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  IAS 2019: Conference on HIV Pathogenesis
Treatment and Prevention
Mexico City
July 21-24 2019
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HIV Prevention at IAS 2019 10th IAS Conference on HIV Science, Mexico City, Mexico 21-24 July 2019
 
 
  Jared Baeten, MD PhD
Connie Celum, MD MPH
University of Washington
 
This year's IAS Conference on HIV Science - the smaller meeting that alternates years with the large international meeting on HIV/AIDS, held last year in Amsterdam and scheduled for next July in San Francisco and Oakland - was held in fabulous Mexico City this year. This year's meeting brought together laboratory science, clinical advancement, epidemiology and prevention, and implementation science, along with policy and advocacy to address the big issues in HIV science. As has been the case at recent meetings, including those hosted by the IAS, much of the scientific program is available online, including abstracts, copies of slides, and webcasts of sessions (searchable program available at http://programme.ias2019.org/Programme/Programme). There were fantastic prevention sessions at this year's meeting, with robust science, exciting symposia, enlightening plenaries, and great new breakthroughs. The use of antiretrovirals - as treatment (ART) for persons living with HIV, resulting in tremendous prevention benefits, and as pre-exposure prophylaxis (PrEP) for HIV uninfected persons - continues to dominate prevention conversations. Other prevention interventions too are being delivered, in synergy with antiretroviral-based strategies, with opportunity still for more impact.
 
Plenary talks related to prevention included ones on treatment scale-up and barriers to treatment ( http://programme.ias2019.org/Programme/Session/9 &
http://programme.ias2019.org/Programme/Session/1)
, PrEP implementation for transgender people (http://programme.ias2019.org/Programme/Session/9), young men who have sex with men (MSM) in Latin America (
http://programme.ias2019.org/Programme/Session/1, and sustainable financing for the global HIV response
(http://programme.ias2019.org/Programme/Session/10).
 
There were many great symposia related to prevention, including related to:
 
• new prevention products (http://programme.ias2019.org/Programme/Session/5)
 
• substance use among young people (http://programme.ias2019.org/Programme/Session/19)
 
• indigenous populations (http://programme.ias2019.org/Programme/Session/147)
 
• community-researcher relationships (http://programme.ias2019.org/Programme/Session/18)
 
• pondering partially-effective vaccines (http://programme.ias2019.org/Programme/Session/165)
 
• HIV testing in the PrEP era (http://programme.ias2019.org/Programme/Session/8)
 
• next-generation PrEP trial design (http://programme.ias2019.org/Programme/Session/11)
 
• gender-transformative HIV response (http://programme.ias2019.org/Programme/Session/30)
 
• prevention cascades (http://programme.ias2019.org/Programme/Session/16)
 
• sexual and reproductive health (http://programme.ias2019.org/Programme/Session/7)
 
• prevention for youth (http://programme.ias2019.org/Programme/Session/31)
 
• HIV outbreak response (http://programme.ias2019.org/Programme/Session/171)
 
• political will get to zero (http://programme.ias2019.org/Programme/Session/3)
 
• implementation science (http://programme.ias2019.org/Programme/Session/146
)
 
These are all worth watching.
 
HIV testing
 
HIV testing is the starting point for treatment and prevention. Tremendous innovations in the delivery of HIV testing - into people's own hands, out of clinics, specifically for persons who otherwise maybe unengaged by health systems, and within partnerships - were reported at this year's meeting.
 
There was great focus on HIV self-testing (HIVST) as a strategy to reach the first 90 in the UNAIDS 90:90:90 targets. Three late breakers reported on innovations related to HIVST.
 
First, from South Africa (abstract LBPEC27, http://programme.ias2019.org/Abstract/Abstract/5054, Majam), there was reported high rates of self-reporting of HIVST results and linkage to care through an interactive voice response telephone line in inner city Johannesburg. The investigators used behavioral economics principles to assess whether SMS reminders and interactive voice response hotline aided reporting of HIVST use and linkage to care. Over 10,000 HIVSTs were distributed between October 2018 and February 2019 and recipients were encouraged to contact a hotline or access a website to report HIVST results; they received two SMS messages, three days and five days after receiving the test. On the seventh day after receiving a kit, all participants who had not reported HIVST use received an automated phone call with a recorded survey. A total of 9,504 unique phone numbers were registered, of whom 5,056 belonged to men (53%). In total, 1,933 (20.3%) respondents reported their test result, and 313 (16%) reported a positive HIVST, of whom 204 (65%) reported that they had or intended to link to care. Median willingness to pay for a HIVST was ZAR50 ($3.47). Given that SMS and recorded hotlines are low-cost, they could be easily integrated into larger implementation programs. The HIVST program was successful in reaching men and young people.
 
Second, from Lesotho, oral HIVST was offered to individuals absent or refusing testing during home-based HIV testing in a cluster-randomized trial (abstract LBPED34, http://programme.ias2019.org/Abstract/Abstract/4982, Glass). The trial (HOme-based SElf-testiNG = HOSENG trial) measured the effect of secondary distribution of oral HIV self-tests (HIVST) on coverage during home-based testing. Clusters were defined as villages in the catchment area of 20 health facilities and were randomized to intervention (HIVST left for household members who were absent or declined testing) or control. The primary outcome was HIV testing coverage (aged ≥12 years) within 120 days after home-based testing, defined as a confirmed HIV test result, known HIV+, or recent HIV- result. In 3110 consenting households, 7846 persons aged ≥12 years were enrolled (intervention: 57 clusters, 1628 households, 4192 household members; control: 49, 1478, 3654). Of those with unconfirmed status, 1278/1382 (92%) household members in the intervention arm and 1118/1224 (91%) of control arm accepted testing. The coverage of testing after the home visits was 63% in the intervention and 60% control arm (p=0.17). Thereafter, in the intervention arm, a HIVST was left for 1463 (77%), and 824 (56%) were returned within 120 days. In control arm, 1695 HM were absent (93%) or refused testing (7%) and 12 (0.7%) were tested at the facility within 120 days. Together then, HIV testing coverage was 3372/4188 (81%) in the intervention versus 2187/3654 (60%) in the control arm (odds ratio [OR] 2.9, 95% confidence interval [CI] 2.5-3.5, p< 0.001). The intervention effect was greater in males (74% vs 44%; OR 4.2, 95% CI 3.3-5.2) than females (86% vs 73%; OR 2.4, 95% CI 1.9-3.0, p-interaction<0.001) and in adolescents (75% vs 38%; OR 5.6, 95% CI 4.4-7.1) than adults (84% vs 71%; OR 2.2, 95% CI 1.8-2.7, p-interaction<0.001). The HIV positivity rate was 3% during home visits and 0.4% with HIVST. Thus, secondary distribution of HIVST achieved an increased HIV testing coverage of >20%, and the intervention was particularly successful among males and adolescents.
 
Third, again from South Africa (abstract LBPED37, http://programme.ias2019.org/Abstract/Abstract/4837, Shamu), the acceptability, feasibility, and motivations for HIVST among young people were assessed in a demonstration community-based study. Given the need for high acceptability of HIVST to reach high coverage rates, they assessed acceptability and feasibility of HIVST in general as well as choice of and motivation for self-testing by kit type (blood-based or oral-swab). The population was 440 HIV-negative young people (aged 18-24 years) in a household demonstration study, of whom, 98.6% accepted to conduct HIV self-testing while 1.4% opted for the standard of care testing by a counsellor. Two-percent tested positive. Reasons for self-testing were trying a new method (36.7%), knowing HIV status (34.7%), preference for privacy and wanting to know results first (11% each). More than four in five (81%) reported never seeing an HIV self-test kit before. The two types of test kits were approximately equivalently preferred: blood-based kit (51.7%) vs. oral test kit (48.3%). More blood-based kit users than oral-based kit users reported difficulties in reading instructions (11.6% vs 4.6% p=0.015), following instructions (10.6% vs 4.6%; p=0.03) and interpreting results (8.7% vs 2.9%; p=0.02). Choice of test kit did not differ by gender, age, education, class and marital status, and differences were not significant related to history of transactional sex, multiple sexual partnerships, STIs, or HIV testing. Choice of test kit did not differ by whether a participant tested with supervision (63.3%), without supervision (24.6%) or with partial supervision (12.1%) (p=0.988). Although 93.8% would recommend the kit to others, no differences were observed by test kit (p=0.171). Common self-testing concerns were unavailability of counsellors to guide (24.8%), counsel (29.1%) and interpret results (14.8%). Thus, HIVST was highly acceptable and there were no socio-demographic characteristics and sexual behaviors that were associated with the choice of self-test kit but the blood-based kit appeared more difficult to use.
 
An excellent oral abstract session entitled "Self-testing: Going the final mile" (http://programme.ias2019.org/Programme/Session/84) was held on Wednesday, which included presentations about innovations in HIVST delivery to reach men and key populations to learn their HIV status and to improve linkage to care. One presentation (abstract WEAC0201, Mee) reported on whether use of HIV self-testing kits leads to unintended effects in a program of peer-based HIVST services for female sex workers (FSWs) in Malawi. Between March and September 2017, FSWs were recruited by the peer-educators and given up to 2 HIVST kits, with interviews at recruitment and 3 months, including questions on coerced HIVST use or results disclosure, intimate partner violence (IPV), regrets about taking the HIVST and relationship problems. Of 131 SWs who completed both interviews and reported having used the HIVST, 18% were first-time testers. 13% reported that HIVST had been initiated by themselves. 23% reported being pressured to HIVST or to share results (primarily by peer distributors). Immediate regrets about HIVST were expressed by 16%. High rates of IPV in the previous 3-months were reported (48% at enrolment and 31% at 3-months). Thus, introducing HIVST through peer-distributors in Malawi led to frequent experiences of FSWs feeling pressured into testing and sharing results, and frequent expression of regrets and relationship difficulties. Background rates of IPV were high. Care needs to be taken when introducing HIVST to ensure uptake is voluntary. Alternative strategies to the use of peer-distributors among FSW should be explored.
 
A second presentation (abstract WEAC0202, Shapiro) focused on closing the testing gap among men and demonstrated high uptake of HIV self-testing in rural and peri-urban KwaZulu-Natal, South Africa through an implementation study of multi-venue HIVST kit distribution (community points, workplace, and social venues) for either on-site or take-home use. Clients could choose blood or oral fluid tests and elect to watch an in-person or video demonstration, and were provided a $2 incentive to facilitate reporting test results by phone or SMS. Between July-November 2018, a total of 4355 HIVST kits were distributed: 96% to men with a median age of 28. 57% chose blood-based HIVST and 43% chose oral-swab kits; 48% used the kit at home. 11% of men were testing for the first time and 40% had last tested more than 12 months earlier. 62% of testers reported their test result to the study team, of whom 244 (9%) screened positive. 25% of testers reported receiving assistance using the kit. 10% of kit users reported they would have preferred oral vs blood HVST. This study demonstrated that HIVST is acceptable to men and rapid distribution is feasible (>1000 kits distributed per month), that a choice of blood-based and oral HIVST responded to different preferences, reached younger men and identified otherwise-undetected infections among men in South Africa.
 
Another presentation (abstract WEAC0203, Gashobotse) reported on peer-mobilized HIVST to increase case detection and linkage to ART among key populations in Burundi, using peers to reach others in their social and sexual networks to be tested for HIV through HIVST. In a 6 month pilot, 1,606 test kits were used by 1,375 FSWs and 231 MSM, of whom 264 screened positive (16%: 227 FSWs, 37 MSM) and 216 (13%) were confirmed HIV positive and 93% were initiated on ART. HIV case identification rates were significantly higher among HIVST compared to other testing modalities (FSWs OR=1.6 and MSM OR = 5.6). These results are encouraging in terms of HIVST to identify FSWs and MSM living with HIV and linking them to ART.
 
From Vietnam (abstract WEAC0204, Nguyen) a study of community-led HIVST was reported, which successfully reached key populations (KP) and their partners. Between January and November 2018, KP and their partners were offered HIVST by peer-educators at drop-in houses or coffee shops and given the choice to test with or without assistance. Community-led outreach and social networks (MSM dating apps, Facebook) were used to promote HIVST and follow-up with self-testers. Of 4014 who were contacted, 50% opted for HIVST, 81% of whom were first-time testers, and 5% were confirmed HIV positive, of whom 98% initiated ART. The greatest proportion of self-testers were MSM (76%) and young (aged ≤25) (69%). 66% chose assisted HIVST. Thus, community-led HIVST with and without assistance successfully reached KP and their partners; including those never tested and undiagnosed HIV.
 
From China (abstract WEAC0205, Wu), a program assessment of social-media based secondary distribution of HIVST among Chinese MSM was reported. Banner ads on a social media platform invited MSM to apply for up to five kits per three-month period. Test kits could be mailed to the applicant under a pseudonym, and MSM were incentivized (about $14.70) if they provided a photograph of the results. They were encouraged to not only use the kits for self-testing but also to distribute the remainder to partners or friends (referred to as "alters"). Between June and December 2018, 427 men applied for 759 kits and 586 valid results were returned: 74% from 340 index men and 26% were from 137 alters. Compared to index MSM, a higher rate of alters never tested for HIV (41% vs. 20%). In total, 12 individuals were found to be HIV positive, with the rate being significantly higher in alters than among indexes (8.0% vs. 0.3%) Thus, integrating social media with secondary distribution of HIVST kits may hold promise to increase HIV testing coverage and case identification among MSM.
 
Other interesting and innovative approaches to use of HIVST for case identification included a presentation about a demonstration project of HIV self-testing among men who purchase sex in Indonesia (abstract TUPEC454, http://programme.ias2019.org/Abstract/Abstract/2656, Wulandari). Men attending seven brothels in Bali were invited to a general health survey, and once they completed the survey, were offered a HIVST. In accepting the test, men could opt to conduct their test off-site or on-site at the brothel (with partial or full supervision). In total, 292 men completed the health survey, only 13% reported a HIV test in the past and overall 65% agreed to have a HIVST, almost all of whom requested to have on-site, most with full supervision including when reading their results. Of the HIVST done, 4 men (2.1%) had a reactive result. 75% of those who completed the follow up survey said there was nothing they did not like about the test; and 78% trusted the result. This study among men who purchase sex involving HIVST distributed by lay workers in brothels showed HIVST was acceptable and increased HIV testing rates by more than 5 times compared to baseline levels. From Kenya (abstract TUPEC458, http://programme.ias2019.org/Abstract/Abstract/1385, Napierala) there was a report on secondary distribution of HIVST by high-risk women. Results were 6-month follow-up data from the intervention arm of an ongoing randomized trial in 66 community clusters in Siaya County, Kenya. Participants received 5 oral fluid-based self-tests at enrollment and additional self-tests, as needed, at 3-month intervals. Follow-up data were collected at 6 months on overall self-test distribution to sexual partners, partner test results, and general changes in sexual behavior. Participants also reported specifically on self-test distribution and sexual behavior in their 3 most recent transactional sex encounters. Among 1,063 participants in the intervention arm, the average age was 27 years and 71% reported sex work as an income source. Over 6 months, participants on average received 8 self-tests and distributed 3.7 to sexual partners. 128 partners had reactive self-tests a rate of HIV-positivity of 5.3%. Among all participants, 13% declined to have sex and 11% used a condom with at least one partner who self-tested HIV-positive or refused self-testing. In 1,375 transactional sex encounters, 67% included an offer of an HIVST to the partner, and HIV status was ascertained in 96% of encounters where partners accepted HIVST. Condom use was significantly higher with transactional partners who obtained an HIV-positive versus HIV-negative result (89% vs. 59%) or versus those who refused to self-test (80% vs. 59%). Thus, providing high-risk women with multiple self-tests facilitated partner testing and accompanying preventive behaviors. Finally, a mathematical modeling analysis (abstract TUPEC452, http://programme.ias2019.org/Abstract/Abstract/3459, Sibanda) assessed secondary distribution of HIVST kits to male partners of female sex workers. Simulating >900 setting-scenarios for adult HIV epidemics and care programs typical of southern Africa using a dynamic-transmission model, and comparing outcomes under continuation of current testing policy to those obtained by also providing HIVSTs to HIV-negative FSW to distribute to their partners, they assessed the epidemiological impact and cost/DALY averted. They assumed that ∼90% of FSW would participate, that of these 70% will distribute HIVSTs to their partners, that 80% of partners-of-sex-workers testing positive with an HIVST would have confirmatory testing by a health care worker (HCW) within 1 year. Their model indicates that the secondary distribution intervention would increase demand for HCW HIV tests by partners-of-sex-workers from ∼10,000 to ∼17,000 tests/year and HIV-positivity among all HCW tests from 31% to 54%, would increase the proportion of partners-of-sex-workers diagnosed from 40% to 68%, and would avert ∼2000 HIV infections/year (3% of all new infections). Assuming a cost/partner-of-sex-worker HIV self-tested of US$5, the estimated ICER was US$164/DALY averted.
 
Additional work on partner testing from Uganda (abstract TUPEC470, http://programme.ias2019.org/Abstract/Abstract/1525, Geoffrey) reported on index partner testing using assisted partner notification (APN). Uganda adopted WHO's APN guidelines in 2017. A total of 73,846 index clients (59% females, 41% males) were eligible for APN; of these, 66% were interviewed, enlisting almost 63,000 sexual contacts in the last 12 months, 81% of whom were notified about their potential exposure to HIV and of these 69% were tested for HIV with 9,211 clients testing HIV positive - a yield of 27% (29% in females, 24% in males). Of the newly identified HIV positive, 91% were linked to care. Thus, APN is relatively high yield and effective in identifying undiagnosed persons with HIV. From Kenya (abstract WEPEB293, http://programme.ias2019.org/Abstract/Abstract/1229, Alons) there was reported innovations in index case contact testing to improve the identification of HIV-infected children and adolescents. Records of deceased index clients were reviewed to determine the eligibility of their children for HIV testing. Ministry of Health patient cards were used to obtain family contact information, and providers contacted them with an offer of HIV home-based testing, without disclosing the HIV status of the deceased family member. The resulting positivity rate was 3.2% among children aged 18 months-4 years, 3.7% among children 5-9 years, and 4.1% among adolescents 10-14 years. Comparatively, index case contact testing of those related to living, HIV-positive adults resulted in a positivity of 1.4% among 27,732 children tested aged 0-14 years.
 
ART for prevention
 
The prevention benefits of antiretroviral therapy (ART) are inarguable. Effective ART - i.e., sustained use that results in viral suppression - stops HIV transmission. At AIDS 2018, there was tremendous talk about the U=U campaign (Undetectable=Untransmittable, https://www.preventionaccess.org/) - i.e., a movement to state clearly that when persons living with HIV is on effective treatment, reducing levels of virus to undetectable, they are incapable of transmitting the virus to sexual partners. U=U is game changing - for reducing stigma, expanding and saving lives, and building enthusiasm for more treatment and prevention success. There was much U=U discussion still at IAS 2019, rightly so.
 
How to translate the individual prevention benefits HIV treatment to the population level has been the focus of discussions related to universal test and treat (UTT) in the past few years. Evaluation of the magnitude of the reduction in population HIV incidence by achieving high rates of HIV testing, linkage to ART, and viral suppression was the primary objective of four large UTT trials in Africa. The largest of these was PopART which presented their primary results at CROI 2019 and which were published at the same time as IAS 2019 (https://www.nejm.org/doi/full/10.1056/NEJMoa1814556). A special symposium at IAS 2019, "Towards zero new infections: Lessons learnt from the HPTN 071 (PopART) trial" (http://programme.ias2019.org/Programme/Session/41) presented analyses to understand that trial's findings. To review, the trial had three arms: Arm A = community health workers doing community-based testing and linkages to care with UTT regardless of CD4 (the full PopART intervention), Arm B = the PopART intervention with ART initiation that followed national ART guidelines (i.e., not all CD4 counts, at least for the first half of the study's follow-up period), and Arm C = standard of care for HIV testing and ART initiation. Approximately 1 million persons were estimated to live in the 21 South African and Zambian PopART communities, of which a population cohort of 52,500 persons ages 18-44 were followed annually for 3 years to directly measure HIV incidence. HIV incidence was reduced 7% in Arm A compared to Arm C and 30% in Arm B compared to Arm C. The investigators hypothesized that the reasons for these somewhat puzzling findings (i.e., bigger effect for the lesser intervention) could have been due to poorer delivery of the intervention in Arm A or sexual risk disinhibition in Arm A, higher migration or mobility in Arm A communities leading to contamination, or chance. Of these hypotheses all except for chance were rejected based on post-hoc analyses of differences between communities. Additional work on mathematically modeling the impact of the PopART intervention to help interpret the results of the trial and project longer-term impact were presented. An individual-based model parameterized demographics, sexual partnerships, HIV transmission in serodiscordant partnerships, disease progression and AIDS death, HIV testing, ART, voluntary medical male circumcision (VMMC, which was a minor part of the PopART study) and those cascades in the PopART communities, and the PopART intervention in the intervention communities. The model outputs included projected HIV prevalence, incidence, ART coverage and transmission networks. The model was run before PopART unblinding and post-unblinding, and it projected from the HIV incidence cohort to the whole population in the PopART communities, and projected the impact from 2020 to 2030. The model projected significantly greater reductions in population HIV incidence with a longer and larger roll-out of the PopART intervention, with a predicted >50% reduction in cumulative population HIV incidence over 2020-2030 compared to standard-of-care. Cost analyses estimated the benefits in terms of infections averted and disability-adjusted life-years (DALYs) averted to assess PopART's impact on morbidity and mortality. The cost-effectiveness if the PopART intervention continued from 2014 to 2030 in Zambia was estimated to be $2032 per infection averted and $1003 per DALY averted, and in South Africa was estimated to be $3652 per infection averted and $764 per DALY averted.
 
Other work highlighted UTT opportunities. To optimize the impact of treatment for prevention (as well as clinical benefits), it is important to identify persons living with HIV among key populations (KP). A multicountry analysis (abstract MOPEB119, http://programme.ias2019.org/Abstract/Abstract/4602, Mahler) presented data from the Linkages Project. They monitored community- and facility-based service sites using standard PEPFAR indicators from July-September 2018, in which data were disaggregated by key population (KP) typologies to examine the effect of "Treat and Test" on HIV case detection. They determined the percent change in case detection overall following the introduction of UTT or compared case detection rates from Treat and Test to traditional outreach and testing activities. In Angola, Democratic Republic of Congo, and Kenya, Treat and Test improved case detection for both FSW and MSM; increases ranged from 176% for HIV case detection among FSW in Angola to 57% for HIV case detection among MSM in Kenya. In Cote d'Ivoire, case detection was highest through Treat and Test (16%) compared to those reached through traditional testing activities (11%). In South Sudan, case detection was 7% through Treat and Test compared to 4% from traditional outreach and testing, and 60% of Treat and Test partners and clients were first time testers compared to 27% from traditional outreach and testing. Thus, Treat and Test can be rapidly integrated into existing KP programs and result in increased case detection. Lastly, a study from South Africa (abstract MOPDD0102, http://programme.ias2019.org/Abstract/Abstract/2115, Maina) presented on UTT to reach underserved farm workers and their families in four sub-districts of uMgungundlovu District in KwaZulu-Natal. In September 2016, South Africa adopted UTT. The project provided HIV testing, TB symptom screening to identify presumptive TB cases from whom sputum was obtained and sent for TB testing, ART and TB treatment following South African guidelines and using mobile clinics. Almost 6000 persons were screened for TB, 1403 presumptive TB cases were identified and 866 PLHWA were identified among the 3463 who were tested for HIV. All clients diagnosed with TB and 87% of new HIV positive cases were initiated into treatment. The investigators concluded that UTT requires multi-pronged approaches to reach underserved populations, and that mobile outreach services and clinics improved access to HIV and TB services by farm workers and their families.
 
PrEP
 
Pre-exposure prophylaxis (PrEP), in which an HIV uninfected person uses an antiretroviral as chemoprophylaxis against HIV, continues to receive substantial attention at global HIV meetings. Indeed, a quick search of the IAS 2019 website finds over 200 abstracts, across 39 sessions, mentioning PrEP. Some of those are summarized here. Most PrEP studies addressed the combination pill emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) but new PrEP options were also discussed.
 
A session entitled "Upping the ante: prevention for impact" (http://programme.ias2019.org/Programme/Session/91) included three important PrEP presentations.
 
From Australia, an update on the EPIC-NSW study was presented (abstract TUAC0201, Grulich). By 2016, New South Wales (8 million people, including metro Sydney) had met the UNAIDS 90:90:90 goal but the annual number of infections was stable at about 300-350, about 80% in MSM. The EPIC-NSW PrEP implementation study evaluated whether targeted, high-coverage, rapid roll-out of PrEP could reduce HIV incidence statewide. HIV incident infections were measured through a statewide register and in-clinic procedures. The primary results were published in 2018, showing a very low incidence among men dispensed PrEP (0.48/1000 person-years) and a 32% decline in state-wide incidence HIV infections (even greater in Australian-born men and those in Sydney). Beginning in April 2018 and through early 2019, Australia transitioned to national coverage of PrEP and the study ended. By the end of the study, nearly 10,000 men had started PrEP - 91% gay, across an age range, about half Australian-born. About half started PREP at a public health clinic and half at private clinics. In total there were 30 new HIV infections among those enrolled - an incidence of 1.52/1000 person-years (95% CI 1.07-2.18); in the absence of PrEP, more than 400 infections would have been expected. Those who acquired HIV had some common characteristics: many had stopped PrEP, many thought their risk had changed, many had mental health and substance issues, and some had personal concerns about toxicity. One case of an M184V HIV resistance mutation was seen - in someone who likely continued PrEP after infection. Younger age (18-24) had greater HIV risk, but still low on PrEP, as was meth use and a rectal STI (or both); men in the postal codes reflecting gay neighborhoods of Sydney seemed to have lower HIV risk than those in outlying areas (perhaps suggesting "herd immunity" type effects of greater PrEP coverage). State-wide, there was a 44% decline in new HIV infections in MSM, including a 65% decline in the Sydney gay neighborhoods. Based on the data, PrEP coverage levels (estimated to be about 50% now for those at higher HIV risk) need to reach 75% to completely stop new infections.
 
From France, an update on the Prevenir study of PrEP roll-out in Paris was presented (abstract TUAC0202, Molina). PREVENIR is an open-label cohort study among high-risk adults living in the Paris region, who could choose daily or on-demand FTC/TDF (including switching back and forth). Follow-up was quarterly. The goal is to see if rolling out PrEP in this way could result in a 15% reduction in new HIV infections among MSM in the Paris region, using data from national surveillance. As of May 2019, 3057 individuals were enrolled across 26 sites. 99% were MSM, and about half chose on-demand PrEP regimen. The average age was ∼35 years. The dosing regimen remained about 50:50 on-demand:daily, with individuals commonly changing back and forth. PrEP adherence was high overall - somewhat greater for daily use (97.3% of sex acts) than on-demand (82.2%), with "no PrEP" being more common for those choosing on-demand PrEP; about 20% of sex acts also had condom use. The overall HIV incidence was 0.09/100 person-years (2 cases); the mean follow-up is 8.7 months and 2208 person-years of follow-up have been accumulated; this translates to 143 cases averted based on expected HIV incidence. Both of the cases of HIV had chosen on-demand PrEP, had taken it for more than a year, then stopped PrEP and acquired HIV several weeks later. Sexual behavior was relatively stable over time. Viral hepatitis occurred at a rate of 1 per 100 person-years, mostly HCV. Bacterial STIs were very common - and there was a 38% increase per year in bacterial STIs (p<0.001), with an incidence higher among those choosing daily PrEP (perhaps reflecting higher behavioral risk - more partners, more condomless sex - than those choosing PrEP on-demand). Adverse events were generally uncommon and treatment discontinuation due to adverse events very rare (just 3 persons, due to gastrointestinal symptoms). In summary, this interim report of PrEP roll-out in Paris confirms low HIV incidence, both for daily and on-demand use of FTC/TDF PrEP, high adherence, high safety, and high incidence of bacterial and viral STIs.
 
A different PrEP option, the dapivirine vaginal ring, was discussed (abstract TUAC0203, Baeten). Phase III clinical trials (MTN-020/ASPIRE & IPM 027/The Ring Study) showed that a monthly vaginal ring containing 25 mg dapivirine was well-tolerated and reduced HIV incidence by approximately 30% compared to placebo. At IAS 2019, the final results of MTN-025/HOPE, one of the two phase IIIb open-label extension trials following those phase III trials, was presented. HOPE initiated in July 2016 and concluded in August 2018. HIV uninfected women who had participated in ASPIRE were offered 12 months of access to the dapivirine vaginal ring at 14 sites in Malawi, South Africa, Uganda, and Zimbabwe. Used rings were returned at each study visit (monthly for 3 months, then quarterly) and were tested for residual levels of dapivirine. A total of 1456 women enrolled into HOPE, 59% of those HIV uninfected at the completion of ASPIRE. The median age was 31 years (12% <25 years), 16% had a curable sexually transmitted infection at enrollment, and 43% used a condom with the last sex act prior to enrollment. Retention was high - 98% of expected visits were attended. Women were offered the choice of the dapivirine vaginal ring - the vast majority initially accepted the ring and most continued throughout 12 months. Specifically, at baseline, 1342 (92%) accepted the dapivirine vaginal ring; ring acceptance remained high: 90%, 89%, 87%, 83%, and 79% at Months 1, 2, 3, 6, and 9 and 73% of women accepted the ring through all 12 months of follow-up. 90% of returned rings had residual dapivirine levels consistent with some use during the prior month (>0.9 mg released) and the average amount of released dapivirine was greater for this open-label population than for the prior clinical trial population. The safety of the product was high. A total of 35 HIV-1 infections were observed (incidence 2.7 per 100 person-years, 95%CI 1.9-3.8); expected HIV-1 incidence was 4.5 per 100 person-years (95% CI 3.7-5.5) in the absence of access to the dapivirine vaginal ring (compared in a counterfactual bootstrap analysis to the placebo arm of ASPIRE). Thus, final results from this open-label extension trial of the dapivirine vaginal ring indicate high uptake and adherence, a well-tolerated safety profile consistent with that seen in the phase III studies, and lower HIV incidence associated with access to the ring than would be expected in the absence of access. These results again emphasize that the dapivirine vaginal ring seems to be an acceptable and used PrEP product for some women - it could have particularly important impact for those not using FTC/TDF PrEP.
 
Another session, entitled, "Start stop restart: Supporting effective PrEP use" (http://programme.ias2019.org/Programme/Session/82) explored PrEP use across settings.
 
The multisite HPTN 082 study (abstract TUAC0301, Celum) was a randomized trial of PrEP PrEP adherence support (counseling, 2-way SMS, and adherence clubs) vs. that same support plus drug level feedback during the first 3 months after PrEP initiation among adolescent girls and young women (AGYW) taking PrEP in South Africa and Zimbabwe. A total of 427 AGYW started PrEP, the median age was 21 years. At month 3, 85% were taking PrEP (as measured by detectable drug in dried blood spots [DBS]), and 25% had high adherence by DBS and 48% by plasma. Drug level feedback did not improve adherence and adherence decreased significantly from after month 3, when visits decreased to quarterly (p<0.0001). However, only four AGYW acquired HIV, which was a very low rate (in contrast, very high HIV rates from South Africa were reported from the recently-completed ECHO trial [abstract LBPEC23, http://programme.ias2019.org/Abstract/Abstract/4835, Palanee-Phillips], emphasizing tremendous ongoing HIV risk for AGYW in that country); in HPTN 082, all 4 who acquired HIV had undetectable plasma tenofovir.
 
From Brazil, a PrEP demonstration study among transgender women was reported (TUAC0302, Jalil). Of 318 transgender women assessed for eligibility, 275 were eligible and 130 were offered PrEP (uptake 48%). The median age was 30 years, almost 1/3 had unstable housing, and 44% were using gender-affirming hormones. More than half reported transactional sex and unprotected receptive anal sex; depression and sexually transmitted infections were common. At week 4 61% appeared to be using PrEP well, and 55% at week 12; however, about 25-30% had poor PrEP engagement at those same visits - associated with unstable housing. In summary, this study suggested good uptake and early adherence to PrEP among transgender women in Brazil.
 
