10/29/2018 PROPHYLAXIS AND TREATMENT: CURBING THE ALARMING SPREAD OF SEXUALLY TRANSMITTED DISEASES DISCLOSURE OBJECTIVES FOR PHARMACISTS GOAL

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1 DISCLOSURE PROPHYLAXIS AND TREATMENT: CURBING THE ALARMING SPREAD OF SEXUALLY TRANSMITTED DISEASES Dr. Feller does not have any actual or potential conflicts of interest to disclose and will not be discussing off-label use of medications. Jade Feller, PharmD PGY-1 Pharmacy Resident Iowa City Veterans Affairs Health Care System November 13, 2018 GOAL OBJECTIVES FOR PHARMACISTS Upon conclusion of the presentation, attendees will be able identify the four sexually transmitted diseases reportable to the Iowa Department of Public Health. Additionally, attendees will be able to discuss HIV preexposure prophylaxis and identify recommended treatment options for chlamydia, gonorrhea, and syphilis. 1. Summarize the US Public Health Service guidelines for use of HIV pre-exposure prophylaxis (PrEP). 2. Formulate three counseling points to discuss with a patient who is starting Truvada (tenofovir disoproxil fumarate/emtricitabine) for PrEP. 3. Select all baseline assessments which must be completed prior to initiating Truvada (tenofovir disoproxil fumarate/emtricitabine) for PrEP. 4. Identify the role of dual therapy with ceftriaxone and azithromycin in treating gonorrhea. 5. Given a patient case, identify what sexually transmitted disease patient has, appropriate treatment, and how re-infection can be prevented. OBJECTIVES FOR PHARMACY TECHNICIANS 1. Recall the definition of pre-exposure prophylaxis. 2. Describe populations at highest risk of acquiring HIV. 3. List the three most common bacterial sexually transmitted diseases in the United States. 4. Summarize the importance of treating bacterial sexually transmitted diseases. 5. Identify the recommended treatment for chlamydia. According to the CDC how many cases of sexually transmitted diseases (STD) were reported in the U.S. in 2017? A. 555,608 B. 1,020,385 C. 1,899,761 D. 2,295,739 1

2 WHAT ARE STD S? BACTERIAL Chlamydia Gonorrhea Syphilis VIRAL Human Immunodeficiency Virus (HIV) Human Papillomavirus (HPV) Hepatitis Viruses Herpes Simplex Virus (HSV) NCHHSTP Newsroom. August U.S. STD Diagnoses, 5-Year Trends Chlamydia Gonorrhea Primary and Secondary Syphilis 2.5 NUMBER OF REPORTED CASES (MILLIONS) Consistent condom use Viral load suppression for HIVpositive partners U=U STD PREVENTION Needle Exchange Programs Vaccines Preexposure prophylaxis (PrEP) YEAR US Public Health Service. Preexposure Prophylaxis: Clinical Practice Guideline ,400,000 HIV PREVALENCE AND NEW INFECTIONS WHAT IS PRE-EXPOSURE PROPHYLAXIS? 1,200,000 Pre-exposure prophylaxis (PrEP): use of antiretroviral medication to prevent HIV transmission prior to exposure Truvada (emtricitabine/ tenofovir disoproxil fumarate) only FDAapproved medication for PrEP Number of People 1,000, , , , , Year People living with HIV New HIV infections US Public Health Service. Preexposure Prophylaxis: Clinical Practice Guideline Centers for Disease Control and Prevention Fact Sheet. Today s HIV/AIDS Epidemic

