10/8/18 LAURA KOGELMAN, MD. Play Bumper Video. Associate Professor of Medicine. Director, Infectious Diseases Clinic. Boston, Massachusetts

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1 LAURA KOGELMAN, MD Associate Professor of Medicine Tufts University School of Medicine Director, Infectious Diseases Clinic Tufts Medical Center Boston, Massachusetts Play Bumper Video 1

2 Disclosures All faculty, course directors, planning committee, content reviewers and others involved in content development are required to disclose any financial relationships with commercial interests. Any potential conflicts were resolved during the content review, prior to the beginning of the activity. The following individuals have a relevant financial relationship with a commercial interest: Faculty Commercial Interest Name What Was Received For What Role Laura Kogelman, MD Gilead Honorarium Speaking and teaching Glenn Treisman, MD, PhD Gilead Sponsorship for lectures For What Clinical Area/Disease State Nonbranded HIV-related talks and PrEP Invited Psychiatry presentation There will be no references to unlabeled or unapproved uses of drugs or products. Educational Objectives Discuss current state of the HIV epidemic in the United States. Discuss recommendations, modalities and rationale for HIV testing. Identify potential candidates for PrEP and understand how to prescribe and monitor patients on PrEP. Review medications used to treat HIV and understand current guidelines for selecting a regimen for a newly diagnosed patient. Describe rationale and approach to switching regimens when indicated. PRE-ASSESSMENT 2

3 Pre-Assessment Question 1 How confident are you in your ability to identify people at high risk who should be screened for HIV? 1. Not Confident 2. Somewhat Confident 3. Neutral 4. Confident 5. Very Confident Pre-Assessment Question 2 How confident are you in your ability to determine when treatment should be initiated in someone with HIV? 1. Not Confident 2. Somewhat Confident 3. Neutral 4. Confident 5. Very Confident Pre-Assessment Question 3 How confident are you in your ability to determine appropriateness of switching a virally suppressed patient to a new treatment regimen? 1. Not Confident 2. Somewhat Confident 3. Neutral 4. Confident 5. Very Confident 3

4 Pre-Assessment Question 4 Currently, the mode of transmission responsible for most new infections of HIV is: 1. Heterosexual contact 2. Maternal-child 3. Men who have sex with men 4. Injection drug use WHO IS AT RISK? BACKGROUND AND DEMOGRAPHICS HIV and AIDS Epidemiology: US ~1.1 million people in the US have HIV/AIDS 15%-20% are unaware of their diagnosis 40,000 cases new cases annually New infections are decreasing EXCEPT in MSM, who account for 67% of new infections 1 in 5 are in ages years old Ann Int Med 2009; 150:125; CCJM 2011; 78(2):95; 4

5 HIV and AIDS Epidemiology: US HIV highest risk groups Young gay and bisexual men Young African Americans (65% of HIV infections in youths) HIV prevalence in Black men in DC is 5.8% Prevalence of HIV is 6% in Kenya Certain geographic areas with limited access to care California: 2.5 times that of Caucasian males Ann Int Med 2009; 150:125; CCJM 2011; 78(2):95; Hess K, et al. CROI Boston, MA. #52. Adapted from CDC Accessed May 2017; 2. White House Office of National AIDS Policy. National HIV/AIDS Strategy for the United States: Updated to Available at: Accessed May 2017.;. Annual Epidemiology and Surveillance Reports for the District of Columbia. HIV/AIDS, Hepatitis, STD and TB Administration (HAHSTA) Annual Report 2014 Currently, the mode of transmission responsible for most new infections of HIV is: 1. Heterosexual contact 2. Maternal-child 3. Men who have sex with men 4. Injection drug use HOW DO YOU FIND OUT? SCREENING AND DIAGNOSIS 5

6 Play Screening/Diagnosis video (Donn, Amanda, Trevor) Approximately what percent of HIV-infected individuals are unaware of their infection status? 1. 10% 2. 15%-20% 3. 25%-30% 4. >30% Guidelines for HIV Testing Targeted testing based on risk misses about 20 % of persons with HIV CDC recommends screening Everyone ages (USPSTF says 15 to 65) All ages in high risk groups All pregnant women (even in labor) Opt-out testing is recommended Interval for HIV screening undetermined CDC recommends all sexually active MSM every 3-6 months 30 April 2013; MMWR 2017 Aug 11;66(31):830 6

7 Awareness of Serostatus Among People with HIV, and Estimates of Transmission ~20% unaware of infection ~49% of new infections ~80% aware of infection account for ~51% of new infections People Living with HIV/AIDS:1,200,000 New Sexual Infections Each Year: ~50,000 Hall et al, AIDS, Impact of Late vs Early Diagnosis With less proactive testing strategies, many HIV-positive individuals already have AIDS by the time their HIV is diagnosed Early identification and treatment of HIV can lead to per person survival benefits of over 11 years HIV is no longer a death sentence 8 classes of drugs, with > 40 products available HIV meds are better tolerated, have better long-term efficacy, and have lower pill burden (eg, 6 single-tablet regimens available) Hall et al, AIDS, HIV Treatment as Prevention (TasP) Early initiation of ART can reduce risk for HIV transmission to uninfected partners HPTN 052: relative reduction of 96% in the number of linked HIV-1 transmissions with early vs delayed treatment of HIV positive partner PARTNER study: NO genetically linked transmissions over median f/u of 1.3 years per serodiscordant couple if HIV positive partner virologically suppressed DHHS guidelines and WHO recommend ART for prevention of transmission of HIV Cohen, et al; NEJM 2011; 365: ; Rodger et al; Jama (2):

8 Recommended Laboratory HIV Testing Algorithm for Serum or Plasma Specimens HIV-1/2 antigen/antibody combination immunoassay (+) (-) Negative for HIV-1 and HIV-2 antibodies and p24 Ag HIV-1/HIV-2 antibody differentiation immunoassay HIV-1 (+) HIV-2 (-) HIV-1 antibodies detected HIV-1 (-) HIV-2 (+) HIV-2 antibodies detected HIV-1 (+) HIV-2 (+) HIV antibodies detected HIV-1 (-) or indeterminate HIV-2 (-) HIV-1 NAT (+) indicates reactive test result (-) indicates nonreactive test result NAT: nucleic acid test HIV-1 NAT (+) Acute HIV-1 infection HIV-1 NAT (-) Negative for HIV-1 Approximately what percent of HIV-infected individuals are unaware of their infection status? 1. 10% 2. 15%-20% 3. 25%-30% 4. >30% 8

9 CAN HIV INFECTION BE PREVENTED? PrEP Pre-exposure prophylaxis should be considered in which of the following? 1. Partner with HIV 2. Recent STI diagnosis 3. User of IV drugs 4. People engaging in transactional sex 5. All of the above 6. 1, 3, and 4 PrEP PrEP stands for Pre-Exposure Prophylaxis Currently only one medication is approved for PrEP tenofovir DF 300mg-emtricitabine 200 mg, in a combination tablet, was approved for this purpose in 2012 Taken correctly can be more than 90% effective preventing in HIV transmission The first step in prescribing PrEP is identifying individuals at risk for HIV infection which means taking a detailed sexual and drug use history PrEP should be part of a comprehensive prevention approach that emphasizes education about safer sex practices, including consistent condom use 9

10 When Should You Discuss PrEP? STI diagnosis, or request for testing for STIs Inconsistent or infrequent condom use Recent npep usage Request for HIV testing Partner with HIV infection Multiple partners or non-monogamous relationships (or concerns that their partners are non-monogamous) Sexual activity in high-prevalence areas or networks Transactional sex Use of drugs or alcohol, especially in relation to sexual activity Use of IV drugs Incarceration of individual or partner Taking a Sexual History Do you have sex with men, women, both (or other) What kind of sexual contact do you have (genital, anal, oral) For MSM/transgender patients, during anal sex are you the receptive or insertive partner, or both Do you know the HIV status of your partners? How frequently do you use condoms and for what activities? Have you ever had an STI? How often do you use drugs or alcohol when having sex? Which kinds of drugs (eg, opioids, methamphetamines, cocaine, inhalants, ecstasy [MDNA], etc) How do you use these drugs (eg, snorting, smoking, injecting, etc) USPHS/CDC Guidelines on Prescribing PrEP Baseline testing: HIV testing (4 th generation assay preferred)* Screen/treat for STDs (Triple dip; HCV screening) Pregnancy test Creatinine clearance, must be >60 ml/min Screen for HBV, o o If positive, be aware that discontinuing PrEP can cause HBV flare If negative, vaccinate Prescribe TDF-FTC, 1 tablet by mouth daily No more than 90 day supply Counsel on continued use of condoms and riskreduction Monitor closely (q 3 mo: HIV test, risk assessment and counseling; at least q6 mos: STI screen;* q6-12 mos Cr level) 10

11 Pre-exposure prophylaxis should be considered in which of the following? 1. Partner with HIV 2. Recent STI diagnosis 3. User of IV drugs 4. People engaging in transactional sex 5. All of the above 6. 1, 3, and 4 HOW, WHY, WHEN AND WITH WHAT? HIV TREATMENT INITIATION Play Initiating Treatment video (Amanda, Trevor) 11

12 Current guidelines generally recommend initiating treatment: 1. When viral load increases by 10% 2. When CD4 count decreases by 10% 3. As soon as possible after diagnosis 4. When sexually active Cascade of Care Morbidity and Mortality in the HAART Era Life expectancy with treatment is similar to uninfected people Mortality is non-aids related in vast majority of cases Causes of morbidity and mortality include: Malignancy (non-aids defining > AIDS defining) Liver failure, usually associated with coinfection Non-AIDS related infections Cardiovascular disease Neurocognitive disorders 12

13 Mortality and HAART Use Over Time HIV Outpatient Study, CDC, Deaths per 100 PY Patients on HAART Deaths per 100 PY Patients on HAART Year DHHS Recommendations for Initiating ART (October 2017) Panel's Recommendations Antiretroviral therapy (ART) is recommended for all HIV-infected individuals, regardless of CD4 T lymphocyte cell count, to reduce the morbidity and mortality associated with HIV infection (AI). ART is also recommended for HIV-infected individuals to prevent HIV transmission (AI). When initiating ART, it is important to educate patients regarding the benefits and considerations regarding ART, and to address strategies to optimize adherence. On a case-by-case- basis, ART may be deferred because of clinical and/or psychological factors, but therapy should be initiated as soon as possible. Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion **based on START and TEMPRANO data, strength of recommendation to start all HIV infected patients changed to AI IAS Guidelines 2018: Initiate ART As Soon as Possible After HIV Diagnosis Rapid start (including same day as diagnosis) ART, unless that patient is not ready to commit to starting therapy Structural barriers should be removed Samples for HIV-1 RNA level; CD4 cell count; HIV genotype for NRTI, NNRTI, and PI; HLA-B*5701 testing; laboratory tests to exclude active viral hepatitis; and chemistries should be drawn before beginning ART, but treatment may be started before results are available. NNRTIs (possible transmitted resistance) and abacavir (without HLA-B*5701 results) should not be used for rapid ART start Saag, Benson, Gandhi, et al, JAMA,

14 Recent Medication Evolution 8 classes of drugs, > 40 products, including 10 STRs Drug Class Mechanism of Action # of Products NRTIs Block reverse transcriptase (RT)* 7 NNRTIs Bind to and later alter RT* 7 Protease Inhibitors (PIs) Block HIV protease* 8 Fusion Inhibitors Block HIV from entering CD4 cells 1 Entry Inhibitors Block protein on CD4 cells that HIV needs to enter the 1 cells Integrase Inhibitors (INSTI) Block HIV integrase* 4 Monoclonal Antibody Blocks HIV entry by attaching to CD4 receptors; prevents conformational change needed for viral entry 1 Pharmacokinetic Enhancers Used in HIV treatment to increase the effectiveness of an 1 HIV drug in a regimen Combination Agents Contain 2 HIV medicines from 1 or more drug classes 14 (10 STRs) NRTIs: nucleoside reverse transcriptase inhibitors, NNRTIs: non-nucleoside reverse transcriptase inhibitors, STRs: Single-tablet regimens. *Reverse transcriptase, protease, and integrase are enzymes HIV needs to make copies of itself Source: What to Start IAS 2018: Recommended Initial Regimens (alphabetical order) INSTI + 2 NRTIs o Bictegravir/TAF/emtricitabine (BIC/TAF/FTC) o Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) o Dolutegravir plus TAF/emtricitabine (DTG + TAF/FTC) DHHS 2018: Recommended Initial Regimens for Most People with HIV (alphabetical order) INSTI + 2 NRTIs o BIC/TAF/FTC o DTG/ABC/3TC (if HLA-B*5701 negative) o DTG + FTC/tenofovir (TAF or TDF) o EVG/c/FTC/tenofovir (TAF or TDF) o RAL (standard or high dose) + FTC/tenofovir (TAF or TDF) Saag, Benson, Gandhi, et al, JAMA, Factors That Influence Regimen Choice for Naïve Patients Pill burden, frequency of dosing, pill size Anticipated compliance Drug-drug interactions (DDIs) Side effects; long-term toxicities Food requirements Baseline resistance* Pregnancy or potential for pregnancy Baseline CD4 count and/or viral load Allergies (eg, HLA-B5701 status) Co-infections Comorbidities 14

15 Dolutegravir and neural tube defects An ongoing study using dolutegravir has been associated with an increase in neural tube defects in babies born to mothers on the drug This is a statistical association and may turn out to be a false signal At this time it is recommended to avoid dolutegravir in patients who may become pregnant Current guidelines generally recommend initiating treatment: 1. When viral load increases by 10% 2. When CD4 count decreases by 10% 3. As soon as possible after diagnosis 4. When sexually active WHAT S NEW? NEW HIV TREATMENT OPTIONS 15

16 Which new agent is now available in a high-dose version that can be taken with or without food? 1. Cobicistat 2. Raltegravir 3. TAF 4. Bictegravir New(er) ART: TAF Due to lower plasma levels, less renal and bone toxicity than with TDF TDF is associated with lower lipid levels; clinical significance of this is unclear IAS guidelines, only recommend FTC-TAF; DHHS recommends FTC-TAF or FTC-TDF Not to be used for PrEP (ie, FTC-TAF cannot replace FTC-TDF at this time) Cannot be used in persons with CrCl < 30 ml/min Limited data on TAF in pregnancy New(er) ART: Simplification with Cobicistat Atazanavir/COBI and darunavir/cobi simplify Atazanavir/ritonavir and darunavir/ritonavir dosing in a single tablet; Component of elvitegravir/tdf (or TAF)/FTC single-tablet regimen No data regarding using COBI containing regimens in pregnancy COBI inhibits CYP3A4, need to use caution regarding DDIs COBI inhibits tubular secretion of creatinine, leading to an increase in serum Cr, decreased GFR Can see an increase of up to 0.14 mg/dl in Cr over first several weeks, then stabilizes

17 New(er) ART: Raltegravir HD Given as two 600 mg tablets ONCE daily (as opposed to 400 mg twice daily dosing) Coadministration with calcium carbonate antacids, rifampin, etravirine NOT recommended (all of the above require no dose adjustments with standard raltegravir dosing) HD dosing not studied in pregnancy Can be taken with or without food New Agents: BIC (BICTEGRAVIR)/FTC TAF Highly potent INSTI STR without boosting Noninferior compared to DTG/ABC/3TC and DTG + FTC/TAF Active against most INSTI-resistant variants; appears to have a high barrier to resistance Metabolized by both CYP3A4 and UGT1A1, few drug interactions Sax PE, et al. 24 th CROI. Seattle, 2017 Abstract New Agents: Dolutegravir/Rilpivirine ONLY approved for use in virally suppressed patients Studies looked at switching from a suppressive 3-4 drug regimen to DTG/RPV showed good results maintaining viral suppression May be a good option for patients who cannot take NRTIs Food restrictions, PPI restrictions would still apply due to RPV Sax PE, et al. 24 th CROI. Seattle, 2017 Abstract

18 New Agents: Darunavir/COBI/FTC/TAF First PI-based STR Good option for patients with more drug resistance or adherence issues Sax PE, et al. 24 th CROI. Seattle, 2017 Abstract New Agents: Ibalizumab Approved March 2018 Monoclonal antibody, blocks HIV entry by attaching to CD4 receptors and stopping the conformational changes needed for the virus to enter the cell Active against both CCR5 and CXCR4-tropic virus Long half-life, IV infusion q 2 weeks Option for highly treatment experienced patients with multi-drug resistance No drug interactions No infusion-related adverse reactions New Agents: Doravirine and Doravirine/3TC/TDF Approved August 2018 Once-daily NNRTI that retains activity against most prevalent NNRTI mutations Appears to have limited drug interactions with other antivirals No food requirements No issues with acid-reducing agents Fewer neuropsychiatric side effects compared to efavirenz Approved as an individual agent and in a fixed-dose combination with 3TC/TDF Week-48 findings of phase 3 trials of safety/efficacy (DOR vs DRV and DOR/3TC/TDF vs EFV/FTC/TDF) showed non-inferior efficacy and improved safety 18

