months post-intrauterine contraceptive insertion measures, by ART status (n = 199).

	LNG-IUS			C-IUD
	Pooled	ART	Non-ART	Pooled	ART	Non-ART
	OR (95% CI) p-value	OR (95% CI) p-value	OR (95% CI) p-value	OR (95% CI) p-value	OR (95% CI) p-value	OR (95% CI) p-value
As-treated analysis	(n = 98)	(n = 62)	(n = 36)	(n = 88)	(n = 63)	(n = 25)
Crude	1.02 (0.65–1.58) 0.94	1.49 (0.58–3.81) 0.41	0.76 (0.36–1.61) 0.48	1.17 (0.80–1.70) 0.43	1.30 (0.67–2.52) 0.44	1.02 (0.55–1.90) 0.94
Adjusted	0.87 (0.47–1.62) 0.66	1.18 (0.39–3.55) 0.77	0.66 (0.16–2.70) 0.57	1.05 (0.67–1.63) 0.84	1.19 (0.59–2.39) 0.63	0.81 (0.28–2.37) 0.70
Intent-to-treat analysis	(n = 101)	(n = 65)	(n = 36)	(n = 98)	(n = 67)	(n = 31)
Crude	1.04 (0.67–1.62) 0.86	1.56 (0.61–4.00) 0.36	0.76 (0.36–1.61) 0.47	1.16 (0.81–1.65) 0.43	1.20 (0.66–2.17) 0.55	1.22 (0.69–2.17) 0.49
Adjusted	0.94 (0.51–1.74) 0.85	1.40 (0.46–4.22) 0.55	0.66 (0.16–2.70) 0.57	1.08 (0.71–1.64) 0.71	1.08 (0.58–2.03) 0.81	1.17 (0.51–2.66) 0.71

aAdjusted for detectable pVL for ART group, pVL (log10 continuous) for non-ART group.

ART, antiretroviral therapy; CI, confidence interval; C-IUD, copper intrauterine device; LNG-IUS, levonorgestrel intrauterine system; OR, odds ratio; pVL, plasma viral load

For the secondary pVL outcome, there was no significant difference in odds of detectable pVL between arms for any analytic approach among ART users (Table 4). For non-ART users, there was no significant difference in mean change in log10 pVL across 6 months; we did not analyze end visit data, as 18.0% (n = 11) of non-ART women reported initiating ART by the exit visit, with 6.3% of initiations occurring by the 12-month visit. These findings were similar in sensitivity analyses identical to those used for gVL (S4–S6 Tables).

Table 4

Plasma HIV RNA viral load outcomes by ART status across 6 and 24 months among women living with HIV using the LNG-IUS or C-IUD, stratified by ART use (n = 199).

	Detectable pVL	Change of log10 pVL through 6-month visit
	ART group (n = 132)	Non-ART group (n = 67)
	AOR (95% CI), p-value	Difference (95% CI), p-value
As-treated analysis
Across 6 monthsa	0.82 (0.36–1.83), 0.62
Across 6 monthsb		−0.05 (−0.25 to 0.15), 0.67
Across 24 monthsa	0.93 (0.48–1.79), 0.82
Intent-to-treat analysis
Across 6 monthsa	0.83 (0.37–1.86), 0.65
Across 6 monthsb		−0.07 (−0.26 to 0.12), 0.59
Across 24 monthsa	0.90 (0.47–1.73), 0.76
Adjusted as-treated analysis
Across 6 monthsc	0.83 (0.37–1.86), 0.64
Across 6 monthsd		−0.10 (−0.29 to 0.10), 0.50
Across 24 monthsc	0.94 (0.49–1.81), 0.85

aAdjusted for baseline detectable pVL and age.

bAdjusted for baseline pVL (log10 continuous) and age.

cAdjusted for baseline detectable pVL, any concurrent RTI, and age.

dAdjusted by baseline continuous pVL (log10 continuous), any concurrent RTI, and age.

AOR, adjusted odds ratio; ART, antiretroviral therapy; CI, confidence interval;; C-IUD, copper intrauterine device; LNG-IUS, levonorgestrel intrauterine system; pVL, plasma viral load; RTI, reproductive tract infection

Safety regarding reproductive and systemic health measures

At least 1 AE was reported by 98% of participants in each arm. Specific AEs potentially related to IUC use were common, and some differed significantly between study arms, with menorrhagia, dysmenorrhea, and anemia more prevalent among C-IUD users and amenorrhea more common among LNG-IUS users (Table 5). Non-ART women reported pelvic pain, dysmenorrhea, and bloating in higher proportions than ART users. There were 39 SAEs, including 2 deaths unrelated to IUC use (LNG-IUS: smoke inhalation; C-IUD: brief illness disclosed by family), 3 cases of PID (2 LNG-IUS, rate = 1.2/100 person-years [p-y], 95% CI 0.3–4.6), 1 C-IUD (rate = 0.7/100 p-y, 95% CI 0.1–4.9, p = 0.68; overall rate = 0.9/100 p-y, 95% CI 0.3–2.9), and 4 pregnancies with IUC in place (2 ectopic pregnancies in C-IUD users; 1 incomplete abortion with no IUC recovered in a C-IUD user, suggesting unrecognized expulsion; and 1 intrauterine pregnancy in an LNG-IUS user). Pregnancy rates with IUC in place were 1.3/100 p-y overall (95% CI 0.4–3.3), with 2.1/100 p-y (95% CI 0.7–6.5) for C-IUD and 0.6/100 p-y (95% CI 0.1–4.6) for LNG-IUS (p = 0.26). There were no recognized cases of uterine perforation.

