04.10.20 | Updates in HIV Prevention from CROI 2020
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This document summarizes key information from an HIV & Global Health Rounds presentation on updates from the 2020 Conference on Retroviruses and Opportunistic Infections (CROI 2020). The presentation covered the global HIV epidemic, contraception and prevention, treatment as prevention, pre-exposure prophylaxis (PrEP), and HIV vaccines. Highlights included findings from the ECHO contraceptive study showing no increased HIV risk from various contraceptives, modest reductions in HIV incidence from universal test and treat trials, long-term efficacy and safety data from the DISCOVER PrEP trial, and the failure of the HVTN 702 vaccine trial to show efficacy.
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04.10.20 | Updates in HIV Prevention from CROI 2020
- 1. HIV & Global Health Rounds The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease and global public health clinicians, physicians, and researchers. The goal of these presentations is to provide the most current research, clinical practices, and trends in HIV, HBV, HCV, TB, and other infectious diseases of global significance. The slides from the HIV & Global Health Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
- 2. Updates in HIV Prevention from CROI 2020 Gabriel Wagner, MD Assistant Professor of Medicine Infectious Diseases & Global Public Health
- 4. Outline • Epidemiology • Contraception and Prevention • TasP • PrEP • Vaccines
- 5. Outline • Epidemiology • Contraception and Prevention • TasP • PrEP • Vaccines
- 6. Summary of the global HIV epidemic (2018) Source: UNAIDS/WHO estimates 0.8millionHIV-related deaths [0.6 million –1.1 million] 1.7million people newly infected [1.4 million – 2.3 million] 37.9million people living with HIV [32.7 million – 44.0 million] 2018 Falls short of the UNAIDS goal of <500,000 by 2020
- 7. Source: UNAIDS special analysis, 2019 Sex workers 6% People who inject drugs 12% Gay men and other men who have sex with men 17% Transgender women 1% Clients of sex workers and sex partners of other key populations 18% Remaining population 46% Distribution of new HIV infections by key population (2018)
- 8. HIV prevalence and risk among Zimbabwean male, transfemale, and transmale sex workers was high Hontelez, CROI 2020
- 9. Factors associated with HIV, HCV, HSV-2 among TW in US (n=551) • Prevalence of HIV, HSV-2, and HCV were 29%, 48%, and 5%. • Higher burden of disease among Black TW • Disease burden increased with age Keruly, CROI 2020
- 10. HIV Screening and Prevalence among TG Men Radix, CROI 2020
- 11. Outline • Epidemiology • Contraception and Prevention • TasP • PrEP • Vaccines
- 12. Contraception and Prevention: Prior Evidence • Some, but not all studies showed that progestin-only injectables (esp DMPA-IM) were linked to increased HIV risk – In meta-analyses, the magnitude was 40-50% (i.e., hazard ratios of 1.4-1.5) Polis et al. AIDS 2016
- 14. HIV incidence 4% infections per year ~400 women infected Ahmed et al. Lancet 2019
- 15. Contraception and HIV Risk Post-ECHO • Why ECHO data were different and surprising: 1. Randomized design alleviated imbalances in condom use 2. Contraceptives are not inert; but biologic changes elicited by DMPA- IM, copper IUD, and LNG implant did not impact HIV susceptibility 3. In face of a stable HIV epidemic among women, contraceptives are not driver of substantial HIV risk • Time to pivot to address problems of access to wide variety of contraceptives and HIV prevention Heffron, CROI 2020
- 16. Outline • Epidemiology • Contraception and Prevention • TasP • PrEP • Vaccines
- 18. Potential Epidemic Impact of ART Scale-Up Grannich et al. Lancet 2009
- 19. Four Universal Test and Treat (UTT) Trials • Started in 2012 and 2013 • Varied by context, design, intervention package, data and outcomes, adaptations • All assessed impact of UTT on HIV incidence Perriat et al. JIAS 2018 De Cock, CROI 2020
- 20. HIV Incidence from Four UTT Trials, 2019 Karim SSA, NEJM 2019
- 21. UTT Trials and the “Three 90s” “First 90” “Third 90” “Second 90” Havlir, HIAS 2020
