Recap: Day 2 of Virtual CROI 2021
Courtesy of the CFAR leadership (Monica, Peter), with special thanks to Lillian Brown MD, PhD, John Szumowski, MD, and Steve Deeks, MD, for helping to provide content for these summaries.
Please note that this summary is by no means meant to be a comprehensive overview of everything presented at CROI 2021, but a highlight from each day with a focus on those presented from investigators from UCSF and our CFAR affiliates.
The future of therapeutic broadly neutralizing antibodies (bNAbs) in HIV
The identification and clinical development of antibodies that neutralize HIV could revolutionize the prevention and treatment of HIV. They are also the basis for many of the current generation of HIV cure studies. Much of what we know about these so-called "broadly neutralizing antibodies" (bNAbs) is based on the work of Dr. Marina Caskey and her team at Rockefeller University. In her excellent and informative plenary presentation, Dr. Caskey summarized a massive and rapidly evolving set of data, highlighting how bNAbs might contribute to HIV prevention, treatment, and cure.
Prevention: While bNAbs work well at preventing the acquisition of sensitive viruses, the HIV envelope is quite polymorphic, which promotes the selection of resistant variants. The recent HVTN 703/HPTN 708 Antibody Mediated Prevention (AMP) study found that the bNAb VRC01 given every two months only had a modest effect in preventing HIV transmission overall, despite 75% efficacy for susceptible viruses, as only 30% of trial participants who acquired HIV were infected with sensitive viruses. Nevertheless, these studies provided proof of principle that bNAbs could be used for prevention as long as breadth could be improved by including multiple bNAbs in the same cocktail, as is starting to be done in treatment studies. Additionally, this study also revealed the levels of antibodies that a vaccine might need to produce to be effective. Although bNAbs will likely never be as effective as antiretroviral drugs in HIV prevention (pre-existing resistance to bNAbs is common), they will at least not select for variants that will impact the effectiveness of ART.
Treatment: Given that bNAbs can be modified so that they persist for months, they are now being actively developed as a partner to integrase inhibitors for treatment; theoretically, long-acting injections will only need to be given every few months. There are also potential immunologic benefits of bNAbs over injectable ART in that they appear to stimulate HIV-specific T cell responses via a so-called “vaccinal” effect, which may prove to be important in HIV cure studies.
Cure: bNAbs have the unique capacity to safely recognize and potentially eliminate cells expressing virus on their surface. Even if this does not occur, the combination of bNAbs and viral particles post-ART can lead to immune complexes that are highly immunogenic (post-vaccinal effect). She also reviewed studies where bNAbs were being combined with other immune-based therapeutics designed to reverse HIV latency and make infected cells more visible to antibodies (including Steve Deeks’s own amfAR trial!).
COVID-19: Lastly, she made the point that the scientific investment in bNAbs for HIV really paid off in rapidly delivering bNAbs for COVID-19 that are already being used clinically (and highlighted in other sessions at the meeting, particularly for prevention). The rapid scale up of COVID-19 bNAbs also demonstrated that it is in fact feasible to scale up bNAb production for HIV if there is a will to do so.
Dr. Linda Gail-Bekker from the University of Cape Town, South Africa, gave an amazing talk on SUSTAINED DELIVERY AND LONG-ACTING AGENTS FOR PREVENTION OF HIV with the ultimate mantra that “choice matters” when it comes to PrEP modalities. She first started with why we have such a hard time taking daily PrEP as summarized below.
She then reviewed data from both the long-acting psychotropic field and the long-acting contraceptive field to review how long-acting medications have been so helpful for adherence in those cases.
And, given that we are in March 2021 and we have these exciting developments in long-acting modalities, Dr. Bekker then turned to those.
On January 26, 2021, the WHO recommended the dapivirine vaginal ring for HIV prevention as an additional option for women. Assessing that the benefits of the DPV-VR outweigh the harms, including its cost–effectiveness, acceptability, demonstrated feasibility, and the potential to increase equity as an additional prevention choice for women worldwide. The two main phase 3 studies and the open-label effectiveness study are summarized below.
In terms of pros of the vaginal ring, less frequent dosing needs; non-systemic administration (few side effects), fewer healthcare visits, self-insertion and discretion are some. Cons are that the vaginal ring can feel foreign, rings should be available and safely stored, multipurpose rings are in the works but not yet out, still need to consider other sexual reproductive health needs.
In terms of the cabogegravir LA prevention modality, this was an exciting year given the results of HPTN083 and HPTN084 clinical studies summarized here:
The pros of long-acting injectables include improved adherence, less frequent reminding, lower number of healthcare visits (if shots are in and out) and that they are discreet. The cons are understanding the “long tail” implications, access when traveling or away rom home, the fact that shots cannot be administered by nontrained individuals at present, and must consider other sexual reproductive health needs.
Overall, this plenary talk was about choice and the ability now to have such choices in the context of HIV prevention so this was an inspiring talk!
This abstract session presented several interesting studies, including the resistance data from HPTN083.
PHASE 1 PK, SAFETY, AND ACCEPTABILITY STUDY OF 3-MONTH DAPIVIRINE VAGINAL RINGS
Our very own Al Liu presented this study. Although the dapivirine vaginal ring is inserted once monthly, this study from the MTN was designed evaluate the safety, pharmacokinetics, adherence, and acceptability of two 3-month dapivirine (DPV) vaginal rings (VR) compared with the monthly DPV VR. Overall 49 HIV-negative women were enrolled into a Phase 1, multi-site, randomized (1:1:1) trial comparing two extended duration (100 or 200 mg DPV) VRs used continuously for 13 weeks to a monthly 25 mg DPV VR. DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF), cervical tissues, and used rings. Overall, were no differences in the safety events.
Drug concentrations across all relevant compartments were higher in the 100 and 200 mg VR arms compared with the 25 mg arm and a majority of participants. 82% reported being fully adherent, with no statistically significant differences between groups. Most participants reported liking the VRs (median (IQR): 8 (6-10) on 10-point Likert scale). Therefore, the extended duration DPV VRs were well-tolerated and achieved higher DPV concentrations compared with the monthly DPV VR, likely translating into at least equal efficacy. Therefore, further evaluation of 3-month DPV VRs for HIV prevention in women will be conducted.
INCIDENCE OF HIV INFECTION WITH DAILY OR ON-DEMAND ORAL PrEP WITH TDF/FTC IN FRANCE
The ANRS Prevenir study is an ongoing prospective cohort study enrolling individuals at high risk for HIV infection on PrEP where. MSM could opt for either daily or on-demand PrEP with TDF/FTC. This follow-up to the main study was to assess overall HIV incidence, as well as incidence of bacterial STIs (including syphilis, gonorrhea, chlamydia and Mycoplasma genitalium) and viral hepatitis.
From May 3rd 2017 to March 2nd 2019, 3067 mainly MSM were enrolled across 22 sites in the Paris region. At enrolment, PrEP was used daily and on demand by 50.5% and 49.5% of participants, respectively. Median number of partners in the last 3 months was 10 (5-20) and median number of condomless sex events in the prior 4 weeks was 2 (0-5). Median follow-up lasted 22 months and six participants (3 daily, 3 on demand) acquired HIV-infection during the study period (P=0.99). Condom use at last sexual intercourse was 19.6%. Overall STIs incidence was 73 (95% CI: 70.7-75.5) per 100 PY which remained stable during follow-up except during the COVID-19 lockdown when it dropped to 32.4 per 100 PY (P<10-4). HCV incidence was 0.69 per 100 PY. So, in conclusion, in this PrEP cohort, HIV incidence was equally low whether participants used daily or on demand PrEP. There was a high incidence of bacterial STIs and HCV infection despite a drop in STIs incidence during the COVID-19 lockdown.
COST-EFFECTIVENESS OF LONG-ACTING PrEP AMONG MSM/TGW IN THE US
This study projected the clinical benefit of CAB-long acting vs. emtricitabine/tenofovir disoproxil fumarate (TDF) and estimated the cost at which CAB-LA would be cost-effective. Using the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) simulation model, we examined 2 strategies: generic F/TDF (or branded F/TAF) and CAB-LA among high-risk men who have sex with men and transgender women (MSM/TGW, i.e. trial-eligible) starting PrEP in the US (n=~476,300). We used trial and published data including: HIV incidence (off PrEP: 5.32/100PY; F/TDF (and F/TAF): 1.33/100PY; CAB-LA: 0.26/100PY); HIV transmissions off-PrEP attributable to high-risk MSM/TGW: 17,800/year (yr); 62% 6yr-PrEP retention. We assumed constant incidence and annual transmissions. Annual costs were: generic F/TDF $8,400 (branded F/TAF $16,900); CAB-LA $28,000, and ART: $24,500-$39,600. Projected outcomes included HIV transmissions averted, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs, $/QALY) over 10 yrs. Overall, CAB-LA would be cost-effective compared to F/TDF or F/TAF over 10 years at a maximum price premium over F/TDF (F/TAF) of $700/yr ($1,800/yr). When offered to all PrEP-eligible MSM/TGW, CAB-LA would be cost-effective over 10yrs if priced at $11,600 a year at a maximum price premium of $200/yr (vs. F/TDF) or $500/yr (vs. F/TAF). In conclusion, with the availability of generic TDF/FTC, CAB LA would need to be priced at around $11,600 per year to be cost-effective.
SOCIAL NETWORKS PREDICT PrEP UPTAKE IN SEARCH STUDY IN RURAL KENYA AND UGANDA
Peer support may be important for increasing PrEP use. This study from SEARCH PrEP – presented by our own Dr. Cait Koss- aimed to assess whether social network contacts predicted PrEP uptake in rural Kenya and Uganda after accounting for known predictors of PrEP initiation. TDF/FTC PrEP was offered in 16 communities during population-level HIV testing starting in 2016-2017. Universal PrEP access with rapid or same-day start was offered to HIV-uninfected adults ≥15 years, with enhanced PrEP counseling for those at elevated HIV risk (based on serodifferent partnership, risk score, or self-identified risk). During population-level testing, persons were asked to name social contacts in 5 domains: health, money, emotional support, food, and free time. Named contacts were matched to community residents to build community-specific, sociocentric networks of 56,770 persons and 124,054 connections.
Study authors then evaluated social network predictors of PrEP uptake within 1 year of population-level testing among persons at elevated HIV risk who had ≥1 matched first-degree contact, accounting for clustering by community and adjusting for sociodemographic factors (sex, age, serodifferent partner, polygamous marriage, mobility, occupation). Among 13,159 persons at elevated HIV risk, 8,898 (68%) had ≥1 matched network contact. Persons with ≥1 contact who started PrEP were 57% more likely to start PrEP (adjusted risk ratio [aRR] 1.57, 95% CI 1.44-1.70, p<0.001) than those with contacts who did not start PrEP. Of note, having a serodifferent partnership, being in a polygamous marriage, being of age <25, being in the fishing, bar or transportation industry or being mobile were all associated with PrEP. in conclusion, persons with a social contact who initiated PrEP were more likely to themselves start PrEP within 1 year of PrEP offer during population-level HIV testing, suggesting interventions around peer support.
LABORATORY ANALYSIS OF HIV INFECTIONS IN HPTN 083: INJECTABLE CAB FOR PrEP
Dr. Raphy Landovitz- in one of the most anticipated presentations of the meeting – provided the pharmacokinetics data and the resistance profile of the 15 failures recorded on injectable cabotegravir given every 8 weeks for HIV prevention among MSM and transgender women enrolled in the HPTN083 study. As a reminder, data presented at AIDS 2020 from HPTN03 showed that the estimated HIV incidence in the long-acting CAB arm was 66% lower than in the oral TDF/FTC-containing arm. The abstract presented at Virtual CROI 2021 was entitled Laboratory Analysis of HIV Infections in HPTN 083: Injectable CAB for PrEP and provided further detail on the 3 baseline infections and the 12 incident or breakthrough infections in the long-acting (LA) cabotegravir arm. Dr. Landovitz stressed that typical diagnostic tests for HIV did not reveal the 3 incident infections and so the open label extension (OLE) study of HPTN083 will include HIV RNA testing to rule out acute infection. In terms of the 12 incident infections, integrase inhibitor resistance evolved in five participants: 1) Q148K and E138K INSTI mutations in one (A2); 2) Q148R, L74I, E138K, G140S INSTI mutations in the second (C1); 3) Q148R and E138A in the third (C3); 4) a R263K INSTI mutation in the fourth (D3); 5) a Q148R and G140A in the fifth (D4).
Although phenotypic susceptibility testing was performed on some of these failures, darunavir/ritonavir with 2 NRTIs was used as the treatment for these breakthrough infections. Therefore, this study showed that 1) Diagnostic testing may require HIV RNA testing at initiation of cabotegravir which will be tested in HPTN083 OLE; 2) Evolution of INSTI resistance in breakthrough infections with CAB is not uncommon and must be carefully evaluated during roll-out.
This symposium was followed by a very lively Q & A session in the Interactive Sessions led by our very own Dr. Diane Havlir and featuring our Dr. Hyman Scott called FROM DAILY PILLS TO MONTHLY SHOTS FOR HIV PREVENTION AND TREATMENT: CAN EFFICACY BE TRANSLATED INTO EFFECTIVENESS? Other speakers in the session includes Drs. Francois Venter, Nittaya Phanuphak, Charles W Flexner, and the session was co-moderated by Dr. Carlos del Rio.
Interactive Session: HIV-1 AND SARS-CoV-2: DURABILITY OF HOST IMMUNE RESPONSES FROM VACCINATION OR INFECTION
This fascinating live interactive session featured great short talks from an all-star cast including Andres Finzi (U Montreal), Julie McElrath (Fred Hutch), Katie Doores (Kings College, London), Bob Seder (VRC/NIAID), and Ignacio Sanz (Emory). Masterful moderators, Drs. Galit Alter and Guido Silvestri, curated a genuine discussion about what is known and what is hypothesized regarding SARS-CoV-2 immunity.
As most of the assembled talent were experts in HIV, there was a fair amount of discussion regarding the overlap between HIV and COVID research. The question of how well the emerging COVID vaccines will work in PWH was brought up several times but never answered, presumably as no one really knows.
Some key insights from the discussion are listed below:
- IgM appears to be responsible for a lot of the virus neutralization in initial natural infection (Finzi), but that titers of neutralizing antibodies decline precipitously within a few months following infection. Nevertheless, neutralizing IgG responses are able to be “re-awoken” upon vaccination in previously infected people, and appear to be longer lived following vaccination than natural infection. T cell responses seem to be remarkably stable. This is particularly true after natural infection, and one hopes with the vaccines.
- Although natural infection seems to induce a potent immune response, it may not be as protective as we had hoped. In the placebo arm of one vaccine study in South Africa, people previously infected before were as likely to get reinfected again as those who had no prior exposure.
- Bob Seder made the point that vaccine-elicited neutralizing antibodies appear to persist for much longer than those from natural infection, perhaps because the vaccines are focused on the right type of immune response with a robust adjuvant.
- A single vaccine in those who were previously infected is very immunogenic. Some trends are emerging that those previously infected and then "boosted" with a vaccine have a particularly strong and broad response.
- A single vaccine may be useful for those in lower-risk populations.
- Not much is known about how immunosuppression - including HIV - will affect vaccine effectiveness. Reassuringly, age does not seem to have a massive effect, particularly for the RNA vaccines.
- CD8+ T cell responses may be broader than the antibody responses. T cells may contribute to protection when antibody levels wane or when partially resistant variants emerge. Julie McElrath showed that SARS CoV-2-specific polyfunctional CD4 responses persist and likely play a supportive role in B cell responses and may contribute to added protection from vaccination.
- Vaccines in PWH might be more likely to induce suboptimal T cell than B cell responses, but this remains just a hypothesis.
- PWH may need vaccine boosts more than the general population.
- Heterologous combinations of vaccine platforms are being considered. In HIV studies, using an adenovirus prime followed by a protein boost has proven to be very effective at inducing T and B cell responses. Such studies are now being conducted for COVID.
- Broadly neutralizing antibodies are revolutionizing the prevention, treatment, and perhaps eventually cure of HIV. These antibodies were found in so-called "elite neutralizers." Efforts are underway to find such antibodies in people recovering from COVID. Some may prove to be effective against current and emerging variants of concern.
Many more fascinating insights came out of this dynamic discussion and we encourage people interested in SARS-CoV-2 immunity to watch the whole hour as it is definitely a high-level and rich discussion.
This session included analyses of SARS-CoV-2 epidemiology, SARS-CoV-2 epidemiology among HIV-infected, and the impact of stay at home orders/lockdown on HIV testing and treatment.
Phylogenetic analysis of the timing of SARS-CoV-2 Introductions into Washington State
The first confirmed case of SARS-CoV-2 in the United States was in Washington state on January 21, 2020. using phylogenetic reconstruction to look at the number and timing of introductions of SARS-CoV-2 into Washington State from January 2020 through September 2020 the University of Washington virology lab estimated at least 287 distinct introductions of SARS-CoV-2 into the state and 204 exported lineages. The majority (73%) of introductions were prior to May 1, 2020 and the most likely source of introductions was from other locations in the United States. Most introductions were single lineages (73%), meaning they did not lead to significant clusters or outbreaks, however 6% resulted in subclades of 20 or more sequences indicating significant community transmission. This genomic surveillance is ongoing and will play a role in monitoring emerging variants and identifying the origin of those variants.
From testing to mortality: COVID-19 and the inverse care law in Switzerland
In this analysis of surveillance data from Switzerland, a country with Universal Health Care, the authors evaluated the relationship between socioeconomic position (SEP) and COVID-19 outcomes. While higher SEP was associated with more testing, lower SEP was associated with higher rates of cases, hospitalizations, ICU admissions, and deaths, a trend which persisted after adjusting for potential confounders of age, sex, time period, and canton (location). The authors speculate that differential exposure to infection and differential access to care contributed to the observed disparities.
Sex/Gender differences in testing, presentation, and outcomes of SARS-CoV-2 Infection
The male bias in mortality in China which was reported early in 2020 continued in multiple countries as the pandemic continued to spread and as of February 8, 20201 the average case fatality ratio was 1.5:1 for males: females globally. In a retrospective analysis of individuals tested in the Johns Hopkins Medicine healthcare system (serving a population of ~7 million), researchers from Johns Hopkins found similar test positivity rates between men and women but men were more likely to be admitted and present with higher initial inflammatory lab values (IL-6, CRP, ferritin) at the time of hospital admission. When stratified by age, the sex disparity in severe disease/death was isolated to men age 18-49 which persisted after adjusting for comorbidity burden, suggesting the sex differences in the observed inflammatory response to SARS-CoV-2 infection may be mediating the differences in outcomes.
Racial Disparities in COVID-19 Positivity among people living with HIV in the US
Racial disparities exist in both COVID-19 and HIV diagnoses. In an analysis of data from the National COVID Cohort Collaborative (N3C), an EMR based data system covering 41 sites and >3 million patients, people living with HIV (PLWH) who were diagnosed with COVID-19 were older and had more comordities than HIV-uninfected with COVID-19. Among the 17,820 PWH, Black PWH were 6x more likely to be diagnosed with COVID-19 and Hispanic PWH were 2x more likely to be diagnosed with COVID-19 than White PWH. As this analysis used EMR data there was no information on social determinants of health that may have affected risk of COVID-19.
HIV and COVID-19 inpatient outcomes: a matched retrospective multicentre analysis
Previous data on HIV and hospital outcomes has been inconclusive due to incomplete coding for HIV, non-matched populations, and lack of CD4, viral load, HIV treatment data for HIV-infected patients. This multi-center retrospective matched cohort study of patients hospitalized with COVID-19 matched 69 PWH to 181 HIV-uninfected on gender, time of first positive COVID-19 test, age, and IMD (a surrogate for socioeconomic deprivation). After adjusting for confounders clinical improvement, discharge, and death were similar between PWH and HIV-uninfected hospitalized patients with COVID-19, and frailty and malignancy were associated with poorer COVID-19 outcomes.
Changes in HIV testing services after COVID-19 in 11 sub-Saharan African Countries
The COVID-19 pandemic has presented many challenges to HIV testing and treatment services, including individual fear of contracting COVID-19 at healthcare facilities, restrictions on movement, reduction in clinic attendance, disruption of supply chain, and shortages of PPE for healthcare workers. In an evaluation of HIV testing and ART initiation in 11 sub-Saharan African countries (Cote d’Ivoire, Cameroon, Nigeria, Namibia, South Africa, Democratic Republic of Congo, Mozambique, Eswatini, Lesotho, Zambia, and Kenya). HIV testing decreased during the COVID-19 pandemic in 6/11 countries and the number of HIV-infected persons initiated on ART decreased in 7/11 countries between January-June 2020 compared to January-June 2019.
Dramatic decline in public sector HIV/STI testing during SARS-CoV-2 Pandemic, Oregon
HIV and STI testing in public sector clinics were compared during “before physical distancing” (Jan – Sep 2019 and Jan – Feb 2020), “the height of physical distancing” (March – May 2020), and “ongoing physical distancing” (June – Jan 2020). Significant decreases were seen in HIV, CT/GC, and Syphilis testing during “the height of physical distancing” order, followed by an increase during “ongoing physical distancing”, but not back to baseline levels. There was also a 12% increase in HIV diagnoses and 45% increase in syphilis diagnoses during “ongoing physical distancing”. The mismatch in availability of sexual health services and ongoing sexual behavior during the pandemic may result in increased HIV and STI transmission. The authors also note many in public health sector were redeployed from sexual health services to COVID-related activities.
