A new review hype the controversy associated with the ‘pink pill’ commonly dubbed as ‘Female Viagra’.

 

Image Courtesy: L.A. Times

The little pink pill or Flibanserin (Addyi, Sprout Pharmaceuticals)  also dubbed  as the "Female Viagra" was approved by the US Food and Drug Administration (FDA) for the treatment of  hypoactive sexual desire disorder (HSDD) in premenopausal women,  in August 2015, despite  being unsure  about suboptimal risk-benefit trade-offs.

Image Courtesy:  Chicago Tribune

Flibanserin, a 5-HT1A agonist, a 5-HT2A antagonist, and a very weak partial agonist on dopamine D4 receptors, increases levels of dopamine and norepinephrine and decreases serotonin in animal brain areas. Therefore, since dopamine and norepinephrine are thought to promote and serotonin is thought to inhibit sexual desire and arousal, it was suggested that flibanserin enhances sexual desire in HSDD,

A recent systematic review and meta-analysis of randomized clinical trials was published on line on February, 2016 in Journal of American Medical Association (JAMA10.1001/jamainternmed.2015.8565) which assessed efficacy and safety of flibanserin for the treatment of HSDD in women.

The approval of Flibanserin by FDA (a failed antidepressant) has always been shrouded in mystery. It was rejected by FDA twice before it was approved by FDA in August 2015; its clinical review team which voted against it advocating that the benefit-harm balance was unfavorable was overruled by the Clinical Pharmacology and Clinical Division Director. He acknowledged ‘the limited efficacy and worrisome harms, but emphasized the unmet need in women for whom other treatments failed.’

In the recent review by Jaspers L et al from the Erasmus University Medical Center, Rotterdam, the Netherlands, Included five published and 3 unpublished studies constituting a total of   5914 women. The Primary efficacy outcomes were number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes were 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue and many others. The inclusion of studies focusing on postmenopausal women took into account the potential off-label use.

The study found minimal benefit by the use of Addyi, specifically the pooled mean difference for a Sexually Satisfying Event (SSE) between 100 mg of Flibanserin and placebo was .49%, 1.63 for ediary desire and .27% for Female Sexual Function Index (FSFI) desire domain.

This means that the drug only added .5 additional satisfying sexual experiences per month, while the incidence of adverse effects increased four fold said the study coauthor Ellen T. M. Laan, PhD, from the Department of Sexology and Psychosomatic Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, the Netherlands, said in a recorded interview with JAMA Internal Medicine.

The risk ratio for study discontinuation due to adverse events was 2.19. The most bothersome was syncope and hypotension that occurred with concurrent alcohol use or CYP3A4 inhibitors, including oral contraceptives and fluconazole.

Meanwhile, many physicians have questioned the results of the study and have reported favorable results with many of the patients using it. They also believe that  the women should be allowed to make an informed decision to choose the ‘pink pill’ as the men are allowed to make an informed decision about ‘Viagra’.

On the basis of the study findings the authors concluded that “The findings of this review suggest that the benefits of flibanserin treatment are marginal, particularly when taking into account the concurrent occurrence of AEs.”

More robust evidence on its safety profile and efficacy is needed before a recommendation can be made in guidelines and clinical practice regarding its use, as majority of American physician indicated that they would prefer an approved HSDD pharmacological product over available non-pharmacological treatments. Further, it is known that an integrative approach involving psychological interventions play a crucial role in treatment of HSDD.

The authors acknowledge the limitation of the study and recommend that future studies should include women from more diverse ethnicity, with a history of somatic and psychological co-morbidities, medication use, and surgical menopause.

References:

http://www.jsm.jsexmed.org/article/S1743-6095%2815%2931530-7/abstract

http://link.springer.com/article/10.1007%2Fs10508-012-0062-0

http://www.cnn.com/2016/02/29/health/female-viagra-gets-mixed-reviews/index.html

http://archinte.jamanetwork.com/article.aspx?articleid=2497781#ioi150116r17

http://archinte.jamanetwork.com/article.aspx?articleid=2497781

http://www.jsm.jsexmed.org/article/S1743-6095%2815%2932579-0/pdf

Microbirthing: The " Vaginal Seeding" is growing fad, but thin evidence concerns physicians!