Table 5

Adverse events compared between women living with HIV using the LNG-IUS or C-IUD, by ART status (n = 199).

	All participants (n = 199)			ART-using women (n = 132)			Non-ART women (n = 67)
Adverse events	LNG-IUS users with ≥1 event; n (%)	C-IUD users with ≥1 event; n (%)	p-value	LNG-IUS users with ≥1 event; n (%)	C-IUD users with ≥1 event; n (%)	p- value	LNG-IUS users with ≥1 event; n (%)	C-IUD users with ≥1 event; n (%)	p-value
Overall events	99 (98.0)	96 (98.0)	1.00	63 (96.9)	65 (97.0)	1.00	36 (100)	31 (100)	1.00
Events potentially related to intrauterine contraception
Bleeding conditions
Amenorrhea	49 (48.5)	11 (11.2)	<0.001	32 (49.2)	8 (11.9)	<0.001	17 (47.2)	3 (9.7)	0.001
Menorrhagia	5 (5.0)	28 (28.6)	<0.001	3 (4.6)	17 (25.4)	0.001	2 (5.6)	11 (35.5)	0.004
Intermenstrual bleeding	23 (22.8)	22 (22.4)	1.00	13 (20.0)	17 (25.4)	0.54	10 (27.8)	5 (16.1)	0.38
Irregular/heavy bleeding	8 (7.9)	13 (13.3)	0.25	4 (6.2)	7 (10.4)	0.53	4 (11.1)	6 (19.4)	0.49
Menstrual disorder	7 (6.9)	5 (5.1)	0.77	7 (10.8)	5 (7.5)	0.56	0 (0)	0 (0)	--
Other gynecologic conditions: pain
Pelvic pain	29 (28.7)	30 (30.6)	0.88	12 (18.5)	15 (22.4)	0.67	17 (47.2)	15 (48.4)	1.00
Dysmenorrhea	6 (5.9)	15 (15.3)	0.04	3 (4.6)	8 (11.9)	0.21	3 (8.3)	7 (22.6)	0.17
Enlarged abdomen	6 (5.9)	7 (7.1)	0.78	3 (4.6)	2 (3.0)	0.68	3 (8.3)	5 (16.1)	0.46
Breast pain	3 (3.0)	7 (7.1)	0.21	0 (0)	1 (1.5)	1.00	3 (8.3)	6 (19.4)	0.28
Lower back pain	5 (5.0)	2 (2.0)	0.45	4 (6.2)	2 (3.0)	0.44	1 (2.8)	0 (0)	1.00
Other gynecologic conditions: symptoms of infection/inflammation
Leukorrhea	5 (5.0)	10 (10.2)	0.19	2 (3.1)	4 (6.0)	0.68	3 (8.3)	6 (19.4)	0.28
Cervicitis	2 (2.0)	1 (1.0)	1.00	2 (3.1)	1 (1.5)	0.62	0 (0)	0 (0)	--
Systemic conditions
Weight gain	11 (10.9)	13 (13.3)	0.67	5 (7.7)	5 (7.5)	1.00	6 (16.7)	8 (25.8)	0.38
Weight loss	2 (2.0)	1 (1.0)	1.00	0 (0)	0 (0)	--	2 (5.6)	1 (3.2)	1.00
Headache	9 (8.9)	7 (7.1)	0.80	7 (10.8)	3 (4.5)	0.20	2 (5.6)	4 (12.9)	0.40
Anemia	3 (3.0)	10 (10.2)	0.05	2 (3.1)	8 (11.9)	0.10	1 (2.8)	2 (6.5)	0.59
Nausea	7 (6.9)	6 (6.1)	1.00	2 (3.1)	5 (7.5)	0.44	5 (13.9)	1 (3.2)	0.21
Acne	0 (0)	4 (4.1)	0.06	0 (0)	4 (6.0)	0.12	0 (0)	0 (0)	--

ART, antiretroviral therapy; C-IUD, copper intrauterine device; LNG-IUS, levonorgestrel intrauterine system

For an objective measure of bleeding, we compared hemoglobin change between arms in AT analysis to present relative change concomitant with IUC use. Generally, change in hemoglobin from baseline was significantly higher among LNG-IUS users compared with C-IUD users (Table 6). Changes were markedly higher at the 6-month visit than at the 24-month visit for non-ART women, compared with steady increases in ART users using the LNG-IUS.