- 22. Reasons for modest HIV incidence reductions in UTT trials • Substantial intervention in control condition – Increased HIV testing through campaigns – Changing standard of care • Difficulty reaching sub-populations who contribute to transmission – Less testing and treatment in young men – Poor linkage to care in some communities – Delayed linkage to care allows for transmission during early infection • Infections occurring from outside the community • May need contribution of primary prevention to maximize effect Buchbinder, CROI 2020
- 23. Outline • Epidemiology • Contraception and Prevention • TasP • PrEP • Vaccines
- 24. DISCOVER Trial Recap from CROI 2019 Hare, CROI 2019
- 25. Hare, CROI 2019
- 26. Longer Term Efficacy and Safety of F/TAF and F/TDF for HIV PrEP: DISCOVER Trial Week 96 Results
- 35. HIV incidence among Black and Hispanic/Latinx DISCOVER Participants • Of 11 infections in Black or Hispanic/Latinx participants, 2 had suspected prebaseline infections • Remaining 9 participants had low or undetectable DBS drug levels at diagnosis DeJesus, CROI 2020
- 36. DBS Adherence among Black and Hispanic/Latinx DISCOVER Participants • Adherence was high in all groups; however, more black participants had medium or low adherence vs nonblack participants • Odds ratio (95% CI) for low adherence: 2.37 (1.17, 4.79) for black vs nonblack and 1.53 (0.89, 2.66) for H/Lx vs non- H/Lx DeJesus, CROI 2020
- 37. PrEP persistence is poor in multiple populations • Multiple studies of MSM in the US show PrEP drop-off of 1/3 to 2/3 of the population by 6- 12 months – Worse in young, rural, people of color, and women • Multiple studies of women in sub-Saharan Africa show equal or poorer persistence – Better for women in serodiscordant couples Krakower JIAS 2019; Chan JIAS 2016; Van Epps JAIDS 2018; Rusie CID 2018; Blackstock AIDS Care 2017; Zucker JAIDS 2019; Dombrowski STD 2018; Spinelli OFID 2019; Serota CID 2019; Celum IAS 2019; Pyra JAIDS 2018; Huang CID 2020
- 38. PrEP Access: Disparity in Prior Authorizations Across US Regions • Compared to QHPs in the Northeast, QHPs in the South were 15.9 (95% CI: 12.6-20.1) times as likely to require prior auth for TDF/FTC (Figure 1). • Within the South, Texas, Florida, Georgia, Mississippi, and Arkansas have highest rates of prior auth (Figure 2). McManus, CROI 2020
- 39. Choice matters: no one size fits all • WHO systematic review (231 articles) showed increased choice was associated with: – Increased contraceptive uptake – Increased persistence on chosen method – Better health outcomes • 12% increase in contraceptive prevalence for each additional method • PrEP options are similar to contraceptive needs: different people have different prevention needs at different times Gray et al. RHRU 2006; Jain AK Stud Fam Planning 1989 Buchbinder, CROI 2020
- 42. MB66 Anti-HIV and Anti-HSV Film • Novel film contains anti-HIV-1 (VRC01) and anti-HSV2 (HSV8) mAbs • Phase I clinical trial to assess safety, PK and ex vivo efficacy of repeated doses of MB66 film delivered vaginally. Cu-Uvin, CROI 2020
- 43. Cu-Uvin, CROI 2020 • 29 women enrolled: 15 allocated to active film and 14 to placebo film • Concentrations of VRC01 and HSV8 mAbs increased significantly in vaginal secretions following insertion of active film, peaking at one hour and remaining elevated 24h post-insertion
- 44. Development of a Real-Time Urine Tenofovir Test Spinelli, CROI 2020
- 45. Real-Time Urine Tenofovir Test is Highly Accurate Spinelli, CROI 2020
- 46. Outline • Epidemiology • Contraception and Prevention • TasP • PrEP • Vaccines
- 47. HVTN 702 (Uhambo) Vaccine Trial • Late-breaking update from the HVTN 702 vaccine trial
- 48. HVTN 702 (Uhambo) Vaccine Trial • Late-breaking update from the HVTN 702 vaccine trial –No efficacy observed
- 49. Background for HVTN 702: RV144 (Thai) Vaccine Trial • Prime: ALVAC vCP1521 • Boost: ALVAC vCP1521 plus VAXGEN Env protein (B/E) • Schedule: 0,1,3,6 months – 16,000+ volunteers – 1:1 vaccine; placebo – Follow up for 3 years Rerks-Ngarm et al. NEJM 2009 31% reduction at study end 60% reduction at 1 year
- 50. Background for HVTN 702: RV144 (Thai) Vaccine Trial Corey et al. Sci Transl Med 2009 Goal: develop a new ALVAC/gp120 regimen to increase subtype C coverage, improve Ab durability, and test if V1V2 IgG is correlate of risk and efficacy
