 shows that these laws are not associated with an increased understanding of the clinical implications of breast density.

The study assessed the association of residing in a state with a DBN law and a woman’s awareness and knowledge about breast density through survey responses. The survey also looked at breast cancer anxiety. 

The internet survey was conducted in 2018 with participants in KnowledgePanel®, an online research panel. Participants were English-speaking women between ages 40 and 59 without a personal history of breast cancer who had received at least one screening mammogram (N = 1928; survey completion rate 68.2%). 

The four main measures of the survey were: 1) reported history of increased breast density; 2) knowledge of the increased risk of breast cancer from dense breasts; 3) knowledge of the masking effect of dense breasts on mammography and 4) breast cancer anxiety.

Based on weighted analysis, 41.3% of women reported a history of increased breast density. A much higher proportion of survey participants who lived in states with DBN reported having increased breast density compared with women who reported living in states with no law (43.6% vs 32.7%, 

In multivariable regression, women residing in a DBN state were more likely to report increased breast density (OR 1.70, 95% CI 1.34-2.17), as were older women, women with a high school education or higher, and with public or private insurance (compared with no insurance).

Black and Hispanic women were less likely than white women to report having increased breast density. Only 23.0% of women overall know that increased breast density was associated with a higher risk of breast cancer and 68.0% of women understood that dense breasts decreased the sensitivity of mammography. 

However, the authors found no difference between women from DBN and non-DBN states for these outcomes, or for breast cancer-related anxiety.

Based on their findings, the authors suggest that state DBN laws are not associated with increased understanding of the clinical implications of breast density. 

Furthermore, they found that women with lower education may be less likely to benefit from DBN laws. 

Ultimately, the authors believe that the clinical implications of a dense breast finding are “complex and personalized and require a conversation between a woman and her provider.”

Kyanko KA, Hoag J, Busch SH, et al. Dense breast notification laws, education, and women’s awareness and knowledge of breast density: A nationally representative survey. 

. August 2020. doi:10.1007/s11606-019-05590-7

Articles

Currently, 38 states and the District of Columbia have enacted dense breast notification (DBN) laws mandating that mammogram results include language informing women of risks related to dense breasts. 

Breast density laws and patient knowledge

Since the discovery of PARP inhibitors (PARPi) in 2005, there has been rapid clinical development of five different agents (olaparib, rucaparib, niraparib, veliparib, talazoparib), leading to seven indications approved by the US Food and Drug Administration (FDA) across breast and ovarian cancer.

In 2014, olaparib became the first PARPi approved by the FDA for use as treatment of recurrent ovarian cancer, followed by rucaparib in 2016 and niraparib in 2019. 

Over this same time period, the FDA approved all three of these PARPi for a different indication – as maintenance therapy intended to prolong the disease-free interval following chemotherapy. 

Across different drugs and clinical settings, use of PARPi has resulted in a prolonged period without cancer recurrence – or disease-free interval – particularly among patients with 

2 mutations, owing to their mechanism of action.

PARPi are a class of oral targeted therapy whose effect is dependent upon a tumor’s inability to repair its DNA. The PARP1 and PARP2 proteins are instrumental in repairing DNA single-strand breaks, which prevents formation of double-strand breaks at the time of DNA replication. 

PARPi block this repair process and thus dramatically increase the number of double strand breaks. Cells can typically repair these resultant double strand breaks in an error-free fashion using the homologous recombination (HR) pathway, but when the pathway is defective, PARPi result in cell death. 

This homologous recombination deficiency (HRD) is frequently a result of a germline or somatic mutation in a gene involved in the HR pathway, notably 

2, but can also be detected in tumors in the absence of such mutations. 

With germline and somatic testing, patients with genetic mutations or tumors with HRD can be identified as those who may derive significant clinical benefit from PARPi use.

With more than 20 trials of PARPi in ovarian cancer alone, there is a growing body of literature on the common side effects of these drugs and their management, as well as their unique financial challenges. 

Ongoing clinical questions being addressed include how best to predict patient response to PARPi therapy, combat drug resistance, and determine the optimal setting(s) for use in individual patients.

Many of the adverse events (AEs) encountered with use of PARPi are shared across agents. Most patients experience some degree of nausea and fatigue. Serious hematologic side effects can occur with any PARPi, and myelosuppressive effects can be exacerbated when these drugs are combined with other therapies. 