Every 4^th baby in UK is born by Caesarean Section. Parents of the Caesar babies are requesting a procedure called as ‘microbirthing’ or ‘vaginal seeding’.

Vaginal seeding involves taking a swab from mother’s vagina and swabbing it over babies face, eyes, mouth and skin immediately after caesarean birth.

This article is based on recent editorial in BMJ (BMJ 2016; 352:i227) by Cunnington A.J. et al “Vaginal seeding” of infants born by caesarean section. How should health professionals engage with this increasingly popular but unproved practice?

Our body is colonized with millions of microbes, collectively called as microbiota. They outnumber our cells by 10:1. The microbiota varies according to parts of our body and also person to person. As described by microbiology professor Graham Rook at University College London, we are designed to live in nature’s biodiverse ecosystem encountering our old microbial friends as part of our early immune education.

During the process of vaginal birth, specific species of good bacteria are transferred to the baby during and immediately after birth via the birth canal, immediate skin-to-skin contact and breastfeeding. This is the seeding of the baby's microbiome. The process heralds the training of baby’s immune system to recognize between ‘good’ and ‘bad’ bacteria and protect the neonate from diseases now and also in future.  Large epidemiological studies and reviews have concluded that babies delivered by C-section have moderately high risk of obesity, asthma, and autoimmune diseases, these  diseases being associated with alteration in microbiota.

For babies entering this world via a C-section, this microbial transfer from the mother to baby is interfered with or bypassed completely. According to the latest research if the baby is not seeded with mother’s bacteria, it can have significant health consequences. Dr Rodney R Dietert, Professor of Immunotoxicology at Cornell University says “Over the past 20-30 years, we've seen dramatic increases in childhood asthma, type 1 diabetes, coeliac disease, childhood obesity. We've also seen increases in Caesarean delivery. Does Caesarean cause these conditions? No. What Caesarean does is not allow the baby to be seeded with the microbes. The immune system doesn't mature, and the metabolism changes. It's the immune dysfunction and the changes in metabolism that we now know contribute to those diseases and conditions.”

So, many researchers advocate that even if vaginal birth is not possible, immediate skin to skin contact and breast feeding should be initiated.

A new documentary “MICROBIRTH” warns how our children are born could have serious repercussions for their lifelong health. “Microbirth” is a new sixty minute documentary looking at birth in a whole new way: through the lens of a microscope. Investigating the latest scientific research, the film reveals how we give birth could impact the lifelong health of our children. http://microbirth.com

In spite of all the hypotheses, we lack scientific proof at present. The newborn may be at risk of developing infection, being exposed to vaginal commensals that the mother maybe harboring without any symptoms. These include group B streptococcus (the most common cause of neonatal sepsis), herpes simplex virus, Chlamydia trachomatis, and Neisseria gonorrhoeae (the last two, causes of ophthalmia neonatorum). These pathogens may also be transferred on a vaginal swab, potentially voiding the protection offered by elective caesarean section.

Clinically we are aware of only one clinical trial going on, called as Potential Restoration of the Infant Microbiome (PRIME) trial. That study is expected to be completed in February, 2019.It is looking at the neonatal microbiota according to mode of birth, the women being screened beforehand for potential pathogens.

Dr. Cunnington, who is the lead author of the article, affirms the lack of sufficient evidence to put vaginal seeding into routine practice. Studies need to be sufficiently large, randomized and need follow up of many years before a recommendation can be made.  

In a statement Dr Cunnington says: "Demand for this process has increased among women attending hospitals in the UK - but this has outstripped professional awareness and guidance. At the moment we're a long way from having the evidence base to recommend this practice. There is simply no evidence to suggest it has benefits - and it may carry potential risks." He also believes in fully informing the risks and harm of this simple procedure to the patients who are demanding it.

