Medroxyprogesterone acetate, unlike norethisterone, increases HIV-1 replication in human peripheral blood mononuclear cells and an indicator cell line, via mechanisms involving the glucocorticoid receptor, increased CD4/CD8 ratios and CCR5 levels

Maritz, Michelle F.; Ray, Roslyn M.; Bick, Alexis J; Tomasicchio, Michele; Woodland, John G.; Govender, Yashini; Avenant, Chanel; Hapgood, Janet P.

doi:10.1371/journal.pone.0196043

Cited by 26 publications

(50 citation statements)

References 54 publications

(80 reference statements)

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“…Unlike other progestins, DMPA is a potent agonist of the glucocorticoid receptor and could plausibly be immunosuppressive especially at higher concentrations. Maritz et al evaluated direct effects of DMPA and Net‐En on HIV‐1 replication in PBMCs from healthy donors ex vivo and found that DMPA significantly increased HIV‐1 replication by threefold in non‐activated PBMCs from female donors, while similar concentrations of Net‐En had no effect. These findings support the observed differential impact of the 2 progestin‐only injectables on immune cells that is reported in our study.…”

Section: Discussionmentioning

confidence: 99%

Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T‐cell responses and expression of immunosuppressive markers

Matubu

Hillier

Meyn

et al. 2019

American J Rep Immunol

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Problem: Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En). Method of study: Peripheral blood mononuclear cells collected from women aged18-34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4).Results: Compared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed.DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline. Conclusion: Activation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient. K E Y W O R D S depot medroxyprogesterone acetate, norethisterone enanthate cytotoxic T-lymphocyte associated protein-4, programmed cell death-1 How to cite this article: Matubu A, Hillier SL, Meyn LA, et al. Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T-cell responses and expression of immunosuppressive markers. Am J Reprod

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Section: Discussionmentioning

confidence: 99%

Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T‐cell responses and expression of immunosuppressive markers

Matubu

Hillier

Meyn

et al. 2019

American J Rep Immunol

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“…6 Since 2016, there is substantial new clinical and in vitro biological and animal data that are largely consistent with increased HIV acquisition for DMPA-IM users via several mechanisms. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] An interesting argument was made in the WHO 2019 guidelines 6 on this issue: ''The GDG recognized that the ECHO trial did not address the etiological or causal question of whether DMPA increases the risk of HIV acquisition when compared with not using any contraception'' followed shortly thereafter by: ''Furthermore, the GDG noted that the high incidence of HIV infection experienced by each contraceptive group during the ECHO trial was similar to the background incidence assumed when designing the trial. This was deemed to be indirect evidence addressing the question, suggesting no increased risk of HIV acquisition among users of these contraceptives compared with women not using any contraception.''…”

Section: What Do the Echo Results Tell Us About The Risks Of Hiv Acqumentioning

confidence: 99%

“…ECHO results for the LNG implant cannot be extrapolated to other methods, including use of LNG in oral contraceptive pills containing estrogen or LNG delivered intravaginally, or etonogestrel implants, due to different pharmacokinetics, doses, and/or progestins. Limited observational clinical data on HIV risk and laboratory data for the two-monthly injectable contraceptive norethisterone enanthate (NET-EN) do not raise concerns about an increased risk for HIV acquisition, 4,5,38,39,[66][67][68] unlike results for MPA. 38,39,41,52,67 In observational studies, DMPA-IM use was significantly associated with increased HIV acquisition compared with NET-EN use [aHR 1.32, (95% CI 1.08-1.61)], 5 a result very similar to the DMPA-IM versus LNG implant comparison in the ECHO trial.…”

Section: What Do the Echo Results Tell Us About The Risks Of Hiv Acqumentioning

confidence: 99%

“…The metaanalysis of observational data for DMPA-IM relative to no contraception or mainly condom use are currently the best estimate of the HIV risks associated with DMPA-IM and are mostly consistent with a large body of other clinical, animal, and laboratory studies indicating several plausible biological mechanisms whereby DMPA-IM may increase HIV acquisition relative to no contraception. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]72 The ECHO trial results on relative HIV risks between the three methods are subject to several limitations and uncertainties. They provide evidence that the LNG implant may be associated with lower HIV risk than DMPA-IM and the copper-IUD.…”

Section: What Do the Echo Results Tell Us About The Risks Of Hiv Acqumentioning

confidence: 99%

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Is the Injectable Contraceptive Depo-Medroxyprogesterone Acetate (DMPA-IM) Associated with an Increased Risk for HIV Acquisition? The Jury Is Still Out