Table 6

Mean relative change in hemoglobin level between women living with HIV using the LNG-IUS or C-IUD across 6 and 24 months, by ART use (n = 186).

	All participants (n = 186)	ART-using women (n = 125)	Pre-ART women (n = 61)
Hemoglobin by study visit	LNG-IUS versus C-IUD (95% CI)p-value
As-treated analysisa
Across 6 months	0.57 (0.24–0.90) <0.001	0.55 (0.11–0.99) 0.014	0.63 (0.20–1.06)0.004
Across 24 months	0.71 (0.47–0.95) <0.001	0.77 (0.45–1.08) <0.001	0.57 (0.25–0.89) <0.001
As-treated analysisb
Across 6 months	0.58 (0.25–0.91) <0.001	0.57 (0.13–1.02) 0.012	0.64 (0·21–1.06)0.004
Across 24 months	0.71 (0.47–0.95) <0.001	0.78 (0.47–1.10) <0.001	0.57 (0.25–0.89) <0.001

aAdjusted for baseline hemoglobin in generalized linear model.

bAdjusted for baseline hemoglobin, age, pVL, and (pooled) ART status in generalized linear model.

ART, antiretroviral therapy; CI, confidence interval; C-IUD, copper intrauterine device; LNG-IUS, levonorgestrel intrauterine system; pVL, plasma viral load

IUC expulsion and discontinuation

IUC continuation was 78% (155/199) across all participants during the cohort period; the overall IUC expulsion rate was 2.8/100 p-y, 95% CI 1.5–5.5. Expulsion (5.6/100 p-y, 95% CI 2.8–11.1 for C-IUD versus 0.6/100 p-y, 95% CI 0.10–4.1 for LNG-IUS, p = 0.03) and all-cause discontinuation rates (35% for C-IUD versus 6% for LNG-IUS, p ≤ 0.001; Fig 3) were significantly higher among women using the C-IUD.

Fig 3

Kaplan-Meier curve comparing IUC continuation rates between LNG-IUS and C-IUD users overall among women living with HIV in Cape Town, South Africa (n = 199).

C-IUD, copper intrauterine device; IUC, intrauterine contraceptive; IUD, intrauterine device; LNG IUS, levonorgestrel intrauterine system.

Elective discontinuation hazards were significantly higher for C-IUD (aHR = 8.61, 95% CI 3.03–24.4, p < 0.001) users. Overall IUC discontinuation did not differ significantly by ART status (aHR = 1.12, 95% CI 0.11–11.40, p = 0.92), though non-ART women tended to request discontinuation earlier than ART users (S1 Fig).

Discussion

We found no significant difference in proportions of women with detectable gVL between LNG-IUS and C-IUD arms and no change in detectable gVL prior to insertion compared across 3 and 6 months following insertion of either IUC. Similarly, there was no significant difference in proportions of women with detectable pVL (for ART users) or mean change in log10 pVL (for non-ART users) between IUC arms. We also demonstrated that the LNG-IUS had significantly higher continuation during the study (96% for LNG-IUS versus 59% for C-IUD), reflecting greater acceptability of the LNG-IUS than the C-IUD. There were few cases of PID, and the IUC had a high overall continuation rate, which is notable among a population with high background rates of curable RTIs. We achieved our study aim to measure IUC safety with regard to HIV disease and AEs, as well as relative acceptability through continuation rates, although the sample size in the non-ART group was smaller than originally planned.

We selected gVL as a proxy measure for transmission risk given association between gVL and sexual transmission to male partners in discordant couples [12,38]. There are limited data regarding quantity at which gVL substantively increases transmission risk, though 1 publication suggests transmission is unlikely below 400 copies/mL in ART-using populations [39]. Our safety findings for odds of having detectable gVL did not change with exposure to either IUC or between study arms across 6 and 24 months even after adjusting for ART use, RTI, and pVL, and in sensitivity analyses adjusted for disproportionate IUC discontinuation between arms. Chinula and colleagues found reduced proportions of women with detectable gVL following LNG implant use at 6 months for tear flow strip samples (17.7% and 3.2%, representing follicular and luteal phase measurements prior to method initiation at baseline, versus 6.1% at 180 days; adjusted risk ratio [aRR] = 0.40 [95% CI 0.18–0.85], adjusted for baseline pVL and CD4 count), compared with no significant change in women using DMPA (12.1% and 10.7% at baseline versus 10.3% at 180 days, aRR = 1.37 [95% CI 0.81–2.33]) among WLHIV reporting ART use in Malawi [40]. For the same cohort followed up to a maximum of 33 months, Kourtis and colleagues found that risk of detectable gVL did not differ significantly over time after initiation of either method (aRR, 0.97; 95% CI 0.84–1.13, per increase of 6 months of follow-up) or between the DMPA study arm compared with the LNG implant study arm (aRR, 1.92; 95% CI 0.97–3.79) [37]. In this extended cohort period, detectable gVL also did not significantly differ before method initiation compared with follow-up visits (p = 0.47). In a prospective cohort of WLHIV initiating ART that measured detectable gVL, defined as >400 copies/mL from endocervical swab, 30.3% of women reporting ART use had detectable gVL at 1 or more visits; and DMPA (OR 0.96, 95% CI 0.44–2.13) exposure was not associated with detectable gVL [34]. In a Burkina Faso cohort of women with high background rates of RTI, 45% (77/170) of women had detectable gVL at 1 or more visits despite ART use with undetectable pVL [22]. In this cohort, neither reported oral contraceptive (aOR = 1.57, 95% CI 0.75–3.27) nor DMPA use (aOR = 1.32, 95% CI 0.42–4.16) was associated with detectable gVL in analysis adjusted for pVL. Our findings bear distinction from a mucosal immunology standpoint, as the LNG-IUS has markedly higher LNG concentrations in genital tract mucosa, reflecting its largely localized effect, in contrast to the LNG implant and DMPA [41]. When compared with the C-IUD, LNG does not appear to drive shedding via gVL; neither IUC appears to increase gVL through hypothesized inflammatory response from foreign body effect.