- 51. HVTN 702 Schema: 5400 South Africans (18-35 yrs) Group N* Primary Vaccine Regimen Boosters Month 0 Month 1 Month 3 Month 6 Month 12 Month 18 1 2700 ALVAC-HIV (vCP2438) ALVAC-HIV (vCP2438) ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 2 2700 Placebo Placebo Placebo + Placebo Placebo + Placebo Placebo + Placebo Placebo + Placebo Total 5400 Corey, CROI 2020
- 52. January 2020: Interim Analysis • Criteria for non-efficacy met • N = 5383 MITT participants; 2689 placebo, 2694 vaccine • Median of 18 months follow-up – 77% of total PYs of follow-up between entry and Month 24 completed – 62.1% of participants reached Month 18.5 (2 weeks post-last vaccination)
- 53. Cumulative incidence of HIV-1 infection Months 0-24 Months 0-36 Gray, CROI 2020
- 54. Pre-Specified Vaccine Efficacy Subgroup Analysis • Assess Month 0-24 vaccine efficacy by sex at birth • Assess Month 0-24 vaccine efficacy among women by age • Assess Vaccine Efficacy in women by region • Assess Vaccine Efficacy by risk score Gray, CROI 2020
- 55. Cumulative incidence of HIV-1 infection Months 0-24 by Sex at Birth Gray, CROI 2020
- 56. Vaccine Effect on HIV Acquisition by Sex at Birth, Months 0-24* Gray, CROI 2020
- 57. Possible Explanations for Lack of Efficacy in HVTN 702 • Immunogenicity and Boosting: differences in immunogenicity, attributable to differences in ALVAC, protein, dose, and/or adjuvant • Viral genetics: probable higher genetic diversity and higher likelihood for vaccine sequence mismatch relative to circulating strains • Host genetics: different Fcγ receptor and HLA genetics vs RV144 • Host factors: potential differences in pre-existing immunity, mucosal inflammation, microbiome, etc. • HIV exposure: more frequent, possibly higher-level to HIV in RSA Corey, CROI 2020
- 58. Other Ongoing Vaccine Efficacy Trials • AMP Study: phase 2b evaluating safety of efficacy of passively administered VRC01 – 1900 women in sub-Saharan Africa • HVTN 705: phase 2b efficacy study of Ad26 vector prime / gp140 protein boost – 2600 women in sub-Saharan Africa • HVTN 706: phase 3 efficacy study of Ad26 vector prime / gp140 protein boost – 3800 MSM and trans persons • Galit Alter: “must remain optimistic and tenacious in the pursuit of a globally relevant HIV vaccine” CROI 2020
- 59. Combining Prevention Methods Reduces Greatest Number of New HIV Infections Harmon, PLOS One 2016 Buchbinder, CROI 2020 29% 34% 78% 91%
- 60. Acknowledgments Mentors Susan Little Davey Smith Slides CROI (Susan Buchbinder) Funding National Institutes of Health
- 61. Two Efficacy Trials of CAB-LA for PrEP • HPTN 083 for MSM/TGW globally • HPTN 084 for women in sub-Saharan Africa • Both have 3 steps: 1. Oral lead-in 2. Loading at 0 and 4 weeks, q8 week injections 3. Oral to cover the PK tail for 1 year • Both trials are using TDF/FTC as comparator • Both currently enrolling • Results expected 2021 Buchbinder, Workshop W-01, CROI 2020
- 62. Background for HVTN 702: Immune Correlates of the RV144 (Thai) Vaccine Trial • Functional non-neutralizing antibodies and CD4+ T-cell responses to Env were correlated with protection Haynes et al. NEJM 2012
- 63. FTC/TDF for PrEP available since 2012
- 64. DISCOVER: Week 96 Conclusions • F/TAF remained non-inferior to F/TDF • BMD declines >3% more common with F/TDF • Renal biomarker changes remained more favorable with F/TAF • F/TDF associated with greater declines in LDL and HDL but total cholesterol:HDL ratios or FG remained similar • Weight gain observed in both arms, 1kg greater in F/TAF • HIV incidence rate was low among Black and Hispanic/Latinx participants, and similar between the F/TAF and F/TDF arms • Adherence was high in all groups; however, more Black participants had medium or low adherence vs non-Black participants
- 66. Source: UNAIDS special analysis, 2019 Key populations and their sexual partners account for: 99% of new HIV infections Globally (2018) 95% 25% of new HIV infections in Eastern Europe and Central Asia of new HIV infections in Middle East and North Africa of new HIV infections in Eastern and Southern Africa 54%
Editor's Notes
- In 2018 for the first time, key populations make up a majority of new infections. Key populations include (the pie chart).