Dose reductions are often necessary in the event of a serious side effect, and if they persist, the drug may need to be discontinued. Of note, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are serious but rare AEs occurring in up to 1% of patients and they have been associated with several different PARPi. 

Embryo-fetal toxicity has been documented in animal studies with exposure to PARPi. These drugs should not be used in pregnant patients, and pregnancy should be avoided for 6 months following last exposure.

Olaparib was the first PARPi to be developed thus is the most extensively studied. The most common AEs with olaparib are fatigue, nausea, and vomiting, which occur in 60% to 75% of patients across studies. 

Serious hematologic AEs can occur in 10% to 20% of patients (anemia, neutropenia), and rarely patients experience severe fatigue (4%).

 Olaparib in combination with vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab or cediranib can increase the rate of hypertension, fatigue, diarrhea, abdominal pain, and small bowel obstruction.

The AE profile of rucaparib is similar to that of olaparib, with nausea and fatigue occurring in more than 70% of patients, and severe anemia in about one-fifth of patients. 

An isolated transaminitis is a unique AE with rucaparib use, resulting in mild to moderate elevations of alanine transaminase (ALT) and aspartate transaminase (AST) noted in one-third of patients and more serious elevations in approximately 10% of patients. Rash and photosensitivity were other specific yet uncommon mild AEs.

Myelosuppression is more frequent among patients taking niraparib, with significantly more thrombocytopenia in particular compared to other PARPi (up to 60% of patients). Notable serious AEs with niraparib are also hematologic, with significant anemia being the most common (25%-30%), followed by thrombocytopenia (20%-30%) and neutropenia (10%-20%). 

Mild nausea and fatigue are seen at rates similar to those in olaparib and rucaparib, and mild constipation can be encountered as well.

Although not FDA-approved for use in the United States, veliparib has shown some efficacy as both monotherapy and in combination with other cancer-directed treatments in numerous trials. Gastrointestinal (GI) AEs were similar to other PARPi, and severe AEs were relatively uncommon.

Talazoparib is only FDA-approved for treatment in patients with advanced breast cancer who have germline BRCA mutations (Table 1). Although fatigue and GI AEs are milder with talazoparib relative to other PARPi, severe hematologic AEs occur in up to 55% of patients.

All PARPi require close monitoring with weekly complete blood count with differential for the first month of therapy, which can be done once a month thereafter, if the patient is stable. A complete metabolic panel should be obtained at baseline and periodically thereafter. 

Cholesterol should be monitored with rucaparib use. Niraparib may result in hypertension, so close observation of blood pressure at baseline and during the first month of therapy is advised.

Although patients may already experience some of the symptoms discussed above at baseline due to prior therapies or disease burden, adequate management of symptoms after starting a PARPi is critical, as these AEs can have a significant impact on physical and psychological well-being. 

Anticipatory counseling about the likelihood of certain symptoms can reduce early discontinuation of drugs due to discomfort from AEs. Given the frequency of nausea, it is important to encourage use of antiemetics and counsel patients that these symptoms can abate after the first 1 to 2 months. 

Common interventions such as exercise and caffeine can be encouraged to improve fatigue, and over-the-counter pain relievers and anti-diarrheal medications should be prescribed for their respective AEs.

Early involvement of supportive and palliative care specialists can also be helpful in managing symptoms. The National Comprehensive Cancer Network (NCCN) guidelines provide further guidance for symptom management.

Financial toxicity is increasingly relevant with use of novel drugs including PARPi for which there are no generic alternatives. This includes both out-of-pocket expenses such as the direct costs (co-pays, medications, co-insurance) and non-medical costs including transportation, lodging, childcare, and lost wages from time away from work. 

Patients undergoing cancer treatments who are low income often spend up to 25% of their annual income on out-of-pocket medical costs.

 In addition, patients with cancer have a greater than two-fold higher risk of filing for bankruptcy compared to patients who do not have cancer, with nearly 60% of medically associated bankruptcies being due to cancer diagnoses.

Financial toxicity has also been shown to negatively affect adherence to treatment.

 Though the oral formulation of PARPi allows patients to avoid costs associated with visits to the infusion center, it may come with a hidden cost due to a different level of insurance coverage. 

For example, when olaparib was initially approved in 2017, the out-of-pocket cost was $12,585 per month without insurance, yet patients with insurance coverage still may pay over $2,000 per month. 