3 ESTIMATED NEW INFECTIONS BY ROUTE OF TRANSMISSION, Iowans Diagnosed with HIV: MSM Heterosexual PWID 25% 8% 3% Number of Persons MSM who Inject Drugs 64% Year of HIV Diagnosis Centers for Disease Control and Prevention Fact Sheet. Today s HIV/AIDS Epidemic Iowa Department of Public Health. State of Iowa HIV Disease End-of-Year 2017 Surveillance Report WHO SHOULD USE PREP? RISK FROM SINGLE HIV EXPOSURE High risk sexually active men who have sex with men (MSM) High risk sexually active heterosexual men and women High risk people who inject drugs (PWID) 1.1 million people in U.S. would benefit Prescribed to 150,000 people Higher Risk Lower Risk Receptive anal sex (1.4%) Receptive vaginal sex (0.08%) Insertive anal sex ( %) Insertive vaginal sex (0.04%) Oral sex (?) Can increase risk: STDs Higher viral load Tearing and abrasions Can decrease risk: PrEP and PEP Lower viral load Circumcision Lubrication US Public Health Service. Preexposure Prophylaxis: Clinical Practice Guideline Putting a number on it: The risk from an exposure to HIV. Prevention in Focus MSM RISK INDEX How old are you today? If score 8 If score 5 If score 2 If 49 years of more score 0 In the last 6 months how many men have you had sex with? If >10 male partners score 7 If 6-10 male partners score 4 If 0-5 male partners score 0 In the last 6 months how often did you have condomless receptive anal sex (you on the bottom)? If 1 or more times score 10 In the last 6 months how many of your male sex partners were HIV positive? If >1 positive partner score 8 If 1 positive partner score 4 If 0 positive partners score 0 In the last 6 months how often did you have condomless insertive anal sex (you on the top) with a man who was HIV positive? If 5 or more times score 6 If 0 times score 0 In the last 6 months have you used methamphetamines like crystal or speed? If yes score 6 If score is 10, evaluate for intensive HIV prevention services including PrEP If score is <10 provide indicated standard HIV prevention services US Public Health Service. Preexposure Prophylaxis: Clinical Practice Guideline PATIENT CASE MJ is a 22 year-old male who presents to his primary care provider to discuss initiating PrEP therapy. He reports frequent sexual encounters with 7 different men and condom usage 80% of the time. To his knowledge, none of his sexual partners are HIV positive. MJ tests negative for HIV and bacterial STD s today. Would you start MJ on PrEP? What HIV risk factor(s) does MJ have? 3

4 TRUVADA TDF-FTC EFFICACY IN MSM Fixed-dose co-formulated tablet containing emtricitabine 200mg/tenofovir disoproxil fumarate 300mg (TDF-FTC) Emtricitabine: nucleoside reverse transcriptase inhibitor (NRTI) Tenofovir disoproxil fumarate: nucleotide reverse transcriptase inhibitor (NRTI) FDA approved for PrEP in 2012 Study Type Randomized, placebocontrolled trial Methods (n) TDF-FTC (1,224) Placebo (1,217) Results 2.9% acquired HIV 5.3% acquired HIV Conclusion Oral TDF- FTC provided protection against HIV infection in MSM Truvada package insert. Foster City, CA. Gilead Sciences, Inc Grant RM, et al. N Engl J Med. 2010;363(27): PREP WORKS IF YOU TAKE IT EFFECTIVENESS AND ADHERENCE IN TRIALS TIME TO ACHIEVING PROTECTION 60 Effectiveness (%) CAPRISA FEM-PrEP IPERGAY IPrEx Partners PrEP (TDF) Partners PrEP (TDF/FTC) PROUD (TDF/FTC) TDF2 VOICE (TDF) VOICE(TDF/FTC) VOICE Maximum rectal tissue concentration: 7 days of daily use Maximum vaginal tissue concentration: 20 days of daily use Maximum blood concentration: 20 days of daily use Recommend adequate protection during 7 day lead-in phase Percentage of Participants Samples with Detectable Drug Levels Effectiveness and Adherence in Trials of Oral and Topical Tenofovir-Based Prevention. AVAC Infographics Gallery US Public Health Service. Preexposure Prophylaxis: Clinical Practice Guideline TISSUE CONCENTRATION ON-DEMAND PREP Phase 1 pharmacokinetic investigation of TDF-FTC TDF concentrations 10 times higher in colorectal tissue Effective for HIV prevention among MSM Alternative to daily PrEP for MSM with infrequent sexual exposures Data lacking for use in other high risk populations Daily use required to prevent HIV transmission via female genital tract Protective colorectal concentrations by third daily dose Adherence of 2 of 7 doses/week (28%) required to protect colorectal tissue Adherence of 6 of 7 doses/week (85%) required to protect female genital tract tissue dosing 2 doses 2-24 hours before sexual activity 1 dose 24 hours after the first dose 1 dose 24 hours later Cottrell ML, et al. J Infect Dis. 2016;214(1): Saag MS, et al. JAMA. 2018;320(4):

