Written by: Catherine Todd, Associate Director, Reproductive, Maternal, Newborn & Child Health
Women living with HIV have higher unmet need for family planning, which may be driven by concerns about method safety with regard to HIV infection and treatment as well as barriers imposed by the need to see different health care providers for HIV and family planning services. People living with HIV are a vulnerable group identified for specialized approaches within rights-based family planning care. One aspect of rights-based family planning is striving for equal access to and availability of safe and acceptable contraceptive methods, and these efforts have spurred price reductions and volume guarantees to make implants among the fastest growing components of method mix in a number of low- and middle-income countries (LMICs) (Jacobstein, 2018). As an obstetrician-gynecologist, I am familiar with, and a big fan of, the levonorgestrel intrauterine system (LNG-IUS), an intrauterine contraceptive that releases hormones to help prevent pregnancy. I wondered if research on safety of and satisfaction with a hormonal implant in LMICs could support price reduction of that branded product to make it accessible to more women.
The National Institutes of Child Health & Development and USAID-funded study I describe here was initially conceived while attending my first International AIDS Conference in 2006 when much of the public health research was merged with advocacy to accelerate expansion of antiretroviral therapy (ART) in LMICs. Within five years of that conference, new evidence suggested that hormonal contraceptives may increase the risk of HIV transmission to male partners, creating an urgent need to determine whether the hormonal LNG-IUS was safe compared to the non-hormonal copper intrauterine device (C-IUD). My colleagues from the University of Cape Town, City University of New York, and Rutgers University and I conducted a randomized controlled trial called “Safety and Acceptability of Two IUDs among Cape Town HIV-positive Women (2IUDnCT)” and published the key findings from the study in 2020.
The hormonal LNG-IUS has been available in high-income countries for nearly 30 years and is very effective at preventing pregnancy along with providing accompanying health and lifestyle benefits, like reduced menstrual bleeding. The good news is that bioidentical hormonal LNG-IUSs with lower price points have been approved as equally safe and effective and are being marketed in a number of LMICs (Rademacher et al., 2016). That said, the non-hormonal C-IUD has been available for decades at low cost and has very low use rates in many countries, while it features as the predominant method in other countries (Cleland et al., 2017). Our study team developed the 2IUDnCT trial to compare the safety of the two intrauterine contraceptives among women living with HIV – one of the first studies to do so. Our hope is that the results might help advance the agenda of reducing cost and expanding availability of the hormonal LNG-IUS, based on both safety and acceptability data, which we present in this post. You can read the full PLOS Medicine paper here.
Context
In sub-Saharan African countries, intrauterine contraceptives (including the non-hormonal C-IUD and hormonal LNG-IUS) comprise a very low proportion of the contraceptive method mix, and many of these countries also have high HIV prevalence rates. As I mentioned above, women living with HIV have higher unmet need for family planning and tend to use less effective methods, resulting in higher mistimed pregnancy rates. Studies in South Africa have shown this trend despite a context where progestin injectables, the non-hormonal C-IUD and contraceptive implants are available in the public sector.
There are contraceptive considerations unique to women living with HIV that merit consideration during provider training and demand-generation activities, such as continually updating providers on intrauterine contraceptive safety data or drug-drug interactions with ART and various hormonal contraceptives. Intrauterine contraceptives are traditionally underutilized by women living with HIV and part of this may reflect the ways those contraceptives are incorrectly perceived by women and their providers. These perceptions may stem from limited awareness of established safety data for intrauterine contraceptives with respect to pelvic inflammatory disease among women living with HIV (Daniele et al., 2017).
Methods
he 2IUDnCT study had several strengths, including a randomized controlled trial design with double-masking of both participants and those who analyzed the data; inclusion and stratified analysis by ART group; and consideration of both plasma and genital tract viral load to assess safety with regard to HIV progression and transmission. The study had a relatively long follow-up period (24 months) and our design allowed women to continue in the trial even if they chose to have the allocated intrauterine contraceptive removed, reducing a woman’s likelihood of keeping an unacceptable contraceptive in place solely to participate.