There was no significant detectable effect of levonorgestrel from the LNG-IUS on pVL measures between study arms within each ART group, consistent with previous studies [10,11]. Additionally, we found that more than 15% of ART users had pVL > 1,000 copies/mL at any visit after enrollment, consistent with trends attributed to ART nonadherence in Cape Town and the association of detectable gVL with detectable pVL in other studies assessing impact of contraception on genital tract shedding [34,37,40,42]. This finding was associated with increased proportions of women with detectable gVL, irrespective of IUC type and potentially augmented by incident RTIs. Given frequent detectable pVL levels that reflect lack of clinical viral suppression with “real-world ART use” and thus increased probability of transmission among our participants, our findings that neither IUC increased detectable gVL to further increase transmission risk is clinically important. Further, these pVL trends emphasize the need to ensure WLHIV are counseled regarding condom use to prevent transmission to partners when their HIV is not fully suppressed.

We found low numbers of related SAEs, particularly PID, despite relatively high RTI prevalence within our cohort. There were 3 PID cases, occurring in both arms and at levels similar to those reported by studies with comparator groups in some contexts [8,43] but higher than in others [17,44,45]. The cohorts with lower rates were European WLHIV comprising mainly experienced ART users with no reported PID cases [14], a postpartum Zambia cohort recruited prior to Option B+ ART coverage [44], and a Ugandan cohort [45]. For the Zambian study, we believe recruiting postpartum women with no history of PID reduced PID risk because of possible reduced sexual activity in the postpartum period and thus lower exposure to pathogens, evidenced by only 1 case of PID within that cohort of 296 women contributing 642 p-y (0.16/100 p-y) of follow-up [44]. The Ugandan cohort reported 5 cases (2 LNG-IUS and 3 C-IUD) of PID among 672 participants (incidence rate ratio = 0.7, 95% CI 0.06–6.04) with all cases diagnosed and managed by the study site [45]. Our 3 cases include 2 that were diagnosed and managed at other clinical sites, and it is possible that IUC use may have predisposed the external provider to PID diagnosis, as noted in other settings [46,47]. RTIs were measured, detected, and treated at screening (prevalence data); continued to occur through the cohort period; and were largely asymptomatic with few findings on exam [48]. Given the high prevalence of asymptomatic infections, RTI testing using point-of-care tests rather than syndromic management (the standard of care) should be added within IUC insertion guidelines to reduce risk of PID specifically related to IUC use and thus address some provider concerns that likely hamper offering IUCs to WLHIV [20,49]. There were 2 ectopic pregnancies, both occurring with the C-IUD, a propensity noted previously and possibly magnified in this cohort because of high RTI prevalence with tubal scarring [50]. The overall pregnancy rate was higher than expected based on some studies that found pregnancy rates between 0.06 and 1.7/100 p-y [45,50,51] but lower than the 3-year cumulative rate for C-IUD users noted in a large multicenter cohort of 2.8/100 p-y (95% CI 1.3–6.0) [43]. We attribute some of the pregnancies and expulsions to IUC malposition, which may have been clinically unrecognizable until the IUC was visible at the cervical os; Bahamondes and colleagues noted similar rates among C-IUD users, which they attributed to issues related to variability in inserter design [43]. C-IUD users had higher expulsion rates, similar to levels reported in other studies [45,52] but in contrast to that noted by Sanders and colleagues in a US cohort, where expulsion rates were 9% at 12 months and significantly higher among LNG-IUS users [51]. We noted partial expulsions during scheduled study visits, particularly for the C-IUD whose narrow inserter may have resulted in clinicians hesitating to move the inserter all the way to the fundus and then back by 1 cm before advancing the IUD into the endometrial cavity because of perforation concerns. AEs potentially related to IUC use were significantly higher for C-IUD users with the exception of amenorrhea, which was higher for LNG-IUS users, and pelvic pain, which was similar between arms. Amenorrhea was not a strong motivator for discontinuation and may have been under-reported as an AE based on individual participant perception. By contrast, menorrhagia was frequently cited as reason for discontinuation based on AE distribution and stated reasons for C-IUD removal.