Although there are medical assistance programs to help offset the cost of some PARPi, not all medical beneficiaries qualify.

It has been well documented that tumors harboring germline or somatic BRCA mutations, and those that are “BRCA-like” with homologous recombination deficiency (HRD), tend to respond better to PARPi than their wild type counterparts.

HRD positivity is seen in approximately 20% of patients with ovarian, fallopian tube, and primary peritoneal cancers who carry a germline mutation in BRCA1/BRCA2 or an associated cancer susceptibility gene such as RAD51C or RAD51D, and up to 50% of tumors.

There are commercially available assays that can identify HRD-positive tumors among BRCA wild-type patients.

Interestingly, some studies have demonstrated efficacy of PARPi even in HR-proficient tumors, though the benefits are less pronounced in this population. Patients whose disease is still considered sensitive to platinum chemotherapy also appear to respond better to PARPi than those with platinum-resistant or -refractory disease.

The mechanism is not fully understood and is an area for further inquiry.

Multiple mechanisms of inherent or acquired resistance to PARPi have been identified and continue to be studied. These are complex mechanisms occurring at both the genomic and cellular levels and tend to disrupt the “synthetic lethality” effect that makes PARPi effective in susceptible cells with HRD.

One such mechanism is acquisition of BRCA reversion mutations which can restore BRCA protein function in BRCA-mutated tumors and make cells homologous recombination proficient. 

With the HR pathway restored, cancer cells can repair DNA double-strand breaks that are induced by PARPi, thereby conferring a PARPi-resistant phenotype. 

A recent study of patients with known germline or somatic BRCA mutations showed that detection of BRCA reversion mutations in circulating cell-free DNA prior to treatment was correlated with decreased progression-free survival and found more commonly among platinum-resistant or -refractory cancers.

Used prospectively, this could become a means of choosing appropriate candidates prior to initiating PARPi therapy.

Another resistance mechanism that has been identified is upregulation of genes that encode for drug efflux pumps, which can lead to decreased intracellular levels of PARPi and thus less drug effect.

Increased levels of proteins such as SLFN11 in tumors may augment the effects of PARPi, so low levels in tumors could eventually be used as a biomarker to predict PARPi resistance.

Novel approaches are being developed to reverse resistance to PARPi by modulating these pathways.

Maintenance therapy is becoming ubiquitous in ovarian cancer care. The first FDA approval was in 2016, for the antiangiogenic agent bevacizumab after chemotherapy in patients with recurrent ovarian cancer. 

Since then, bevacizumab has also been approved as frontline maintenance therapy, to be given after primary treatment. PARPi are now approved for use as maintenance in some patients in both settings (Table 1). 

The question remains whether to administer maintenance therapy to all patients, and how to choose the most appropriate agent.

All three PARPi that are FDA-approved for use in ovarian cancer have indications for maintenance therapy in recurrent disease. Although these are irrespective of BRCA mutation or HRD tumor status, the magnitude of the benefit differs substantially by these factors, including sensitivity to the prior platinum chemotherapy treatment. 

The number of disease-free months gained with PARPi use (compared to placebo) approaches 15 months in patients with a BRCA mutation, while this benefit is up to 9 months for those with HRD tumors and just 3 months in patients with HR-proficient disease (Table 2).

Among PARPi, only olaparib is approved for frontline maintenance therapy, and is specifically for patients who harbor germline BRCA mutations. Veliparib and niraparib have been investigated in this setting as well with promising results, although the indication currently is not FDA-approved. 

Interestingly, the combination of bevacizumab and olaparib as frontline maintenance led to significant prolongation of the disease-free interval for patients with BRCA mutations and HRD tumors.

In the near future, many patients with recurrent ovarian cancer will have already been exposed to a PARPi as frontline maintenance therapy or as treatment for a prior breast cancer, and they could potentially be candidates for repeat PARPi use. Little is known about the efficacy and tolerability of PARPi in this setting. 

The ongoing OReO trial (NCT03106987) is evaluating the potential benefit of repeat exposure to olaparib maintenance therapy in patients with recurrent, platinum-sensitive ovarian cancer who have previously been treated with olaparib, regardless of BRCA mutation status. 

MOLTO (NCT02855697) is also investigating the impact of repeat olaparib exposure, but it is limited to patients with germline BRCA mutations.