- Centre for Sexual Health and HIV/AIDS Research Zimbabwe Outreach intervention: peer educator 603 male and transgender sex workers Data compared to program data from 12k female sex workers.
- Serum samples collected from 551 TW residing in Boston, NY, Baltimore, Washington DC, Atlanta, and Miami from March 2018 to March 2019. Participants also had collected sociodemographic, behavioral, and SE data.
- 577 patients of the Callen-Lorde Community Health Clinic in NYC 14%AA, 55%W Significant heterogeneity of HIV risk among TG men HIV prevalence was 11.1% among transmasculine people having sex with cisgender men only. Studies investigating HIV prevalence in TG populations should investigate behavioral risk as well as gender identity TG men need to be included in HIV prevention efforts
- Forest plot from a 2016 systematic review.
- Rates of HIV acquisition were not different in the three arms of the study. So DMPA did not increase risk for HIV. Unfortunately incidence rate was quite high.
- If you live with HIV and have been undetectable on tx for at least 6 months, no risk of transmitting HIV to sexual partner. We know that U=U works at the individual level, but the question was, would universal treatment work at the population level?
- Lancet paper in 2009 suggested that universal HIV testing with immediate ART would eventually eliminate a hypothetical HIV epidemic with South African severity.
- Four trials were conducted between 2012 and 2017: Ya Tsie in Botswana, PopART in South Africa + Zambia, TasP in South Africa, and SEARCH in Kenya and Uganda.
- UNAIDS Fast-Track Targets: By 2020, 90% of positive diagnosed, 90% of those on ART, and 90% of those suppressed. 90-90-90- estimates by individual trial. Baseline, light green; end of study, dark green. First 90 target was achieved across the board. For the second 90, TasP suffered from poor linkage but the other studies achieved 88-97% uptake of ART. For the third 90, viral suppression, ranged from 87-97%. So three of the four studies achieved the 90-90-90 UNAIDS Fast-Track targets.
- The DISCOVER trial was presented last year at CROI. F/TAF compared to F/TDF in MSM and TGW. The interim analysis was presented last year when 100% participants completed Week 48 and 50% participants completed Week 96.
- 22 infections over 8000 PY of f/u. On the left we can see that 7 infections occurred in the F/TAF arm in green and 15 infections in the F/TDF arm in gray. This translates to an incidence rate of 0.16 in F/TDF and 0.34 in F/TAF. In the right panel is the Incidence Rate Ratio of 0.47 is shown with a 95% CI that is below the pre-specified 1.62 cutoff. Thus F/TAF was non-inferior to F/TDF for use as PrEP. Both drugs were well tolerated with low rates of AE. F/TAF had significantly better bone and renal safety outcomes vs F/TDF.
- At Week 96 only one additional infection in the F/TAF. MSM with poor adherence to drug (drug levels in PBMC below limit of detection).
- Incidence Rate Ratio 0.54. Again CI fits squarely within the NI margin. Confirms non-inferiority of F/TAF to F/TDF.
- BMD substudy on 375. DEXA scans at baseline and Weeks 48 and 96. Both figures show that for F/TAF users experienced increases in BMD as opposed to F/TDF who experienced declines. Reported fracture events were the same in both arms. These differences were more pronounced in younger participants <25y in a subanalysis.
- Plot on left shows trajectories of change in GFR over time. At Week 48 median GFR in F/TAF users increased by 1.8, but decreased by 2.3 in F/TDF. Separation persisted at Week 96 with F/TAF experiencing a slight decline and F/TDF a larger decline. Biomarkers of proximal tubular injury. Elevated in F/TDF users while remaining unchanged or decrased in F/TAF users. One patient in F/TDF arm had Fanconi syndrome. Subanalysis was done stratified by age >50 and above and similar observations
- F/TDF was associated with greater declines in total cholesterol, LDL, and HDL but TotalCholesterol:HDL ratios or fasting glucose remained similar across both study arms at Week 96.
- Weight gain was observed in both arms at. 96 weeks and was approximately 1kg greater in the F/TAF arm. Weight gain with F/TAF was similar to that observed in the placebo arm of iPrEx trial and the general population.
- Subanalysis done among Black and Hispanic/Latinx participants through Week 96. Included ~240 Black in each arm and ~630-680 H/Lx in each arm. Incidence rate was low overall among Black and Hispanic/Latinx DISCOVER participants, and similar between the F/TAF and F/TDF arms. Higher incidence of HIV among Blacks vs NonBlack in both arms; difference among H/Lx were minute.
