Drug interactions between non-rifamycin antibiotics and hormonal contraception: a systematic review

AbstractObjectiveTo determine whether interactions between non-rifamycin antibiotics and hormonal contraceptives result in decreased effectiveness or increased toxicity of either therapy.Data sourcesWe searched MEDLINE, Embase, clinicaltrials.gov and Cochrane libraries from database inception through June, 2016.Study eligibility criteriaWe included trials, cohort, case-control, and pharmacokinetic (PK) studies in any language addressing pregnancy rates, pharmacodynamics or PK outcomes when any hormonal contraceptive and non-rifamycin antibiotic were administered together versus apart. Of 7291 original records identified, 29 met criteria for inclusion.Study appraisal and synthesis methodsTwo authors independently assessed study quality and risk of bias using the United States Preventive Services Task Force evidence grading system. Findings were tabulated by drug class.ResultsStudy quality ranged from good to poor and addressed only oral contraceptive pills, emergency contraception pills and the combined vaginal ring. Two studies demonstrated no difference in pregnancy rates in women using oral contraceptives with and without non-rifamycin antibiotics. No differences in ovulation suppression or breakthrough bleeding were observed in any study combining hormonal contraceptives with any antibiotic. No significant decreases in any progestin PK parameter occurred during co-administration with any antibiotic. Ethinyl estradiol area under the curve decreased when administered with dirithromycin but no other drug.ConclusionEvidence from clinical and PK outcomes studies does not support the existence of drug interactions between hormonal contraception and non-rifamycin antibiotics. Data are limited by low quantity and quality for some drug classes. Most women can expect no reduction in hormonal contraceptive effect with concurrent use of non-rifamycin antibiotics

The Promise of the Dual Prevention Pill: A Framework for Development and Introduction

Women of reproductive age need multipurpose prevention technology (MPT) products to address two overlapping health risks: unintended pregnancy and HIV. Currently, condoms are the only available MPT, however male condoms are not within the control of a woman, and the use of female condoms has been limited by low acceptability and cost. Oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, yet uptake and adherence among women have been low to date. Women globally need more options for HIV and pregnancy prevention. Several MPTs for simultaneous HIV and pregnancy prevention are in various stages of development and clinical testing, although most are many years away from market launch. A dual prevention pill (DPP), a daily oral pill combining oral contraceptives and PrEP, both of which are licensed, approved products in many low- and middle-income countries (LMIC), is likely to be the fastest route to getting an MPT product into the hands of women. The DPP is one option that could enhance method choice, particularly for women who are already using oral contraceptives. By leveraging the oral contraceptive market and reaching women currently using condoms or with an unmet need for contraception, the DPP has the potential to increase the uptake of PrEP. The successful rollout of the DPP will require careful consideration of user-, provider-, and product-centered factors during product development and introduction. Early attention to these interrelated factors can help ensure that the DPP has the ideal characteristics for maximum product acceptability, that effective and quality services are designed and implemented, and that users can make informed choices, demand the product, and use it effectively. The proposed framework outlines key considerations for the effective development and introduction of the DPP, which could also facilitate integration models for future MPTs

Reproductive Healthcare Needs and Desires in a Cohort of HIV-Positive Women

Background. The aim of this study was to determine current contraceptive use, contraceptive desires and knowledge, future fertility desires, and sterilization regret in a cohort of HIV-positive women. Study Design. 127 HIV-positive women receiving care at an urban infectious disease clinic completed a survey addressing their contraceptive and reproductive histories as well as their future contraceptive and fertility desires. Results. The most common forms of contraception used were sterilization (44.4%) and condoms (41.3%). Less than 1% used a long-term reversible method of contraception (LARC) despite these being the methods that best fit their desired attributes of a contraceptive method. Overall, 29.4% desired future fertility. Only 50.6% of those sexually active had spoken with a provider within the last year regarding their contraceptive plans. There was a high degree of sterilization regret (36.4%), and 18.2% of sterilized women desired future fertility. Multivariate analysis found women in a monogamous relationship had a statistically increased rate of regret compared to women who were not sexually active (OR 13.8, 95% CI 1.6–119, P = 0.17). Conclusion. Given the diversity in contraceptive and fertility desires, coupled with a higher rate of sterilization regret than is seen in the general population, integration of comprehensive family planning services into HIV care via increased contraceptive education and access is imperative

Delta Opioid activation of the Mitogen-activated protein kinase cascade does not require transphosphorylation of Receptor Tyrosine Kinases