With an abundance of recent data in ovarian cancer, the role of PARPi is rapidly evolving, and new standards of care are being developed. The paradigm for deciding which, if any, PARPi to give to a patient is complicated by the availability of bevacizumab as an alternative for maintenance therapy and traditional chemotherapy for treatment of recurrence. 

Although the benefits of PARPi are clear in delaying disease recurrence among many patients with BRCA-mutated and HRD tumors, there is much to be learned about predictors of response and resistance to PARPi. Further, the associated cumulative AEs and their impact on overall survival is not yet known, and some patients and providers may be reluctant to use a PARPi for this reason.

Nonetheless, the addition of PARPi to the landscape of treatments for ovarian cancer represents an exciting breakthrough in the age of personalized medicine. Patients can safely be given PARPi for extended periods of time and maintain a high quality of life. 

With knowledge of AE profiles, PARPi can be selected for a given patient based on her pre-existing symptoms and comorbidities, as these will impact the tolerability of specific PARPi. 

Differential insurance coverage for each PARPi may further determine what is feasible for a given patient. With the anticipation of more FDA-approved indications for PARPi in ovarian cancer, it is hoped that these drugs can become more accessible to everyone.

Have you used PARPi to treat patients? What kind of success have you had using the treatment? What challenges have you encountered? Let us know on 

1. Lynparza (olaparib) tablets [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; December 2019.

2. Talzenna (talazoparib) [prescribing information]. New York, NY: Pfizer Labs; September 2019.

3. Zejula (niraparib) [prescribing information]. Waltham, MA: Tesaro; October 2019.

4. Rubraca (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology; April 2018.

5. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. 

. 2012;366(15):1382-1392. 6. Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. 

7. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. 

8. Kristeleit R, Shapiro GI, Burris HA, et al. A Phase I–II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2 -mutated ovarian carcinoma or other solid tumors. 

9. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. 

 (London, England). 2017;390(10106):1949-1961.

10. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. 

11. Coleman RL, Sill MW, Bell-McGuinn K, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study. 

12. de Bono J, Ramanathan RK, Mina L, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. 

13. Moore KN, Monk BJ. Patient counseling and management of symptoms during olaparib therapy for recurrent ovarian cancer. 

14. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/default.aspx#supportive.

15. Langa KM, Fendrick AM, Chernew ME, Kabeto MU, Paisley KL, Hayman JA. Out-of-pocket health-care expenditures among older americans with cancer. 

16. Ramsey S, Blough D, Kirchhoff A, et al. Washington State Cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. 

17. Doshi JA, Li P, Huo H, Pettit AR, Armstrong KA. Association of patient out-of-pocket costs with prescription abandonment and delay in fills of novel oral anticancer agents. 

18. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. 

19. Watkins JA, Irshad S, Grigoriadis A, Tutt ANJ. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. 

20. Bell D, Berchuck A, Birrer M, et al. Integrated genomic analyses of ovarian carcinoma. 

21. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA Carrier ovarian cancer correlating with platinum-free interval. 

22. Lin KK, Harrell MI, Oza AM, et al. BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. 

23. Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. 

24. Murai J, Feng Y, Yu GK, et al. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. 

Across different drugs and clinical settings, use of PARPi has resulted in a prolonged period without cancer recurrence.

PARP inhibitors: Choosing what to use in epithelial ovarian cancer

Vulvovaginitis may be infectious or non-infectious in etiology, and it is often underdiagnosed or misdiagnosed. Chronic or recurrent vulvovaginitis is frustrating to patients and a burden to the health care system. 

The three types of infectious vulvovaginitis most commonly seen in reproductive-age women are bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) and trichomoniasis. 

Other differential diagnoses to consider include herpes simplex infection, allergic reaction to irritants and non-infectious vaginitis such as lichen planus, genitourinary syndrome of menopause (GSM), and desquamative inflammatory vaginitis (DIV). 

Infection and/or inflammation of the vulva and vagina are associated with itching, burning, irritation, dyspareunia, and abnormal and/or malodorous vaginal discharge.

This article focuses on the diagnosis and treatment of recurrent and chronic cases.

All patients who present with complaints suggestive of vulvovaginitis should have a complete history; physical examination of the vulva, vagina and perianal area; saline microscopy (including pH, 10% potassium hydroxide (KOH) whiff test) if available; point-of-care testing if available; and culture and molecular diagnosis testing as needed.

History should include relationship of symptoms to sexual intercourse, menstrual cycle, use of feminine products and practices, over-the-counter medications, and medical and medication history.