- Subanalysis done among Black and Hispanic/Latinx participants through Week 96. Included ~240 Black in each arm and ~630-680 H/Lx in each arm. Higher incidence of HIV among Blacks vs NonBlack in both arms; difference among H/Lx were minute.
- Figure 3. Kaplan-Meier curves of percentage of Medicaid patients aged 18–64 years using human immunodeficiency virus pre-exposure prophylaxis (PrEP) who persisted with PrEP, by race, 2012–2017. Unless provided in the caption above, the following copyright applies to the content of this slide: Published by Oxford University Press for the Infectious Diseases Society of America 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.This work is written by (a) US Government employee(s) and is in the public domain in the US.
- Due to the United States Preventive Services Task Force issuing PrEP with a Grade A rating, QHPs must start offering PrEP without cost-sharing in 2021. However, there is limited regulation on QHPs’ use of prior authorization. Federal or state-level health policy laws may be necessary to address this system-level barrier to maximize the impact of PrEP on ending the HIV epidemic in the US.
- From contraceptive literature: choice matters.
- Islatravir is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI). It has multiple mechanisms of action that contribute to high potency against HIV variants and high barrier to resistance.
- 12 Indian rhesus macaques: 6 treated with ISL, 6 untreated controls. All challenged with SIVmac IV. A single ISL dose 24h after challenge prevented infection in 4/6 macaques. Results support potential utility as PEP in humans, although feasibility of clinical trial is challenging.
- 29 women enrolled: 15 allocated to active film and 14 to placebo film. Repeated dose vaginal application of the MB66 film was safe and well tolerated Signifiant film dissolution after one hour Ex-vivo: significant neutralization of all 3 HIV strains AND HSV-2, 24h after multiple film insertion.
- Team previously isolated antibodies that were highly selective for TFV derivatives. Developed LFA. Adherence measured over 4-7 days (recent exposure). Advantage over traditional PrEP drug measurement: cheaper, does not require trained personnel, no sample processing or shipping time.
- 684 samples from 324 participants from Partners PrEP and IBrEATHe studies LFA compared to ELISA with a lower limit of detection of 1000ng/ml
- The RV144 trial evaluated a combination of two vaccines: a replication-defective canarypox vector (ALVAC) plus a recombinant gp120 protein (AIDSVAX). Study conducted in 16k Thai men and women and led to a 31% in HIV acquisition at end of study. But there was a 60% reduction in HIV acquisition at 1 year which was when the immune response was sooner after the peak of immune response.
- Waning efficacy over time was associated with waning immune responses. Hence the hypothesis that improving the durability and the level of the immune responses could be associated with higher vaccine efficacy.
- Global initiatives were geared towards extending the RV144 concept into the Clade C regions of the world. Manufacture a new vaccine regimen based upon the ALVAC vector and the gp120 booster but one that could be designed to tackle the clade C epidemic and improve on the immunogenicity of the RV144 design.
- Kaplan Meier curves do not separate. Even in the later parts of study follow up.
- Vaccine team will be evaluating vaccine efficacy by all of these factors.
- Among women 109 infections occurred in the placebo arm and 115 in the vaccine arm. In men, the numbers in both arms were the same. Receipt of vaccinations were in the 80s%
- Unique qualities of ad26 vector prime, gp120 boost: Mosaic insert (includes HIV sequences from around the world) 92% coverage Protection in non-human primate (NHP) studies 94% protection against each intra-reactal challenge 67% complete protection against 6 intra-rectal challenges Durable immune response Early stage trials suggest higher immune response in humans than in NHPs Durable responses last at high levels at least 2 years
- To close, modeling study that addresses why we need multiple modes of prevention strategies. If you were to add either TasP or PrEP/microbicides to standard prevention methods, you would get about 29-34% additional reduction in HIV incidence. If you were to develop an HIV vaccine even if it was partially effective it would reduce 78% infections. If you were to combine all of the above you would get 91% reduction. Choices are important.
- The RV144 trial evaluated a combination of two vaccines in 16k Thai men and women and led to a 31% in HIV acquisition at end of study. But there was a 60% reduction in HIV acquisition at 1 year which was when the immune response was at a peak level with regards the immune correlates of protection.
- FTC/TDF available since 2012 when the US FDA licensed it and WHO came out with guidance regarding use of PrEP
- Comparison graph of F/TDF vs F/TAF. Both highly effective for MSM and TGW. Only F/TDF has been tested for heterosexuals and PWID. Small safety improvement in renal and bone toxicity for F/TAF and small iimprovement in LDL and body changes for F/TDF. Both are relatively similar for many people in population, F/TDF is more universal and F/TAF if worried about toxicities.