19 Looking Ahead: In Phase 3 Cabotegravir/rilpivirine (integrase; oral and IM formulations) long-acting coformulation for treatmentnaïve patients: high rates of virologic response and good tolerability; under study for PrEP; currently available under compassionate-use program Dolutegravir/3TC STR studied in both naïve and experienced Which new agent is now available in a high-dose version that can be taken with or without food? 1. Cobicistat 2. Raltegravir 3. TAF 4. Bictegravir ARE YOU EXPERIENCED? SWITCHING REGIMENS 19

20 Play Changing Regimens video (Donn, Amanda) Which factor does NOT warrant consideration of switching to a new regimen? 1. Simplification of regimen 2. Mitigation of side effects 3. Emergence of new comorbidity or drug-drug interaction 4. Food restrictions 5. Consistency with partner s regimen Reasons for a Regimen Switch (in a Virologically Suppressed Patient) Simplification (pill burden) Mitigation of side effects Minimize long-term toxicity New DDIs New (or at risk for) comorbidities Pregnancy or plans for pregnancy Food restrictions Minimize copays or satisfy payer formulary requirements 20

21 Considerations in Switching Regimens Proactive switching from TDF to TAF is recommended for patients at high risk of renal or bone toxicity. Review of comedications is essential to ensure no change in dosing is required with the use of TAF If the older regimen is well tolerated without evidence of toxicity, switching to a newer regimen is not necessary Switching from 3-drug to certain 2-drug regimens in the setting of viral suppression can be considered in patients with no prior virologic failure or transmitted drug resistance (Longer-term follow-up is needed to confirm durability) Saag, Benson, Gandhi, et al, JAMA, Safe Switching Review ART treatment history and any and all prior resistance testing Review all other current and anticipated medications (including OTC/herbal meds) Careful attention to comorbidities If there is underlying resistance to NRTIs, recommend against switching from a boosted PI containing regimen to one with a lower genetic barrier to resistance (eg, NNRTI, raltegravir) Make sure patient is on board with the concept of switching Review, reinforce, and reemphasize details of meds that are being changed with the patient Communicate with pharmacy re: changes being made Close follow-up with patient by phone or in person to make sure meds are being taken correctly and that there are no new issues HIV viral load should be checked at least one month after the switch to ensure viral suppression has been maintained Saag, Benson, Gandhi, et al, JAMA, Which factor does NOT warrant consideration of switching to a new regimen? 1. Simplification of regimen 2. Mitigation of side effects 3. Emergence of new comorbidity or drug-drug interaction 4. Food restrictions 5. Consistency with partner s regimen 21

22 Key Takeaways New HIV infections are continuing to occur, with young, MSM of color being disproportionately affected All patients should be screened for HIV at least once; those at higher risk should be screened more frequently PrEP is a highly effective option to prevent HIV infection; therefore, taking a detailed sexual history to identify those at risk is critical Close follow-up with retesting and STD screening is fundamental to prescribing PrEP Guidelines recommend that all HIV-positive individuals start antiretroviral therapy, regardless of CD4 counts, with an emphasis on starting as soon as possible Key Takeaways Guidelines emphasize treatment regimens that include integrase strand transfer inhibitors and focus on simplicity, tolerability and efficacy Products approved in the last year include 3 new STRs (new versions of familiar agents to improve pill burden) With multiple new, simple, safer, well-tolerated options (TAF, bictegravir, raltegravir), patients on older regimens may have the option to switch, though this must be done carefully Starting and keeping patients on highly efficacious, well-tolerated regimens with minimal toxicity is critical to long-term compliance, which subsequently benefits the long-term health of people living with HIV who can now expect a close to normal life expectancy POST-ASSESSMENT 22

23 Post-Assessment Question 1 How confident are you NOW in your ability to identify people at high risk who should be screened for HIV? 1. Not Confident 2. Somewhat Confident 3. Neutral 4. Confident 5. Very Confident Post-Assessment Question 2 How confident are you NOW in your ability to determine when treatment should be initiated in someone with HIV? 1. Not Confident 2. Somewhat Confident 3. Neutral 4. Confident 5. Very Confident Post-Assessment Question 3 How confident are you NOW in your ability to determine appropriateness of switching a virally suppressed patient to a new treatment regimen? 1. Not Confident 2. Somewhat Confident 3. Neutral 4. Confident 5. Very Confident 23

24 Q&A THANK YOU FOR COMING. 24