He also emphasizes that there are other ways of   influencing baby’s microbiota at birth and “Encouraging breast feeding and avoiding unnecessary antibiotics may be much more important than worrying about transferring vaginal fluid on a swab.”

References:

http://www.criver.com/about-us/eureka/blog/april-2014/early-immune-education

http://articles.mercola.com/sites/articles/archive/2014/12/27/seeding-baby-microbiome.aspx

http://www.actionbioscience.org/genomics/the_human_microbiome.html

http://www.nytimes.com/2013/08/29/science/human-microbiome-may-be-seeded-before-birth.html?_r=0

http://www.huffingtonpost.co.uk/toni-harman/microbirth-babys-mircobiome_b_4947959.html

https://clinicaltrials.gov/show/NCT02407184?link_type=CLINTRIALGOV&access_num=NCT02407184

                                          

Vaginal Ring: Could it be a potential option for HIV prevention?

Currently 35million persons are living with HIV-1 infection and about half of them are women. The majority of these live in sub Saharan Africa, which has the highest incidence of HIV infection in any given population.

Using antiretroviral (tenofovir ) as pre exposure prophylaxis ( PrEP) in the form of  pills and vaginal gel  is assuring  approach against fight against  HIV, but patient compliance is very poor and protection was not shown.

Vaginal rings containing exogenous hormones for contraception (Nuvaring ) and HRT are licensed and in use since long and provide a sustained and control release of medication.

The results of two studies were presented at Conference on Retroviruses and Opportunistic Infections (CROI) from February 22 to February 25, 2016,   in Boston, Massachusetts.

One of the study (ASPIRE study) was published today in New England Journal of Medicine and the result of other study( Ring study) was presented as an abstract in the conference.

The trials evaluated the safety and efficacy of a monthly vaginal ring (Ring-004), containing 25 mg of Antiretroviral (ARV) dapivirine, which women placed themselves and replaced each month.

Both the dapivirine and placebo rings were manufactured by QPharma under contract with the International Partnership for Microbicides.

Both studies were double blind randomized placebo controlled trials. The ASPIRE study enrolled 2629 healthy, sexually active, nonpregnant, HIV-1–seronegative women between the ages of 18 and 45 years at 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe women: 1313 in the dapivirine group and 1316 in the placebo group.

In the ring study 1959 women (1762 in South Africa and 197 in Uganda) were randomized in a 2:1 ratio to receive either a dapivirine ring or a placebo ring.

In both studies,the primary efficacy end point was HIV-1 infection, identified with the use of a standard seroconversion algorithm and the primary safety endpoint was incidence of adverse events (AEs).

In both trials the ring was found to be effective in reducing the incidence of HIV-1 infection by 27% (ASPIRE study) and 31% ((Ring study). Both study found that in women less than 21 years of age, the risk of acquiring the infection was not much decreased; probably the women were not compliant enough.

Compliance is also a big issue with the Truvada (Tenofovir disoproxil/emtricitabine), the once a day oral PrEP. Studies have found it to be effective in preventing infection in 92% of cases, but adherence to daily regimen is a problem.

The ring adds a new tool in HIV prevention armament, which could be used discreetly by women, without asking her male partner to use protection. It is especially useful in African countries were women are at highest risk. In the study about 1 in 3 infection were prevented.

The ring is also cost effective, costing only $5 as compared to other PrEP which costs thousands of dollars. Although it is not in the market yet, it gives a lot of hope and optimism for HIV prophylaxis.

Reference:

http://www.avac.org/press-release/first-evidence-vaginal-ring-hiv-prevention

http://www.nejm.org/doi/full/10.1056/NEJMoa1506110#t=articleDiscussion

http://www.healthnewsreview.org/review/vaginal-ring-for-hiv-prevention-small-details-would-have-elevated-good-coverage-to-great/

http://www.croiconference.org/sessions/safety-and-efficacy-dapivirine-vaginal-ring-hiv-1-prevention-african-women