On examination, patients with BV may have a malodorous grey, creamy or thin homogeneous discharge whereas patients with VVC may present with evidence of inflammation such as erythema, edema, fissures, or excoriations in moderate to severe cases, while patients with trichomoniasis may exhibit signs of inflammation like erythema.

Patients with GSM may show signs of vulvovaginal atrophy while patients with DIV may show signs of inflammation (Figures 1 to 4). Vaginal samples should be obtained from the posterior fornix in BV and lateral vaginal wall in VVC and microscopy performed. (Table 1).

Office based testing of the vaginal discharge using pH test, 10% KOH and saline microscopy is preferred if available. This approach may provide immediate diagnosis, and treatment can be initiated. 

The United States Food and Drug Administration (FDA)-approved commercially available tests (point-of-care test or molecular diagnostics) can be used as alternatives.

BV, the most common cause of abnormal vaginal discharge in reproductive-age women is characterized by abnormal vaginal flora, decreased or absent lactobacilli, and an increased number of anaerobes and facultative anaerobes. 

It is a dysbiosis, and some of the associatedbacteria include 

BV is associated with increased risk of pelvic inflammatory disease; increased risk of acquisition and transmission of sexually transmitted infections (STIs); adverse obstetric and gynecologic outcomes such as preterm labor, preterm birth, and chorioamnionitis; and vaginal cuff cellulitis post-hysterectomy. 

Patients may describe the malodorous discharge as “rotten egg or fishy” and worse after sexual intercourse or a menstrual period. The diagnosis is usually clinical (Table 1). 

Presence of three of four Amsel criteria is needed to make the diagnosis

Gram stain with Nugent score is the gold/reference standard used in research settings, while Amsel criteria are used in clinical setting. 

Although microscopy is preferred and cost effective, it may not be available in all clinical settings and data evaluating US Food and Drug Administration (FDA)-approved commercially available tests have acceptable performance against the reference standards.

FDA-approved commercially available tests can be used to diagnose BV but should be interpreted alongside patient history and examination.

Recurrent bacterial vaginosis (RBV) is defined as three or more episodes in 12 months.6,12 Recurrence rate is high, and often involves frequent telephone calls and visits to the clinic; multiple treatments are prescribed in the absence of curative therapy.

Bradshaw et al. reported recurrence rates of 58% over a 12-month period in women treated with oral metronidazole for 7 days. In their study, recurrence was associated with prior history of BV, lack of hormonal contraceptive use, having the same sex partner throughout the study duration, and having female sex partners.

Other factors that have been associated with recurrence include douching, frequent sexual intercourse without condoms, and failure to reestablish a 

-predominant vaginal flora. It has also been suggested that formation of a vaginal biofilm in BV could be one of the factors in RBV.

Women with RBV should be appropriately treated based on the Centers for Disease Control and Prevention (CDC) recommended conventional therapy of nitroimidazole or clindamycin administered orally or vaginal and offered additional suppressive therapy with 0.75% metronidazole intravaginal gel twice weekly for 4 months.

In a multicenter study, Sobel et al randomized patients with RBV to twice- weekly intravaginal metronidazole gel or placebo for 16 weeks after initial treatment. He documented that during 28-week follow-up, recurrence was less in the suppressive therapy group. 

Recurrence occurred in 51% of treated women compared with 75% of women receiving placebo.16 Patients should be educated about the risk of possible yeast infection during the suppressive therapy phase.

Another option for RBV is a combination of oral nitroimidazole with intravaginal boric acid as the induction phase, followed by suppression therapy. Reichman et al treated women who met criteria with either tinidazole or metronidazole 500 mg orally twice daily for 7 days followed by intravaginal boric acid 600 mg at bedtime for 21 days as the induction phase.

Asymptomatic patients then proceeded to the maintenance phase of intravaginal metronidazole gel twice weekly. In this study, the cure rate was 92% at 7 weeks, 88% at 12 weeks, and 50% at 36 weeks. We have modified the suppression therapy in our clinical practice, and documented success with 0.75% metronidazole intravaginal gel once a week for 4 months.

VVC is the second most common cause of vulvovaginitis. Although

 is the most common cause of VVC (85%-90%), other non- albicans candida (NAC) (

) could be colonizers or pathogenic.12,17

Diagnosis should not be based on clinical findings alone due to lack of specificity; symptoms of external dysuria, itching, and burning are not always sufficient to make a diagnosis.