BACKGROUND: In this study, we investigated the mechanism(s) by which delta opioids induce their potent activation of extracellular signal-regulated protein kinases (ERKs) in different cell lines expressing the cloned δ-opioid receptor (δ-OR). While it has been known for some time that OR stimulation leads to the phosphorylation of both ERK isoforms, the exact progression of events has remained elusive. RESULTS: Our results indicate that the transphosphorylation of an endogenous epidermal growth factor receptor (EGFR) in the human embryonic kidney (HEK-293) cell line does not occur when co-expressed δ-ORs are stimulated by the δ-opioid agonist, D-Ser-Leu-enkephalin-Thr (DSLET). Moreover, neither pre-incubation of cultures with the selective EGFR antagonist, AG1478, nor down-regulation of the EGFR to a point where EGF could no longer activate ERKs had an inhibitory effect on ERK activation by DSLET. These results appear to rule out any structural or catalytic role for the EGFR in the δ-opioid-mediated MAPK cascade. To confirm these results, we used C6 glioma cells, a cell line devoid of the EGFR. In δ-OR-expressing C6 glioma cells, opioids produce a robust phosphorylation of ERK 1 and 2, whereas EGF has no stimulatory effect. Furthermore, antagonists to the RTKs that are endogenously expressed in C6 glioma cells (insulin receptor (IR) and platelet-derived growth factor receptor (PDGFR)) were unable to reduce opioid-mediated ERK activation. CONCLUSION: Taken together, these data suggest that the transactivation of resident RTKs does not appear to be required for OR-mediated ERK phosphorylation and that the tyrosine-phosphorylated δ-OR, itself, is likely to act as its own signalling scaffold

Integrating family planning services into HIV care: use of a point-of-care electronic medical record system in Lilongwe, Malawi

Background: Integrating family planning (FP) services into human immunodeficiency virus (HIV) clinical care helps improve access to contraceptives for women living with HIV. However, high patient volumes may limit providers’ ability to counsel women about pregnancy risks and contraceptive options

Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women

Little is known about fertility choices and pregnancy outcome rates among HIV-infected women in the current combination ART era

Equipping providers to offer novel MPTs: Developing counseling messages for the Dual Prevention Pill in clinical studies and beyond

IntroductionThe pipeline for multi-purpose prevention technologies includes products that simultaneously prevent HIV, pregnancy and/or other sexually transmitted infections. Among these, the Dual Prevention Pill (DPP) is a daily pill co-formulating oral pre-exposure prophylaxis (PrEP), and combined oral contraception (COC). Clinical cross-over acceptability studies for the DPP require training providers to counsel on a combined product. From February 2021–April 2022, a working group of eight HIV and FP experts with clinical and implementation expertise developed counseling recommendations for the DPP based on existing PrEP/COC guidance.Assessment of policy/guidelines options and implicationsThe working group conducted a mapping of counseling messages from COC and oral PrEP guidance and provider training materials. Six topics were prioritized: uptake, missed pills, side effects, discontinuation and switching, drug interactions and monitoring. Additional evidence and experts were consulted to answer outstanding questions and counseling recommendations for the DPP were developed. Missed pills was the topic with the most complexity, raising questions about whether women could “double up” on missed pills or skip the last week of the pack to recover protection faster. Uptake required aligning the time to reach protective levels for both DPP components and explaining the need to take DPP pills during week 4 of the pack. The potential intensity of DPP side effects, given the combination of oral PrEP with COC, was an important consideration. Discontinuation and switching looked at managing risk of HIV and unintended pregnancy when stopping or switching from the DPP. Guidance on drug interactions contended with differing contraindications for COC and PrEP. Monitoring required balancing clinical requirements with potential user burden.Actionable recommendationsThe working group developed counseling recommendations for the DPP to be tested in clinical acceptability studies. Uptake: Take one pill every day for the DPP until the pack is empty. Days 1–21 contain COC and oral PrEP. Days 22–28 do not contain COC to allow for monthly bleeding, but do contain oral PrEP and pills should be taken to maintain HIV protection. Take the DPP for 7 consecutive days to reach protective levels against pregnancy and HIV. Missed pills: If you miss 1 pill multiple times in a month or 2+ consecutive pills, take the DPP as soon as you remember. Do not take more than 2 pills in a day. If 2+ consecutive pills are missed, only take the last missed pill and discard the other missed pills. Side effects: You may experience side effects when you start using the DPP, including changes to monthly bleeding. Side effects are typically mild and go away without treatment. Discontinuation/switching: If you decide to discontinue use of the DPP, but want to be protected from HIV and/or unintended pregnancy, in most cases, you can begin using PrEP or another contraceptive method right away. Drug interactions: There are no drug-drug interactions from combining oral PrEP and COC in the DPP. Certain medications are not recommended due to their contraindication with oral PrEP or COC. Monitoring: You will need to get an HIV test prior to initiating or restarting the DPP, and every 3 months during DPP use. Your provider may recommend other screening or testing.DiscussionDeveloping recommendations for the DPP as a novel MPT posed unique challenges, with implications for efficacy, cost, and user and provider comprehension and burden. Incorporating counseling recommendations into clinical cross-over acceptability studies allows for real-time feedback from providers and users. Supporting women with information to use the DPP correctly and confidently is critically important for eventual scale and commercialization

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

NOTCH3 Expression Is Linked to Breast Cancer Seeding and Distant Metastasis

Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα+) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7Raf-1) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. Results: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα+ and TNBC models. ERα+ breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44low/CD24high/ERαhigh phenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. Conclusions: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer