The contraceptive medroxyprogesterone acetate, unlike norethisterone, directly increases R5 HIV-1 infection in human cervical explant tissue at physiologically relevant concentrations

Ray, Roslyn M.; Maritz, Michelle F.; Avenant, Chanel; Tomasicchio, Michele; Dlamini, Sigcinile; Spuy, Zephne van der; Hapgood, Janet P.

doi:10.1038/s41598-019-40756-7

Cited by 19 publications

(19 citation statements)

References 114 publications

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“…In addition to the obstacles that hinder clinical studies from defining precise relationships between HIV susceptibility and exogenous progestins, this public health controversy is fueled by the belief that putative connections lack biological plausibility (17). Addressing this long-standing concern using basic science and clinical research, the capacity of progestins to promote genital mucosal epithelial thinning and genital inflammation, alter the vaginal microbiota, suppress antivirus immunity, and enhance HIV replication have been identified as mechanisms with the potential to underlie this relationship (18)(19)(20)(21)(22). Alternatively, we showed that pharmacologically relevant serum levels of medroxyprogesterone acetate (MPA) in mice were associated with reduced genital expression of the cell-cell adhesion molecules desmoglein-1a (Dsg1a) and desmocollin-1 (Dsc1) (23).…”

Section: Introductionmentioning

confidence: 99%

Norethisterone Enanthate Increases Mouse Susceptibility to Genital Infection with Herpes Simplex Virus Type 2 and HIV Type 1

et al. 2020

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Norethisterone enanthate (NET-EN) and depot-medroxyprogesterone acetate (DMPA) are two forms of injectable progestin used for contraception. Whereas clinical research indicates that women using DMPA are more susceptible to HIV and other genital pathogens, causal relationships have not been determined. Providing an underlying mechanism for this connection, however, is recent work that showed DMPA weakens genital mucosal barrier function in mice and humans and respectively promotes susceptibility of wild-type and humanized mice to genital infection with HSV type 2 and HIV type 1. However, analogous effects of NET-EN treatment on antivirus immunity and host susceptibility to genital infection are much less explored. In this study, we show that compared with mice in estrus, treatment of mice with DMPA or NET-EN significantly decreased genital levels of the cell-cell adhesion molecule desmoglein-1 and increased genital mucosal permeability. These effects, however, were more pronounced in DMPA-versus NET-ENtreated mice. Likewise, we detected comparable mortality rates in DMPA-and NET-ENtreated wild-type and humanized mice after intravaginal infection with HSV type 2 or cell-associated HIV type 1, respectively, but NET-EN treatment was associated with slower onset of HSV-induced genital pathology and lower burden of systemic HIV disease. These findings reveal DMPA and NET-EN treatment of mice significantly reduces genital desmoglein-1 levels and increases genital mucosal permeability and susceptibility to genital pathogens while also implying that NET-EN generates less compromise of genital mucosal barrier function than DMPA. ImmunoHorizons, 2020, 4: 72-81.

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Section: Introductionmentioning

confidence: 99%

Norethisterone Enanthate Increases Mouse Susceptibility to Genital Infection with Herpes Simplex Virus Type 2 and HIV Type 1

et al. 2020

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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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“…Further, acetate (AcO − ) ions play a vital role in the physiological process and detection of these ions is of high importance due to their utilisation in food, chemical, paint, dye, solvent and pharmaceutical industries [6] . Naturally, low concentration of acetate ions are present in mammalian blood, [7] tissues, [8] acetyl coenzyme, [9] and they are the building blocks of biomolecules such as fatty acids [10] . They are used in various medical applications such as during hemodialysis, [11] anti‐inflammatory, [12] in the correction of acidosis, [11] enzyme metabolism, [13] and as a source of bicarbonate.…”

Section: Introductionmentioning

confidence: 99%

Colorimetric Receptors for the Detection of Biologically Important Anions and Their Application in Designing Molecular Logic Gate

et al. 2020

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Three new colorimetric receptors were synthesised for the detection of biologically important anions such as fluoride and acetate in the aqueous medium. All receptors showed significant colour change for F À and AcO À ions. The synthesised receptors were characterized by spectroscopic methods such as NMR techniques for structural confirmation. The UV-vis and 1 H NMR titrations were performed to understand the binding mechanism of the receptors with F À and AcO À ions. Further, Job's plot was used to explore the stoichiometry between receptor and analyte. Besides, the visual and spectroscopic changes of receptor R1 upon the addition of F À ion was utilised to study the reversible behaviour by adding Cr 3 + ions. This concept was explored to mimic the logic gates at the molecular level with "set-reset" Boolean operations as a proof of concept.

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The contraceptive medroxyprogesterone acetate, unlike norethisterone, directly increases R5 HIV-1 infection in human cervical explant tissue at physiologically relevant concentrations

Cited by 19 publications

References 114 publications

Norethisterone Enanthate Increases Mouse Susceptibility to Genital Infection with Herpes Simplex Virus Type 2 and HIV Type 1

Norethisterone Enanthate Increases Mouse Susceptibility to Genital Infection with Herpes Simplex Virus Type 2 and HIV Type 1

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

Colorimetric Receptors for the Detection of Biologically Important Anions and Their Application in Designing Molecular Logic Gate

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