WLHIV allocated to the LNG-IUS generally had significant and steady increases in hemoglobin [53]. This increase was more dramatic among non-ART women in the first 6 months than in the interval between 6 and 24 months and may reflect interaction with untreated disease, as many women enrolled in the non-ART group later reported ART use, evidenced by increase in proportions with undetectable pVL by 18 months.

In this trial, the primary and secondary outcomes focused on ensuring IUC safety for WLHIV before and during ART use; however, as IUCs are meant to be LARC methods, acceptability is critical in determining actual use. In this context, the significantly higher LNG-IUS continuation rate observed here is notable. Kakaire and colleagues found similar continuation rates between the C-IUD and LNG-IUS, both exceeding 90%, among WLHIV in Uganda across 12 months [43]. We found much higher LNG-IUS continuation, and among women requesting IUC removal, mean time to discontinuation for both IUCs was less than 1 year, which may reflect differing contextual norms around tolerance of contraceptive side effects or perceived contraceptive availability [43,52].

Our IUC study is among few whose follow-up duration exceeds 12 months, and the high LNG-IUS continuation rate documented here should contribute to expanding access to this LARC method, permitting women broader choice across the reproductive period. Although the LNG-IUS is more expensive than the C-IUD, the significantly higher continuation rate may lead to increased cost-effectiveness relative to other LARC methods that have higher discontinuation rates and thus provide a strong rationale for including the LNG-IUS as a contraceptive option in low- and middle-income countries. This finding is important, as newer versions of the LNG-IUS, bio-identical to the predominant marketed product and approved by regulatory bodies, have been introduced recently with a substantially lower unit cost [54]. These products may potentially make widespread access to LNG-IUS contraception possible, similar to market changes that enabled increased global access to the contraceptive implant [55].

The strengths of this study include the masking of participants and outcome assessors, the randomized design, the inclusion of a nonhormonal method control, the inclusion of both ART and non-ART users, and use of menstrual cup specimens for gVL measurement [30]. However, several limitations are important to note. Our sample size was small for the non-ART group, which was difficult to enroll in light of changing ART guidelines. We also note that among non-ART women screened, many were not eligible because of low CD4 lymphocyte counts constituting ART eligibility by guidelines in effect at study start in 2013. We hypothesize that some non-ART WLHIV preferred not to disclose their status and hence avoided any clinical setting related to HIV care, including the clinic where this study’s clinical activities were conducted. Additionally, a further 17 women were not eligible for their 24-month visit at study closure, resulting in truncated 24-month visit outcome data. We conducted telephone follow-up of these women for the IUC continuation measure when they would have been eligible for the 24-month visit and reached 11 of 17 women, but VL data were missing. Last, the VL assay used by NHLS changed during the study period with VL measures conducted on 2 separate assays for most participants. These assays are both validated but have different LoDs and may have resulted in classification bias with differing precision around VL values.

These data suggest that, compared with the C-IUD, the LNG-IUS does not increase gVL or pVL and has low levels of contraceptive failure and associated PID in WLHIV with high background rates of RTIs. The LNG-IUS had significantly lower overall and elective discontinuation and expulsion rates, suggesting it is a highly acceptable method for WLHIV. These findings may be used to strengthen policies related to IUCs for WLHIV as well as to educate HIV and family planning service providers, and WLHIV themselves, regarding IUCs as a safe contraceptive option.

CONSORT 2010 checklist of information to include when reporting a randomized trial.

(DOC)

Click here for additional data file.

Odds of detectable genital tract viral load comparing women using the LNG-IUS with those using the C-IUD with linear regression weighted for differential intrauterine contraceptive discontinuation rates, stratified by ART status, among women living with HIV in Cape Town, South Africa.

ART, antiretroviral therapy; C-IUD, copper T-380 intrauterine device; LNG-IUS, levonorgestrel intrauterine system

(DOCX)

Click here for additional data file.

Odds of detectable genital tract viral load comparing women using the LNG-IUS with those using the C-IUD with linear regression adjusted by visit month, stratified by ART status, among women living with HIV in Cape Town, South Africa.

ART, antiretroviral therapy; C-IUD, copper T-380 intrauterine device; LNG-IUS, levonorgestrel intrauterine system

(DOCX)

Click here for additional data file.

Odds of detectable genital tract viral load comparing women using the LNG-IUS with those using the C-IUD with linear regression using working independent correlation structure, stratified by ART status, among women living with HIV in Cape Town, South Africa.

ART, antiretroviral therapy; C-IUD, copper T-380 intrauterine device; LNG-IUS, levonorgestrel intrauterine system

(DOCX)

Click here for additional data file.