Hapgood

2020

AIDS Research and Human Retroviruses

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Intramuscular depo-medroxyprogesterone acetate (DMPA-IM) is the most widely used hormonal contraceptive in sub-Saharan Africa. Previous meta-analyses of observational studies found a significant 40%-50% increased risk associated with DMPA-IM use, relative to no contraception or infrequent condom use. This raised substantial concerns, although these studies had important limitations. Consequently, the open-label randomized Evidence for Contraceptive Options and HIV Outcomes trial was conducted, designed primarily to detect a 50% or greater difference in HIV risk between DMPA-IM, the levonorgestrel (LNG) implant, and the copper-intrauterine device. The ECHO study, published in July 2019, concluded that there is no substantial difference in HIV risk among the methods evaluated, and that all three methods are safe and highly effective. In response, the WHO relaxed the Medical Eligibility Criteria for DMPA-IM use among women at high HIV risk in August 2019. However, two of the three comparisons in the ECHO trial could rule out neither a 50% increase nor no change in HIV risk for one contraceptive compared with another. The study had limitations and the results contained considerable uncertainty. They also did not inform on associated HIV risk for any one of the individual methods due to the absence of a control group such as no contraception or only infrequent condom use. The HIV risks associated with LNG implant and copper-IUD relative to no contraception or infrequent condom use are unknown and these cannot be seen as controls, nor did the authors claim them to be. The results will be discussed in the context of their limitations, what they add to the body of work to date on contraception and HIV acquisition, and the implications of the findings and reports thereof for future research and contraceptive choice.

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“…1 However, there are concerns about the safety of intramuscular depot medroxyprogesterone acetate (DMPA-IM), in particular, amid high rates of HIV infection in this region. 2 Immunological and animal studies suggest an increased HIV susceptibility with medroxyprogesterone acetate, [3][4][5][6] supported by observational studies and meta-analyses suggesting an association between DMPA-IM and HIV incidence. 2,7,8 However, randomised clinical trials (RCTs) have failed to show a statistically signi cant increase in HIV acquisition with DMPA-IM compared with the copper intrauterine device (IUD) or the levonorgestrel (LNG) implant.…”

Section: Introductionmentioning

confidence: 99%

Behavioral Effects of Different Contraceptive Methods and HIV Acquisition: An Ancillary Study of the ECHO* Randomized Trial

Singata‐Madliki

Lawrie

Balakrishna

et al. 2020

Preprint

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BackgroundThe ECHO trial randomised 7829 women to depot medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (IUD) and the levonorgestrel (LNG) implant (1:1:1) and found no clear difference in HIV incidence between these three groups. We have previously hypothesized that oligo-amenorrhoea induced by DMPA-IM may have a protective effect on HIV acquisition. The aim of this ancillary study was to assess the effects of DMPA-IM, the IUD and the LNG implant on menstrual symptoms and sexual behavior and to correlate these with HIV acquisition.Methods At the Effective Care Research Unit (ECRU) in South Africa, women already randomised to DMPA-IM, the copper IUD and the LNG implant (1:1:1) were asked to participate. Participants completed a 28-day symptom and behavior diary following their one-month ECHO trial visit and returning it at their 3-month follow-up visit. HIV acquisition data were retrieved from ECHO trial records.ResultsOf 487 women enrolled on the ancillary study, 390 (80%) completed their daily diary; 130, 133, and 127 received DMPA-IM, IUD, and LNG implant, respectively. Thirty-three (8·4%) of these women acquired HIV. Women on the progestin-only contraceptives were more likely to experience amenorrhoea, as expected, and were less likely to have intra-menstrual coitus than IUD users (p < 0·001 for DMPA-IM vs IUD and P = 0·002 for implant vs IUD). Overall coital frequency was highest and condom usage lowest among DMPA-IM users. Intra-menstrual coitus correlated positively, and duration of menstruation correlated negatively, with HIV acquisition, although these effects were not statistically significant (p=0·09 and p=0·079, respectively).ConclusionsFindings support the hypothesis that oligo-amenorrhoea and the associated reduced intra-menstrual coitus may mitigate the potential for an increased biological risk of HIV acquisition with DMPA-IM but more evidence is needed. Study registration number: PACTR201706001651380

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Medroxyprogesterone acetate, unlike norethisterone, increases HIV-1 replication in human peripheral blood mononuclear cells and an indicator cell line, via mechanisms involving the glucocorticoid receptor, increased CD4/CD8 ratios and CCR5 levels

Cited by 26 publications

References 54 publications

Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T‐cell responses and expression of immunosuppressive markers

Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T‐cell responses and expression of immunosuppressive markers

Is the Injectable Contraceptive Depo-Medroxyprogesterone Acetate (DMPA-IM) Associated with an Increased Risk for HIV Acquisition? The Jury Is Still Out

Behavioral Effects of Different Contraceptive Methods and HIV Acquisition: An Ancillary Study of the ECHO* Randomized Trial

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