5 DAILY VS ON-DEMAND PREP ON-DEMAND PREP EFFICACY Study Type Methods (n) Results Conclusion Randomized, placebocontrolled trial TDF-FTC (199) Placebo (201) Incidence: 0.91 per 100 patient-years Incidence: 6.60 per 100 patient-years Relative risk reduction: 86% TDF-FTC before and after sexual activity provided protection against HIV infection in MSM Molina JM, et al. N Engl J Med. 2015;373(23): PATIENT CASE MJ is a 22 year-old male who presents to his primary care provider to discuss initiating PrEP therapy. He reports frequent sexual encounters with 7 different men and condom usage 80% of the time. To his knowledge, none of his sexual partners are HIV positive. MJ tests negative for HIV and bacterial STD s today. Is MJ a candidate for on-demand PrEP? Why or why not? Common Adverse Effects Serious Issues Truvada package insert. Foster City, CA. Gilead Sciences, Inc MONITORING Baseline Every 3 months HIV Status Every 6 months Renal function (ecrcl & SCr) Sexually Transmitted Infection Screening Based on risk Hepatitis B Testing &Vaccination Hepatitis C Testing Pregnancy Test (if applicable) Assess side effects, adherence, and risk behaviors Evaluate need to continue PrEP Every 12 months FUTURE PREP OPTIONS Intravaginal ring Long-acting injectable Long-acting implant Vaccine Microbicides US Public Health Service. Preexposure Prophylaxis: Clinical Practice Guideline AASLD-IDSA. HCV testing and linkage to care. Recommendations for testing, managing, and treating hepatitis C. SMAIF. Potential Future Options. HIV.gov. U.S. Department of Health & Human Services 5

6 PREP TAKE AWAY Rate of HIV diagnoses has remained stable over last three decades MSM continue to be the most effected population Truvada is safe and effective at preventing HIV transmission when taken daily Truvada dosing effectively prevents HIV transmission in MSM Notable monitoring parameters for Truvada include HIV status and renal function STD GUIDELINES Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines, 2015 RISK FACTORS DIAGNOSIS More than one sexual partner A partner who has or has had more than one sexual partner Sex with someone who has an STI History of STDs Clinical presentation First catch urine, tissue swab, blood draw Nucleic acid amplification test or serologic tests Use of intravenous drugs or partner use of intravenous drugs Health Care Systems for Underserved Women - ACOG COMPLICATIONS EXPEDITED PARTNER THERAPY Chlamydia Gonorrhea Syphilis Treating primary partners of those who receive chlamydia or gonorrhea diagnoses without examination Infertility Pelvic inflammatory disease Screen high risk individuals annually Screen pregnant women in 1 st and 3 rd trimester Infertility Pelvic inflammatory disease Disseminated gonococcal infection Screen high risk individuals annually Organ damage Blindness Dementia Screen high risk individuals Screen pregnant women in 1 st trimester Significant decline in rate of chlamydia or gonorrhea reinfection Recommend to routinely offer to heterosexual patients Should not be used routinely in MSM >5% of MSM receive HIV diagnosis when evaluated as partners of patients with STD 6