Odds of detectable pVL for women using ART or difference in mean change of log10 pVL among women not using ART at enrollment, comparing women using the LNG-IUS with those using the C-IUD, with linear regression weighted for differential intrauterine contraceptive discontinuation rates, among women living with HIV in Cape Town, South Africa.

ART, antiretroviral therapy; C-IUD, copper T-380 intrauterine device; LNG-IUS, levonorgestrel intrauterine system; pVL, plasma viral load

(DOCX)

Click here for additional data file.

Odds of detectable pVL for women using ART or difference in mean change of log10 pVL among women not using ART at enrolment, comparing women using the LNG-IUS with those using the C-IUD, with linear regression adjusted by visit month, among women living with HIV in Cape Town, South Africa.

ART, antiretroviral therapy; C-IUD, copper T-380 intrauterine device; LNG-IUS, levonorgestrel intrauterine system; pVL, plasma viral load

(DOCX)

Click here for additional data file.

Odds of detectable pLV for women using ART or difference in mean change of log10 pVL among women not using ART at enrolment, comparing women using the LNG-IUS with those using the C-IUD, with linear regression using working independent correlation structure, among women living with HIV in Cape Town, South Africa.

ART, antiretroviral therapy; C-IUD, copper T-380 intrauterine device; LNG-IUS, levonorgestrel intrauterine system; pVL, plasma viral load

(DOCX)

Click here for additional data file.

Kaplan-Meier continuation rate estimates for women using the LNG-IUS compared with women using the C-IUD among women living with HIV in Cape Town, South Africa, by antiretroviral therapy status.

C-IUD, copper T-380 intrauterine device; LNG-IUS, levonorgestrel intrauterine system

(TIF)

Click here for additional data file.

Protocol: Comparison of Two IUDs among Cape Town HIV-positive Women: A Randomized Controlled Trial Assessing Safety of Registered Products in South Africa.

FHI 360 Study 10369, Version 10.0.

(PDF)

Click here for additional data file.

Comparison of Two IUDs among Cape Town HIV-positive Women: A Randomized Controlled Trial Assessing Safety of Registered Products in South Africa.

Statistical Analysis Plan, Version 9.0.

(PDF)

Click here for additional data file.

15 Jan 2020

Dear Dr. Todd,

Thank you very much for submitting your manuscript "Comparison of safety and continuation of the levonorgestrel intrauterine system versus the copper intrauterine device among women living with HIV in South Africa: a randomized controlled trial" (PMEDICINE-D-19-04204) for consideration at PLOS Medicine.

Your paper was evaluated by an academic editor with relevant expertise and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to invite you to submit a revised version that fully addresses the reviewers' and editors' comments. You will appreciate that we cannot make a decision about publication until we have seen the revised manuscript and your response, and we expect to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We hope to receive your revised manuscript by Feb 05 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions. Otherwise, we look forward to receiving your revised manuscript in due course.

Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

-----------------------------------------------------------

Requests from the editors:

Please finalize the arrangements for data deposition.

If devices used in the study were donated by commercial entities, please state this in the financial disclosure (metadata).

Please add the start and end dates of participant recruitment to your abstract, and identify the primary endpoint early in the "methods and findings" subsection.

In the abstract, please add a few words to clarify "related SAEs".

Please quote 1-2 further study limitations in the abstract.

In the "conclusions" subsection of your abstract, please adapt the wording of the first sentence to use the past tense, e.g., "In this study, we found that ... did not increase ... and had ...".

In the abstract and throughout the paper, please add p values alongside 95% CI where available.

After your abstract, please add a new and accessible "author summary" section in non-identical prose. You may find it helpful to consult one or two recent research papers in PLOS Medicine to get a sense of the preferred style.

Please remove the final sentence of the introduction; you may wish to include this element of discussion later in the paper.

Please remove the "role of the funding source" information from the text (this information will be included in the article metadata in the event of publication).

Throughout the ms, please quote p values as p<0.001 or exact values.

Please remove trade marks, throughout the article.

Please add additional access details to reference 22, as needed.

Please include a completed CONSORT checklist as a supplementary document, referred to in the methods section of your main text. In the checklist, individual items should be referred to by section (e.g., "Methods") and paragraph number rather than by page or line numbers, as the latter generally change in the event of publication.

Comments from the reviewers:

*** Reviewer #1:

The authors present the findings for a randomised controlled study comparing viral load in two different contraceptive strategies in women with HIV in South Africa: LNG-IUS and C-IUD in stratified by both ART and non-ART groups. The findings show that there was no difference in outcomes in HIV viral load outcomes between interventions in both ART and non-ART groups. The primary limitation was, as the authors mentioned, not achieving the target sample size in the non-ART group due to guidelines changing during the trial. The authors did a nice job following CONSORT reporting guidelines and appreciate that the authors were transparent in their decision making regarding the rational for changing the primary outcome from pVL to gVL due to a guideline recommendation change (with pVL retained as a secondary outcome). Given the lack of trials in this area, with low quality observational studies to date, this study should merit publication and be informative to many in this field. I have a few comments that could be considered. Given the stratified analyses by non-ART/ART groups, generalised linear models are appropriate model of choice here.

