Top 10 Stories in HIV Medicine Diane Havlir, MD Professor of Medicine University of California, San Francisco 1 Disclosures n Receive funding for research from NIH n Gilead sciences provides antiretroviral therapy for NIH funded SEARCH research study 2 1
Story 1: ART Guidelines 3 AR1: In 2019, new ART Guidelines recommend which of these 2 drug regimens in initial therapy for “most persons living with HIV?” A. Dolutegravir+ lamivudine ( DTG+ 3TC) B. Dolutegravir + rilpivirine (DTG+ RPV) C. Darunavir(boosted) + DTG D. All of the above E. None of the above 4 2
Answer: None 2019: What to start in“most patients” CLASS REGIMEN INSTI BIC/TAF/FTC INSTI DTG/ABC/3TC INSTI DTG/TAF/FTC INSTI* RTG/TAF/FTC* *HHS Guidelines only Some options TDF or TAF recommened HHS guidelines, October 2018 IAS-USA Guidelines, JAMA, July, 2018 5 2019 Updates n Start ART for HIV-2 upon diagnosis and use INSTI (integrase strand transfer inhibitor) n Address substance use disorders when screening and treating persons for HIV infection n Provide gender affirmative care for transgender population HHS guidelines, July, 2019 6 3
Summary n This past year, there were some new recommendations but not “transformative” changes in specific ART regimens n We anticipate guideline changes in the coming year upon approval of long-acting injectable cabotegravir/rilpivirine and as more information is forthcoming on combinations and agents 7 Story 2: ART imperfections 8 4
Association of Neural Tube Defects (NTD) and Dolutegavir during conception: less, but detectable Tsepamo Study, Botswana 0.9 0.3 NTD with DTG at conception 0.1 NTD non-DTG at conception 0.08 NTD HIV-negative Zash, NEJM, 2019 9 HHS Recommendations for women of childbearing potential n DTG should not be prescribed for individuals: • Who are pregnant and within 12 weeks post-conception • Who are of childbearing potential and planning to become pregnant • Who are of childbearing potential, sexually active, and not using effective contraception n For those who are using effective contraception, a DTG- based regimen can be considered after weighing the risks and benefits of DTG n Similar recommendations for bictegravir n Elvitegravir not recommended (pharmacokinetics); little data on raltegravir HHS guidelines, July, 2019 10 5
Weight Gain and ART Large Randomized Study: “ADVANCE” • South Africa • Treatment naïve • No TB, pregnancy • Primary endpoint: viral suppression • Secondary endpoints: renal, bone, metabolic Venter, IAS and NEJM, 2019 11 Large weight gains over time: greatest in DTG/TAF/FTC arm Recipients of DTG/TAF/FTC: • 10 kg mean weight increase in women • 5 kg mean weight increase in men Venter, IAS and NEJM, 2019 12 6
Increasing proportion of obesity: greatest in TAF/FTC+ DTG Venter, IAS and NEJM, 2019 13 Summary n Integrase strand transfer inhibitors (INSTIs) remain the cornerstone of HIV therapy but dolutegravir • was associated with small risk for neural tube defects in Botswana • was associated with unplanned weight gain in randomized studies conducted in Africa n As providers we must discuss evolving information with our patients for decision making in optimal ART regimens 14 7
Story 3: To TANGO or not? “2 Drug Regimens” 15 Stage Setting n One of the most dynamic areas in ART management is “2 drug therapy” n Why? • We now have several proven potent “2 drug” combinations to maintain viral suppression • Toxicity can potentially be reduced with these combinations n Why not? • Unwise use of these regimens can lead to drug resistance of agents we want to preserve • Requires both drugs are fully active • Data are mostly from tightly controlled clinical trials where prior resistance can be identified and adherence may be higher 16 8
Start: ART Naïve: DTG + 3TC vs DTG + 3TC + TDF are comparable HIV RNA <50 c/mL at 48 weeks 92% 2 DR • Gemini Study N=1441 93% 3 DR • DTG + 3TC vs DTG + TDF/FTC • Inclusion: ART naïve, no resistance, no hep B or C • HIV RNA <50 c/mL at 48 weeks similar; 3 drug appears betters CD4 <200 • Adverse events: 24% (3 drug) vs 18% (2 drug ) 3 drug better when CD4 < 200 Cahn, Lancet 2019 17 Switch: ART experienced with viral suppression n Randomized 741 patients on 3 drug ART to switch to 2 drug ART or stay on 3 drug ART TANGO study Van Wyk. IAS 2019. 18 9
Switch to 2 drug regimen was comparable to staying on 3 drug regimen n HIV viral load suppression 48 weeks 93.2% vs 93% n Similar adverse events in both arms n No new drug resistance Van Wyk. IAS 2019. 19 Switching to a 2 drug regimen – Cohort “Experience” n Spanish Cohort 2016-2019 n Any switch to INSTI regimen • Switch to 2 DR N= 617 • Switch to 3 DR N= 5047 n Over 2-fold higher virologic failure with 2 DR vs 3 DR n Over 2-fold higher virologic failure vs 3 DR among those with viral suppression at time of switch Teira, EAC, 2019 20 10