7 CHLAMYDIA TRACHOMATIS CHLAMYDIA Over 1.7 million cases reported in 2017 Prevalence highest in people aged 24 years Iowa: 12,983 cases in 2016 Johnson County: 862 cases in 2016 Obligate intracellular parasite Knodel LC, et al. Pharmacotherapy: A Pathophysiologic Approach, 10e: McGraw-Hill PRESENTATION TREATMENT Males More than 50% asymptomatic Dysuria Females More than 66% asymptomatic Dysuria Recommended regimens Azithromycin 1 gram orally in single dose Or Doxycycline 100 mg orally twice a day for 7 days Mucoid to purulent discharge Increased frequency of urination Abnormal vaginal discharge Abnormal uterine bleeding Alternative regimens Erythromycin 500 mg orally four times a day for 7 days Or Levofloxacin 500 mg orally once daily for 7 days Or Ofloxacin 300 mg orally twice a day for 7 days Knodel LC, et al. Pharmacotherapy: A Pathophysiologic Approach, 10e: McGraw-Hill CHLAMYDIA SUMMARY Most common bacterial STD in the U.S. Frequently asymptomatic GONORRHEA Women <25 years old and those at high risk should be screened annually Recommended treatment options are azithromycin or doxycycline 7

8 NEISSERIA GONORRHOEAE PRESENTATION Over 555,000 cases in 2017 Iowa: 2,600 cases in 2016 Johnson County: 128 cases in 2016 Gram-negative diplococcus Intracellular Only natural host: humans Males Commonly symptomatic Dysuria Urinary frequency Purulent discharge Females Asymptomatic or minimally symptomatic Dysuria Urinary frequency Mucopurulent vaginal discharge Abnormal uterine bleeding Knodel LC, et al. Pharmacotherapy: A Pathophysiologic Approach, 10e: McGraw-Hill Knodel LC, et al. Pharmacotherapy: A Pathophysiologic Approach, 10e: McGraw-Hill TREATMENT ANTIBIOTIC RESISTANCE Recommended Regimen Alternative Regimen Ceftriaxone 250 mg intramuscularly in a single dose PLUS Azithromycin 1 gram orally in a single dose Cefixime 400 mg orally in a single dose PLUS Azithromycin 1 gram orally in a single dose Late 1940 s Sulfonamide resistance common Sulfonamides ( ) Mid-1980s Chromosomal penicillin and plasmid-mediated tetracycline resistance spreads Penicillin ( ) Late 1970s High level penicillin resistance due to β lactamase plasmids 2007 Fluoroquinolones no longer recommended by CDC treatment guidelines Fluoroquinolones ( ) Early 2000s Fluoroquinolones resistance prevalent in Western Pacific regions and Hawaii 2010 High level azithromycin resistance reported in Latin America, Europe and U.S. Extended Spectrum Cephalosporins ( ) 2012 CDC designates Neissera Gonorroeae a super bug Dual Therapy Ceftriaxone + Azithromycin (2010-now) Extensively drug resistance strains identified in Japan, Spain and France Adapted from The Journal of Applied Laboratory Medicine NEISSERIA GONORRHOEAE ANTIMICROBIAL SUSCEPTIBILITY SURVEILLANCE 2014 Tetracycline-R Penicillin-R Fluoroquinolone-R Cefixime-RS COMPARING CEPHALOSPORIN PHARMACODYNAMICS Percentage Azithromycin-RS Study Type Pharmacodynamic analysis Methods Ceftriaxone 250mg IM time >MIC 90 Cefixime 400mg PO time >MIC 90 Cefuroxime 1g PO time >MIC 90 Results 41 hours 22.4 hours 10 hours Conclusion Ceftriaxone or cefixime should be agents of choice; cefuroxime is a poor substitute Kirkcaldy RD, et al. MMWR Surveill Summ 2016;65(No. SS-7):1 19. Ison CA, et al. Sex Transm Infect, 2004;80:

9 OTHER TREATMENT OPTIONS GONORRHEA SUMMARY Cephalosporin or IgE-mediated Penicillin Allergy Azithromycin Allergy Gemifloxacin 320 mg orally in a single dose PLUS Azithromycin 2 grams orally in a single dose OR Gentamicin 240 mg intramuscularly in a single dose PLUS Azithromycin 2 grams orally in a single dose Ceftriaxone 250 mg intramuscularly in a single dose PLUS Doxycycline 100 mg orally twice a day for 7 days 2 nd most common bacterial STD in the U.S. Highly resistant to most antibiotics Women <25 years old and those at high risk should be screened annually Recommended treatment: ceftriaxone PLUS azithromycin TREPONEMA PALLIDUM SYPHILIS Spirochete Obligate human pathogen known for invasiveness Can progress to chronic systemic disease if untreated More than 30,000 cases in 2017 Iowa: 275 cases in 2016 Knodel LC, et al. Pharmacotherapy: A Pathophysiologic Approach, 10e: McGraw-Hill PRESENTATION Primary Single painless lesion (chancre); Multiple painful purulent lesions uncommon Secondary Rash, mucocutaneous lesions, flulike symptoms Tertiary Lesions involving any organ or tissue; Cardiovascular; Neurosyphilis Knodel LC, et al. Pharmacotherapy: A Pathophysiologic Approach, 10e: McGraw-Hill Toney JF. Lecture presented at National Antimicrobial Stewardship Conference; 2018 Sep 24 9

10 TREATMENT PENICILLIN SHORTAGE Recommended Regimen IgE-mediated Penicillin Allergy Treatment Failure Benzathine penicillin G (Bicillin L-A) 2.4 million units intramuscularly in a single dose Doxycycline 100mg orally twice daily for 14 days Tetracycline 500mg orally four times daily for 14 days Penicillin desensitization followed by penicillin treatment Benzathine penicillin G (Bicillin L-A) 2.4 million units intramuscularly weekly for 3 weeks Primary and secondary syphilis Refrain from using benzathine penicillin G for treatment of other infectious diseases where alternatives are available Adhere to recommended single dose as additional doses do not enhance efficacy If no drug available, contact Pfizer directly No changes to recommended treatment regimens Penicillin G benzathine (Bicillin-LA) Shortage. Drug Notices. CDC EFFICACY OF CEFTRIAXONE VS PENICILLIN FOLLOW UP Study Type Methods Results Conclusion HIV testing for all patients with primary or secondary syphilis Metaanalysis Included 7 RCT s involving 281 participants 3 month response rate: month response rate: month response rate: 1.04 Ceftriaxone efficacy for syphilis is not significantly different from penicillin Clinical and serologic evaluation at 6 and 12 months following treatment Treatment failure Persistent signs or symptoms Failure of titer to decline fourfold within 6-12 months of therapy Liang Z, et al. Int J Antimicrob Agents. 2016;1:6 11. SYPHILIS SUMMARY PATIENT CASE Can progress to chronic systemic disease if untreated Presents as a single painless lesion in primary phase Screen high risk patients and pregnant women Recommended treatment: benzathine penicillin G Clinical and serologic evaluation recommended 6-12 months after treatment MJ returns to clinic 9 months after beginning daily PrEP therapy. He reports 1 new sexual partner since his last visit and reports condomless sex. He has tested negative for HIV and STDs when tested every 3 months since starting PrEP. He has no symptoms of an STD, urine culture is negative, rectal swab positive for N. gonorrhoeae. What is the appropriate treatment for MJ? 10

11 FINAL TAKE AWAY Truvada is effective in preventing HIV transmission Imperative to counsel patients on Truvada use and close monitoring The United States is observing steep and sustained increases in STD prevalence Questions Antibiotic resistant gonorrhea is a public health threat Patients with STD diagnoses and their partners should receive guideline concordant treatment 11