1) Abstract: it would helpful to report the allocation ratio here as well

2) Introduction: From the introduction, it appears from the literature of other small observational there is some uncertainty in either LNG-IUS compared to C-IUD. I just want to understand the hypotheses better, that given some uncertainty of previous studies described in the introduction. Are the authors saying that null is no difference in primary outcomes with the alternative being "there is a difference between primary outcomes" - typical superiority design OR Are they suggesting that the null is treatments differ and the alternative hypothesis is the treatments are same within a tolerable margin? - non-inferiority design. It would good if the authors can clarify this.

3) Introduction: Last sentence - this should go in the discussion as a limitation instead of the introduction

4) Methods - statistical analysis: As the authors will probably appreciate, at-treated analysis is aimed to estimate the effect of the treatment "as delivered" or "as recieved" opposed to ITT "as assigned" to account for treatment non-adherence. Non-ITT or as-treated analysis usually presented as secondary analysis but in this paper it is presented the other way around. I can understand why this was done given the authors captured adherence parameters but i think the authors should give some rationalisation towards this decision in the analysis section to help understanding.

5) Methods -statistical analysis: Sentence beginning with "adjusted models for both ART groups..." referring to pre-specified confounders - can you refer to this in the pre-specified analysis plan.

6) Methods - statistical analysis: Statement on participants with "undetectable" or lower than LoD results being assigned values...this needs some justification or reference associated with this decision

7) Methods - statistical analysis: On methods regarding Cox models for discontinuation - please indicate if these adjustment for covariates were pre-specified and proportional hazards assumptions were checked (i.e. Schoenfeld residuals)

8) Results - CONSORT flow diagram: indicate in flow diagram during follow-up boxes in each arm that the numbers included for the primary analyses were analysed in as-treated or non-ITT analysis either as * or footnote

9) Results - statement on Page 14 regarding clinical activity closures - It's unclear what this means - is this study closure and the participants were unmasked, therefore they could not be eligible? Is this the correct interpretation?

Overall, this is a nicely presented trial and should be informative for clinicians and health care policy-makers.

*** Reviewer #2:

This is a clear, well-written manuscript describing important results from an RCT evaluating impacts of IUD (LN vs copper) on acceptability, plasma HIV RNA, and genital HIV RNA shedding. The manuscript would be strengthened by additional attention to the reason gVL was chosen as the primary outcome, the clinical significance of detectable gVL, and the significance of the lack of a difference in gVL for the question of HIV transmission among women using IUD. Additional comments below:

--An inclusion criterion was to be screened with cervical cytology within the last year. Given the poor prevalence of cervical ca screening in SA, how does this impact the generalizability of the findings?

--Another inclusion criterion was interest in IUC use for contraception. How unique is this group?

-- Please provide additional information about why detectable gVL was chosen as an outcome and what is known about what absolute levels are required for efficient transmission. There are a lot of data re. genital HIV shedding in the presence of plasma HIV-RNA suppression - and yet the data re plasma undetectable = uninfectious are compelling and now accepted by most as "trumping" information re. genital VL. What are the data that suggest that gVL matters for this question? And what were the cut-offs and what data inform that? And for power, what is the meaning of a 19% difference in detectable gVL? And why is the assumed pooled baseline proportion or women with detectable gVL estimated to be 42.8%? Overall, given that gVL is the primary outcome, it would be helpful to say a bit more about this measure and the existing data that should inform interpretation of these data in the intro/discussion.

- Methods state, "Due to clinical activity closure, 19 women (17 ART users, two non-ART users) were not eligible for the 24-month visit." Please clarify what this means.

- An important point for methods and discussion - were women exited when they discontinued IUD? If so, that would likely alter (increase) continuation rates given 2dary benefits of being in a clinical trial in RSA.

- An important point that is missing from the current version of the discussion is that 40% of women had a curable RTI which may not have been picked up via standard of care syndromic screening. Contraceptive programs should be supported by MOH to implement testing protocols.

- Table 7 the back-slash (/) before p-value is odd looking in table. This can be managed in journal formatting.

- Consort Figure 1 - The reason for 21 of those excluded from the pre-ART arm is "other". Could you describe since this is 10% of those screened?

*** Reviewer #3:

This is a well conducted, double blinded, randomized trial of the LNG versus vs copper IUD in HIV-infected women in South Africa. It provides important evidence on the acceptability, efficacy, and safety of these two underutilized contraceptive methods in a population that could greatly benefit from more options. The manuscript follows CONSORT guidelines for reporting. The analysis adheres to a priori study questions and follows the plan outlined in protocol version 10, which was provided alongside the study materials. The conclusions drawn are reasonable and the trial strengths and weaknesses are adequately addressed.

* It is unclear in Figure 1 whether the 6 women who declined, were ineligible, or who could not have the IUD inserted are post-randomization. If so, these women should be included in the ITT analysis.