Clinical features may include curd-like vaginal discharge.

On examination, patients may have erythema, edema, fissures, or excoriations. Microscopy with or without addition of 10% KOH may reveal fungal elements. Fungal culture is helpful in patients with clinical features suggestive of VVC but who have a negative saline microscopy.

 It is also helpful in patients who have failed therapy or those with suspected resistance to commonly used anti-fungals.

 FDA-approved molecular testing is commercially available for providers who do not have access to microscopy. 

Some molecular testing has rapid turnover, but may not give speciation and sensitivities. Although fungal culture results may take a week to be returned, they may be needed to plan treatment.

RVVC isdefined as at least three symptomatic episodes in 12 months.19 Risk of recurrence is increased in patients who frequently take antibiotics, are chronic users of corticosteroids, on prolonged immunosuppressant (e.g. transplant patients) or immunosuppressed patients (uncontrolled HIV/AIDS), have uncontrolled or poorly controlled diabetes, or have azole-resistant or non- 

Patients with RVVC would benefit from maintenance therapy after the induction treatment phase has been successfully completed.

 should have sensitivity testing performed and be treated based on the results. 

Sobel et al and Marchaim et al have documented success with compounded medications in patients with azole resistance and those who have failed multiple doses of first-line medications.

In patients with azole-resistant VVC, treatment options include intravaginal boric acid 600 mg daily for 14-21 days, intravaginal 15.5% flucytosine vaginal cream (5 g) daily for 14 days, and intravaginal amphotericin B 50-mg vaginal suppository daily for 14 days. 

It is important to consider other differential diagnosis of vulvovaginal itch. All that itches is not yeast and patients with persistent itching despite treatment should be referred to a specialist. 

Examples of vaginal specialist-recommended regimens for RVVC include:

Fluconazole 150 mg orally every 72 hours x 3 doses; followed by fluconazole orally 150 mg weekly x 6 months or miconazole 1200 mg vaginally weekly x 6 months (for patients who prefer vaginal route for maintenance therapy).

Itraconazole 200 mg orally twice daily x 3 days followed by itraconazole orally, 100-200 mg daily for 6 months.

Trichomoniasis is the most common non-viral STI in women worldwide.

 It is associated with reproductive morbidity and increased risk of HIV acquisition and transmission. Patients may be asymptomatic or present with abnormal yellow –green vaginal discharge, inflammatory symptoms such as itching, burning, and dyspareunia. 

On examination, there may be erythema of the vulva, vagina and “strawberry cervix.” Microscopy, if available, may reveal motile trichomonads; other diagnostic modalities include point-of-care testing or FDA-approved commercially available molecular testing. 

Nucleic acid amplification testing (NAAT) is recommended for diagnosis of trichomoniasis.

Treatment of the patient and her sex partner(s) is recommended.

 Nitroimidazole is the drug of choice. Treatment is usually a single 2-g dose of metronidazole or tinidazole.

Kissinger et al, in a randomized trial of single-dose 2-g metronidazole versus 7 days of metronidazole, showed that the 7-day oral-dose metronidazole is the preferred treatment for trichomoniasis treatment in non-HIV-infected women.

Reinfection is more common than treatment failure, but patients suspected to have failed treatment or who have nitroimidazole resistanceshould be referred to an infectious disease specialist. 

Patients with nitroimidazole allergy should be referred for desensitization. CDC offers resistance testing by request. Health providers can access the CDC website and contact the office in charge for this service.

In women who fail 2 g metronidazole without evidence of reinfection, metronidazole 500 mg orally twice daily x 7 days is recommended. If treatment fails, tinidazole or metronidazole 2 g orally for 5 days is then recommended. 

If persistent infection is documented despite the previous therapy without evidence of reinfection, there are case series and reports documenting success using high-dose tinidazole and compounded paromomycin in management of refractory trichomoniasis, as follows:

Tinidazole 500 mg orally 4 times daily for 1 week OR

Tinidazole 500 mg orally 4 times daily PLUS Tinidazole 500 mg vaginally twice daily x 14 days OR

Tinidazole 1 g orally 3 times daily plus 5 g of compounded 5% intravaginal paromomycin nightly X 14 days.

We have had success in our clinical practice with use of 5 g of 5% compounded paromomycin alone x 14 days in three patients who were allergic to nitroimidazole. 