From Australia (abstract TUAC0303, Bavinton) additional analyses from the EPIC-NSW trial were presented, exploring PrEP stopping. Analyses included 1,682 participants (almost all MSM); of whom 220 reported stopping PrEP for ≥3 months. Among these, median days to first time stopping PrEP was 494 days (IQR=122-591) and 45% had at least one period of restarting PrEP after stopping. Stopping PrEP for ≥3 months was significantly associated with younger age, lower partner numbers and less condomless anal intercourse in the previous week. But, 8% of those who stopped PrEP had >20 partners, 30% and 15% reported party-drug and methamphetamine use, and 52% reported any condomless anal intercourse. Thus, men who stopped PrEP for ≥3 months had lower HIV risk than those who continued use; however, risk was not zero for all those who stopped. PrEP stopping and starting is thus to be expected, but interventions to time being on PrEP to periods of risk will be important to develop. Another study, from AGYW in Kenya and South Africa, also assessed PrEP re-initiation after interruption (abstract TUAC0304, Omollo), finding that interruptions were common but 20% restarted PrEP, often within a month of stopping.
 
Finally, from a large implementation study of PrEP among pregnant women in Kenya (abstract TUAC0305LB, Pintye), PrEP use was assessed. Overall, 4,376 women initiated PrEP. Median age was 24 years and 78% were married (8% had a known HIV-positive partner). Dried blood spots were tested from 232 randomly-selected follow-up visits (5% of all visits) at a median of 8 weeks post-initiation and 66% had detectable tenofovir diphosphate (TFV-DP) with a median concentration of 535 fmol/punch (IQR 357-719). Almost all (62/65, 95%) samples among women with HIV-positive partners had detectable TFV-DP versus 68/109 (62%) for women with partners of unknown HIV status and 23/58 (40%) for women with HIV-negative partners (p< 0.001). Detectable TFV-DP was less frequent among visits with pregnant women (52% pregnant vs 70% non-pregnant, p=0.019) and younger women (53% < 24 years vs 76% ≥24 years, p< 0.001). One woman tested HIV-positive during follow-up; TFV-DP was not detected in DBS collected at seroconversion. These results were very encouraging: PrEP programs for African women can achieve reasonable PrEP adherence.
 
A program testing same-day PrEP initiation for MSM and transgender women in Brazil, Mexico, and Peru reporting encouraging results (abstract TUAC0404LB, http://programme.ias2019.org/Abstract/Abstract/4894, Veloso). Clients were screened and enrolled on the same day and received a 30-day supply of TDF/FTC. Creatinine, hepatitis B, C and STI testing were performed. A total of 4954 individuals were enrolled in Brazil (3205), Peru (1010) and Mexico (739), and the median age was 29 years. 94% were MSM. Only 44 (1.1%) had an estimated glomerular filtration rate (eGFR) <60 mL/min. STIs were common. Overall, early continuation was achieved by 80% and PrEP adherence was 97%. Early continuation was lower among transgender women (56%) and young MSM (71%). HIV incidence was 0.6 per 100 person-years - quite low. These fantastic results show that same day PrEP initiation in Latin America is feasible and safe, with good early continuation and adherence.
 
A highly-covered session entitled, "Hot off the press: What's new in HIV prevention" (http://programme.ias2019.org/Programme/Session/167) presented data on two new PrEP options. First, a first-in-human trial of a drug-eluting implant containing the potent new antiretroviral agent MK-8591 (islatravir, a nucleoside reverse transcriptase translocation inhibitor [NRTTI]) was reported. Islatravir has been used to date by <300 humans, nearly all taking an oral form, some without HIV and some PLHIV; the medication has been well-tolerated, with a long half-life and high anti-viral effects. An implant program, in addition to the oral program, has been initiated. The target dose for PrEP was 0.05 pmol of the phosphorylated form of islatravir per million cells based on nonhuman primate viral challenge data. The implant first-in-human trial included 16 persons using islatravir implants (either 62 or 54 mg) or placebo (6:6:4), placed subdermally in the upper arm of the nondominant hand for 12 weeks. The primary outcomes were safety and pharmacology. The intracellular concentrations stayed about target for all persons for the higher dose implant (and for most with the lower dose), and concentrations fell as expected after implant removal. Modeling work predicted that the 62 mg implant would sustain target concentrations for at least 12 months. Safety data were generally reassuring, with some local erythema and induration at the implant site. These data are really exciting, although they are still based on just 12 people followed for 12 weeks - the road is still long for this product to show HIV protection and reach the hands (or, really, nondominant upper arms, of people at risk). The second abstract (TUAC0403LB, Spinner) presented new data from the DISCOVER study, which at CROI 2019 reported that daily oral emtricitabine/tenofovir alafenamide (FTC/TAF) was non-inferior for HIV prevention for MSM and transgender women compared to daily oral FTC/TDF. The IAS 2019 update examined pharmacologic and behavioral data to better characterize the DISCOVER results. Week 4 PBMC tenofovir diphosphate (TFV-DP) levels were 6.3 fold higher for FTC/TAF vs. FTC/TDF and 98% of FTC/TAF vs 65% of FTC/TDF participants had TFV-DP above the in vitro estimated protective threshold (p<0.001). In addition, carefully-monitored pharmacology studies found that FTC/TAF achieved protective levels within hours of a first dose, compared to 3 days for FTC/TDF, and protective levels were sustained longer after cessation. The authors suggested this may make FTC/TAF more forgiving than FTC/TDF as daily PrEP, though it is still important to recall that FTC/TDF is an exceptionally highly protective PrEP drug when taken with good adherence.
 