* Table 2 is dense and I found it difficult to interpret. The reader is left to calculate the "deltas" on his/her own. Would it not work better to split it into a figure for the visit trends and then report the 6- and 24-month deltas in a separate table? I'm not really sure, but Table 2 seems to bury your primary results. Also, it is confusing how the "% (n)" designation in table 2 differs from table 1, which uses "n (%)."

* While there was no difference observed between the two methods with respect to genital HIV shedding, it might be informative to the reader to provide comparative data from HIV infected women on other methods. I found myself wondering whilst reading the discussion whether I should be concerned that 10-30% of women on ART had detectable virus in their vaginal samples. How does this compare to other contraceptive methods?

* The frequency of PID in this study, while low, is higher than that reported from analogous trials in Zambia (not referenced, but probably should be) and Uganda (ref #26). It might be helpful to report this outcome as a rate (events/person-years of follow-up) to allow comparison with other research.

* The pregnancy rate also seems higher than expected. The results might benefit from conversion to rates and the discussion from a few point estimates from other sources for comparison (even if only available in HIV- women). In fact, for each of the important events: continuation, expulsion, pregnancy, PID - it would be helpful to have these reported as rates so that the reader could compare to other papers.

* I don't understand why 19 women were "not eligible" for their final visit.

* There's a statement on pp 25-26 that says: "Among women discontinuing their allocated IUC, median time to elective discontinuation was significantly shorter for C-IUD users (7.2 months for C-IUD vs 11.2 months for LNG-IUS; Fig 2)." It doesn't seem appropriate (or necessary) to report this rate among women who discontinued their method, since it would no longer be a randomized comparison. One way to report this and maintain the randomization would be to right censor those who continue at 24 months (like Figure 2 does) and report median time on contraception. If you do decide it is important to include this calculation, I would advise not referring to Figure 2, since that KM appears to include all women.

* CONSORT calls for the discussion to address sources of "potential bias, imprecision, and, if relevant, multiplicity of analyses." The imprecision issue seems particularly relevant here. For instance, the proportion of women on ART with detectable gVL was increased nearly 3-fold between randomization and 24 months in the cIUD group, compared to very little change in the LNG-IUG group. With a larger sample, would we be worried about this?

* Finally, while the trial analysis follows that which is outlined in the protocol, it is unclear why the authors opted for an adjusted analysis as primary. The randomization procedures described were convincing and I found myself most interested in the unadjusted ITT analysis. Perhaps the pooling approach mandates this, but I think most clinical readers will search for unadjusted head-to-head comparisons.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

25 Feb 2020

Submitted filename: ResponseLetterTodd_2IUDnCT_24FEB20.docx

Click here for additional data file.

18 Mar 2020

Dear Dr. Todd,

Thank you very much for re-submitting your manuscript "Comparison of safety and continuation of the levonorgestrel intrauterine system versus the copper intrauterine device among women living with HIV in South Africa: a randomized controlled trial" (PMEDICINE-D-19-04204R1) for consideration at PLOS Medicine.

I have discussed the paper with our academic editor and it was also seen again by one reviewer. I am pleased to tell you that, provided the remaining editorial and production issues are dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions. Otherwise, we look forward to receiving the revised manuscript shortly.

Kind regards,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

------------------------------------------------------------

Requests from Editors:

Please finalize the arrangements for data deposition.

As a general observation, we suggest mentioning the non-inferiority design (line 154) in the abstract. In places (e.g. line 65, "did not increase") the wording might suggest to some readers that a superiority trial was done, and we suggest some judicious rewording (e.g., "there was no significant difference").

On this same point, around line 250 the wording seems to imply that your aim was to "detect a difference", and we suggest amending this to "... gave 80% power to exclude a difference of 27.7% or more", for example. Are you able to state a non-inferiority margin for the primary endpoint assessment in your methods section?

We suggest amending the title to "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" or similar.

Please trim the discussion of limitations in your abstract; for example, the comment about change of assay could be compressed to "... and a change in the assay used for viral load testing during the study" or similar.

Where you make claims such as "the first" (e.g., at line 98) please add "to our knowledge" or similar.

Please remove the "TM" symbol at line 199 and any other instances (including in the metadata).

Please refer to the attachments (protocol, statistical analysis plan and CONSORT checklist) at suitable points in the methods section of your main text.

We suggest harmonizing the study start and end dates quoted in your abstract and results section.

Comments from Reviewers:

*** Reviewer #1:

The authors have addressed all the revisions and made the necessary changes to the manuscript. No additional comments to address

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

13 Apr 2020

Submitted filename: ResponseLetterTodd_2IUDnCT_26MAR20.pdf

Click here for additional data file.

13 Apr 2020

Dear Dr. Todd,

On behalf of my colleagues and the academic editor, Dr. Lynne Meryl Mofenson, I am delighted to inform you that your manuscript entitled "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" (PMEDICINE-D-19-04204R2) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

PRESS

A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Richard Turner, PhD

Senior Editor

PLOS Medicine

plosmedicine.org