We recruited interested women through community promotional events, from waiting rooms at HIV and family planning service sites, and through radio and print advertisements. We tested eligible, consenting women for pregnancy and other reproductive tract infections at a screening visit and, after enrollment, at each visit. We randomized consenting, eligible women to receive the T-380 C-IUD or the LNG-IUS at 1:1 ratios. Our participants could come to the clinic for any reason, including removal, between scheduled visits.
We compared the primary outcome – proportion of women with detectable genital tract HIV viral load – and several secondary outcomes (e.g., plasma viral load and adverse events related to intrauterine contraceptive use) between the non-hormonal C-IUD and hormonal LNG-IUS groups, while we looked at continuation rates between groups to measure acceptability.
Findings
We found that, among 199 women participating in the trial, there was no significant change in proportion of women with detectable genital tract HIV virus. This finding was similar for changes between the time before insertion and six months after insertion for either intrauterine contraceptive – and when comparing the two methods to each other at six and 24 months after insertion. This means that neither method caused significant changes in genital HIV viral load in the short-term following placement. Further, neither method increased the odds of detectable genital HIV viral load or of higher plasma HIV viral load, compared to each other overall, compared in smaller groups determined by ART use at enrollment, and when we conducted sensitivity analysis to adjust for differential discontinuation rates.
However, we found that women receiving the hormonal LNG-IUS were more than eight times as likely to use that method until the end of the trial. In addition to requesting removal much more frequently, non-hormonal C-IUD users experienced twice the expulsion rate as LNG-IUS users. We also found that women using the hormonal LNG-IUS at six and 24 months had a significant increase from study start in hemoglobin, a measure of blood iron level that is reduced with anemia, compared to no significant change in hemoglobin among women using the non-hormonal C-IUD.
There were some serious adverse events related to intrauterine contraceptive use, like pelvic inflammatory disease (three cases) and pregnancy with the intrauterine contraceptive in place (four cases), without a clear pattern linked to either contraceptive and within case rates reported by other studies. However, of women reporting side-effects likely related to intrauterine contraceptive use, we found that heavy and irregular bleeding and pelvic pain were the main reasons for requesting removal.
What’s interesting about the study
Our study is among the first comparing a hormonal to non-hormonal long-acting reversible contraceptive method with detectable genital tract HIV as the primary outcome among women living with HIV. The randomized, masked design helped produce high-quality data. We hope that the high continuation rates and safety of the LNG-IUS will prompt hormonal IUS inclusion within the offered mix to all women, including women living with HIV, in LMICs.
Our results come at a time when a cost-competitive hormonal LNG-IUS is being marketed in some LMICs at a price point that may be feasible for public sector formulary inclusion. These results may be used to advocate for adding the hormonal LNG-IUS within the public sector method mix in LMICs, including those in countries with high HIV prevalence. Further, these results come at a time when the COVID pandemic may have women and their partners and families preferring contraception that does not require frequent refills or stable supply at stores or drug sellers.
Reflecting on our experience, we had difficulty recruiting women to participate in the study, which we owe partially to perceptions that intrauterine contraceptives are for limiting rather than spacing births as well as to negative provider and peer perceptions of intrauterine contraceptives, both generally and as an appropriate method for women living with HIV. As the tide turns to bring the hormonal LNG-IUS within reach of more women globally, we hope the results of this and other studies help shape the advocacy platform to expand what may be a highly acceptable method for women living with HIV and other women globally.
Acknowledgment: We appreciated in-kind donations from Bayer Pharmaceuticals (Mirena® LNG-IUS), the Western Cape Government (C-IUDs), Sekisui Diagnostics (a portion of Osom® BV Blue and Trichomonas), Cepheid Inc (a portion of Xpert CT/NG cartridges), and Alere-Abbott (Determine Syphilis RDTs). This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Development R01 HD071804 and by the U.S. Agency for International Development Prevention Technologies agreement (No. GHO‑A‑00‑09‑00016-00).