With all the PrEP enthusiasm it is important to remember that delivery of PrEP, currently pills but maybe more in the future, is not without challenges. Another session, entitled, "It's complicated: PrEP in practice" (http://programme.ias2019.org/Programme/Session/99) addressed PrEP delivery across settings. From Mexico (abstract MOAD0301, Holloway) a survey of 2467 conducted among MSM using a social networking app assessed PrEP knowledge, finding 70% had knowledge of PrEP, 36% intended to use PrEP in the next 6 months, but only 3% were current PrEP users. From Kenya (abstract MOAD0302, Were), a qualitative study emphasized the impact of stigma as a barrier to PrEP use among MSM and FSW, with a strong emphasis on identity and behavioral stigma. From Australia (abstract MOAD0303, Ryan), an analysis of PrEP discontinuation assessed that approximately 20% had a discontinuation, and from Brazil (abstract MOAD0304, Ornelas Pereira) PrEP discontinuations were more common for transgender women than for MSM. Another study among transgender women in Brazil (abstract TUAC0103, http://programme.ias2019.org/Abstract/Abstract/4573) emphasized the common frequency of syndemics, including tobacco use, alcohol and cocaine abuse, sexual violence, childhood abuse and trauma, and suicide risk.
 
HIV vaccine
 
A number of abstracts explored ongoing work to develop an effective prophylactic HIV vaccine. One session (http://programme.ias2019.org/Programme/Session/83) included both clinical and preclinical work in this important area. The ASCENT study, a phase 2a, randomized, double-blind, placebo-controlled study of the safety and immunogenicity of mosaic antigens reported results (abstract TUAC0402LB, http://programme.ias2019.org/Abstract/Abstract/4979, Stieh). The trial was conducted in adults in Kenya, Rwanda, and the US. Participants were randomized to one of three regimens: 1) Ad26.Mos4.HIV (at weeks 0 and 12) plus Ad26.Mos4.HIV + Clade C gp140 at weeks 24 and 48, 2) the same as 1) with combination gp140 (Clade C plus Mosaic), and 3) placebos. The sample size was 152 persons. The vaccines were well-tolerated. The bivalent regimen induced broader immune responses and use of the Mosaic did not diminish Clade C responses (and improved Clade B responses). Thus, these data support using bivalent clade C-Mosaic1 gp140 with Ad26.Mos4.HIV for expanded clade coverage in the soon-to-start phase 3 efficacy study trial starting in 2019 (MOSAICO, which will include 3800 persons).
 
Other prevention strategies
 
While abstracts on antiretroviral-based prevention, particularly PrEP, were common at IAS 2019, there were many important abstracts devoted to other aspects of comprehensive prevention.
 
From Eswatini, a cluster-randomized trial of financial incentives to reduce HIV prevention among adolescent girls and young women (AGYW) was reported (abstract TUAC0205LB, http://programme.ias2019.org/Programme/Session/91, Mabuza). Eswatini has the highest HIV prevalence in the world, and high rates of school drop out (only 33% enrollment in secondary school), youth unemployment, and transactional sex. The trial (called Sitakhela Likusasa = we are building our future) implemented two kinds of interventions in school years 2016, 2017, and 2018: 1) education incentives, for enrolling in, attending, and completing school (including some tuition fees for tertiary education) and 2) a raffle incentive if negative for syphilis or trichomoniasis. The trial started in 2015 and enrolled 4389 AGYW aged 15-22 years from 266 areas of Eswatini - 50% were out of school and 80% were from rural areas. The 266 areas were randomized to education, raffle, both, or neither. Follow-up concluded between November 2018 and April 2019. Intervention coverage was high - 59% of those assigned to the education incentives received something (including 31% post-secondary tuition) and 19% received a raffle prize. Follow-up was >85% for all four arms. The education incentive reduced HIV risk - 8.08% incidence in the control vs. 6.34% in the treatment (OR 0.77, 95% CI 0.60-0.98, p=0.037), a 23% decrease. The raffle was not significantly associated with lowering HIV risk. However, the greatest effect was the combination: compared to no intervention (incidence 8.84%), raffle only (7.38%, OR 0.82, =-0.245), education (6.87%, OR 0.76, p=0.116), and both (5.79%, OR 0.63, p=0.013) had increasing prevention benefits. Factors associated with HIV acquisition included being out of school and having a "risk-loving" profile (measured by a survey economics game); lower HIV risk included education and socioeconomic status. There was a greater effect of more incentive receipts at the individual level (i.e., greater participation in the program) on lower HIV incidence (p<0.01). These data provide more data on the idea of financial incentives for prevention of HIV in AGYW.
 
Ironically, one oral abstract session was entitled, "Prevention is more than PrEP" (http://programme.ias2019.org/Programme/Session/101) and it brought together a wide range of work. One modeling analysis (abstract TUAD0201, Stoner) assessed the HIV prevention benefit for AGYW in rural South Africa (aged 13-20 years) of staying in school plus additional potential prevention interventions. The work used advanced epidemiologic modeling methods, which are worth exploring more for those who are most interested. Low school attendance, transactional sex, and depression had the largest population effects on incident HIV infection. The models may help in policy-making decisions for crafting maximally-effective combination prevention interventions. Two studies explored maternal-child services. The first (abstract TUAD0202, Montandon) assessed a church congregation-based intervention (Baby Shower events) to improve HIV testing and linkage to care of pregnant women in Nigeria, finding that the intervention facilitate identification of HIV-positive pregnant women and male partners who were not otherwise engaged in facility-based care: 99% of attendees had HIV status ascertained, 2.8% of women and 2.2% of men received a new HIV diagnosis, and 84% of women linked to care. The second (abstract TUAD0203, Machaku) did a large-scale chart review of early infant male circumcision (EIMC) data from rural Tanzania, finding that establishment of an EIMC program was associated with greater postnatal clinic attendance for women who had delivered their children at home - testifying to an important co-benefit of an HIV prevention service integrated into routine care services. Finally, an abstract pulled together data on R&D investment in HIV prevention and implementation (abstract TUAD0205, Warren), finding that KP-specific prevention research was insufficiently resourced, both for development of well-designed new products and delivery of successful prevention tools.