Of significance, the compounded creams could be irritants to the skin and should be inserted inside the upper and mid third of the vagina at bedtime. 

Patients should apply an emollient as barrier to the vulva, and refrain from all sexual intercourse while using compounded vaginal medications. Compounded medications are also expensive.

A review of chronic/recurrent vulvovaginitis would not be comprehensive without a discussion of the two commonly encountered non-infectious causes: GSM and DIV.

DIV, a diagnosis of exclusion, is a chronic vulvovaginitis that is poorly understood.

 It occurs mostly in perimenopausal and postmenopausal women, and may be associated with low estrogen levels. 

Diagnosis is usually clinical with patients complaining of copious yellow–green discharge. They may describe the discharge as thick, “sticky,” mucoid staining of their underwear. Patients sometimes wear panty liners or sanitary pads due to the volume or discoloration of their undergarments. 

They may complain of itching, pain, burning, and sometimes dyspareunia. On examination, the vulva maybe erythematous, friable and may bleed on contact. 

The vagina may be erythematous and purulent yellow-green discharge noted. Microscopy shows sheets of white blood cells and parabasal cells maybe present if the patient is hypoestrogenic.

At least one symptom (vaginal discharge, dyspareunia, pruritus, pain, irritation or burning)

Leukorrhea +/- parabasal cells on microscopy

Management involves counseling and education about this poorly understood condition. 

Initial treatment is 2% intravaginal clindamycin for 4 to 6 weeks. Patient who fail to respond to vaginal clindamycin may repeat treatment with 10% intravaginal compounded hydrocortisone for the same duration. 

Patient education should include the possibility of failed therapy and relapse. Presence of parabasal cells indicates a hypoestrogenic state and vaginal estrogen twice a week should be included in the regimen. 

Patients who relapse should be referred to a vaginal specialist.

GSM is often seen in postmenopausal patients or hypoestrogenic women such as those who are breastfeeding or who have undergone menopause due to surgery or exposure to chemotherapy or radiation. 

Patients may present with vaginal dryness, pain, itching, thin watery discharge, and dyspareunia.

 On examination, the vagina may be pale, with loss of elasticity. Vaginal pH is elevated in symptomatic patients. 

Microscopy may show some parabasal cells, paucity of normal vaginal epithelial cells, and lack of lactobacilli. 

Management should include evaluation for secondary bacterial and fungal infections and treatment.

First-line management is with vaginal lubricants and moisturizers.

Patients who remain symptomatic and have no contraindications to use of hormones may benefit from systemic or vaginal hormones. In our practice, we usually start with vaginal estrogen in various formulations or vaginal dehydroepiandrosterone before considering systemic formulations.

1. Stockdale CK, Boardman L. Diagnosis and treatment of vulvar dermatoses. 

2. Sobel JD, Reichman O, Misra D, Yoo W. Prognosis and treatment of desquamative inflammatory vaginitis. 

3. Koumans EH, Sternberg M, Bruce C, et al. The prevalence of bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive health. 

4. Anderson MR, Klink K, Cohrssen A. Evaluation of vaginal complaints. 

5. 2015 STD Treatment Guidelines. https://www.cdc.gov/std/tg2015/default.htm. Accessed January 20, 2020.

6. Bradshaw CS, Morton AN, Hocking J, et al. High Recurrence Rates of Bacterial Vaginosis over the Course of 12 Months after Oral Metronidazole Therapy and Factors Associated with Recurrence. 

7. Amsel R, Totten PA, Spiegel CA, Chen KCS, Eschenbach D, Holmes KK. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. 

8. Cartwright CP, Lembke BD, Ramachandran K, et al. Development and validation of a semiquantitative, multitarget PCR assay for diagnosis of bacterial vaginosis. 

9. Cartwright CP, Lembke BD, Ramachandran K, et al. Comparison of nucleic acid amplification assays with BD affirm VPIII for diagnosis of vaginitis in symptomatic women. 

Recurrent or chronic vulvovaginitis is frustrating to patients and a burden to the health care system. Here is a guide to addressing it.

Vol 65 No 04

Breast density laws and patient knowledge

PARP inhibitors: Choosing what to use in epithelial ovarian cancer

Practical approach to recurrent vulvovaginitis

Can a healthier diet reduce menopause symptoms?

Did delay in bladder repair cause urologic issues?