Summary n There are excellent data and options for 2 drug therapy for persons starting or switching therapy n However, Use carefully! • 2 drug therapy should be applied for patients that are similar to those in the clinical trials • Do not use in those with resistance to a regimen drug, poor adherence, low CD4, or starting “same day” n Depending on your clinical practice, the proportion of your patients that qualify for 2 drug switches may vary n This is rapidly evolving field that will change with anticipated approval of 2 drug injectable therapies 21 Story 4: Two New Drugs under study GS-6207 MK-8591, Islatravir 22 11
GS-6207: Long Acting Capsid Inhibitor n Novel mechanism of action n Active against ART resistant virus in vitro studies n Sub-cutaneous regimen n Long acting 23 GS-6207: Long half life n Supports 3-6 month SQ dosing interval n Potent antiviral activity: 2 log HIV RNA reduction at 10 days 24 12
MK-8591 (Islatravir) + Doravirine dose finding study n Translocation deficient RTI (TDRTI) n Blocks RT through multiple steps n Oral formulation for treatment Molina, CROI and IAS, 2019 25 2 6 MK-8591:Antiviral activity Molina LBPED46 Molina, CROI and IAS, 2019 26 13
MK-8591: Two drug continuation phase ISL 0.25 mg ISL 0.75 mg ISL 2.25 mg + DOR+ + DOR +DOR DOR TDF + 3TC N 29 30 31 31 d/c before 0 0 4 3 week 24 HIV RNA 89% 90% 77% 84% <50 c/mL week 48 Molina, CROI and IAS, 2019 27 Summary n GS-6207 and MK-8591 are promising new agents in development with unique mechanisms of action n Current planned studies are pairing these drugs with other oral drugs for new combination regimens 28 14
Story 5 : HIV “outbreaks” 29 AR2 : What country has 160,000 persons living with HIV and a recent outbreak among children? A. Swaziland B. Ukraine C. Honduras D. Pakistan 30 15
Answer: Pakistan n April 2019. Media alerted government officials about a surge of HIV cases in the Larkana District in Pakistan n 872/30,192 persons tested were HIV+; 719 were less than 15 years of age n Risk Factors: unsafe needle use, unsafe deliveries, blood banking, hospital infection control Source: UNAIDS, WHO, photo from NYTimes 31 Public Health Response n Open a new HIV/ART clinic for children n Close down unauthorized labs, blood transfusion centers, clinics with infection control violations n Continue testing to identify scope of infected persons n Support country efforts to improve overall prevention and care 32 16
Summary: HIV epidemic in children globally n 160,000 new HIV infections in children in 2018 • Gaps in ART during pregnancy and increasingly during breast feeding • Outbreak in Pakistan is a wake-up call for another important transmission route often overlooked n 1.8 million children living with HIV, only 940,000 children accessing ART n In high burden countries children are 5% of HIV population but account for 15% of deaths n Gaps between adults and children are widening in prevention and treatment and need urgent attention 33 Story 6: From youngest to oldest 34 17
AR3 : How many persons over the age of 55 years are living with HIV in the United States? A. 100,000 B. 200,000 C. 300,000 D. 400,000 E. 500,000 35 Answer: 300,000 US HIV epidemic is aging 327,000 persons • over 55 yrs living with HIV Of these, 60% • have viral suppression Source: CDC 36 18
Aging and HIV: Equity or Disparity? n No 2 people age the same n Heterogeneity in prior exposures of HIV + persons n Gaps in knowledge on HIV and aging JIAS, 2019 37 Aging: Cancer Risk n Risk higher HIV+ vs HIV- after 50 years of age for anal, lung, liver, oral cancers n Acceleration in risk in general population after 60 years n What will be impact in HIV population? Mahale, CID, 2018 38 19
Aging: Cancer outcomes n Retrospective review U.S. Medicare database n 288 HIV+ (colon, lung, prostate, breast cancer) 307,890 HIV- n Overall mortality was higher among HIV infected vs uninfected persons n Cancer specific mortality higher for prostate and breast cancer n Relapse rates higher for prostate or breast cancer in the persons with HIV Coghill, JAMA Oncology, 2019 39 Aging: Long–term care n Considerations of prior history including “triggers” living with other ill persons n Stigma and discrimination from extended care providers and residents n Medical treatments that call for agents that may interact with HIV medications 40 20
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