COVID-19 Impact on HIV Testing in 5 high prevalence Indian districts
India has recorded the second highest number of COVID-19 cases in the world. This analysis evaluated program data on HIV testing in Maharashtra and Andhra Pradesh, which account for ~30% of HIV burden in India, across 3 time periods: pre-pandemic, lockdown (severe restrictions on movement), and post-lockdown. Health services were exempt from lockdown restrictions, however many clinics were located in areas not served by public transportation during the lockdown. New HIV diagnoses decreased 93% during lockdown and 71% post-lockdown. Total number of contacts named by index cases decreased during lockdown and post-lockdown compared to pre-pandemic numbers, but number of contacts elicited per index case increased and HIV test positivity increased among contacts tested during lockdown period. These findings could be due to the staff spending more time eliciting contacts from a reduced patient load as well as higher risk patients being most likely to come in despite the barriers imposed by lockdown. Linkage to ART improved and time to ART also decreased relative to pre-pandemic levels, but there is an urgent need to understand who was missed. Testing still hasn’t returned to pre-pandemic levels. The authors also noted many staff had been seconded to COVID-19 related duties
Oral Abstract Session: SARS-CoV-2 VS HOST: VIROLOGY, IMMUNOLOGY, AND PATHOGENESIS
SARS CoV-2 causes microbial translocation! Leila Giron (Wistar Institute), who works with Mohammed Abdel-Mohsen (who in turn trained in our own CFAR community with the late Teri Liegler and Satish Pillai), presented a fascinating talk demonstrating that even mild COVID-19 results in a leaky gut barrier and microbial translocation, which could contribute to the systemic inflammation observed. It will be particularly interesting to see whether this is exacerbated in people with HIV, who already have microbial translocation prior to COVID-19 exposure. It will also be interesting to see whether this relates to “long COVID” symptoms.
SARS CoV-2 persists in the gut for up to 7 months! In a fascinating talk linked nicely with the previous presentation, Minami Tokuyama (Mt Sinai) demonstrated using immunofluorescence, in situ hybridization, and electron microscopy approaches that SARS-CoV-2 persists for many months, and in some cases up to 7 months, after even mildly symptomatic infection in the small intestines, particularly within goblet cells. While it is unclear whether this is infectious virus, it certainly could be enough to drive local (microscopic) inflammation, contributing to the microbial translocation described in the previous presentation. Whether the persistence of the virus in the gut contributes to inflammation and long COVID symptoms remains to be assessed. Whether this is even more abnormal in people with HIV is also an unanswered question.
SARS CoV-2 Plasma viral load predicts disease severity. Another interesting presentation by Jana Jacobs (U Pitt) established that plasma SARS CoV-2 RNA levels are detectable in 100% of intubated ICU patients, around half of individuals with severe disease and rarely present in individuals with mild symptoms. Electron microscopy confirmed that the measured plasma RNA reflected virions. These data suggest that plasma SARS-CoV-2 RNA levels may be a helpful measure to risk stratify hospitalized patients and confirm the systemic dissemination of the virus in severe disease.
Are Targets the best catalyst for PrEP scale-up?
Experts: Mark Dybul, Elizabeth Irungu
This lively interactive session started off with a reminder of the UNAIDS 2030 goals to decrease new HIV infections from 1.7 million globally in 2019 to 200,000 in 2030, and includes 3 million on PrEP (a significant increase from the 900,000 on PrEP at the end of 2020). However, prevention targets are complicated because the population at risk is dynamic and the outcomes are more difficult to measure than treatment targets. UNAIDS published the document Prevailing against Pandemics ahead of World AIDS Day 2020 detailing prevention targets for both key populations and the general populations. Experts Mark Dybul and Elizabeth Irungu then debated the question: Are targets the best catalyst for PrEP scale-up?
Mark Dybul took the position that while targets are not inherently bad, they need to be taken into the context of other interventions to reduce incidence and in combination with interventions targeted towards those most at risk (The option “something else” in the poll, which was also selected by 12% of the audience). He argued for incidence reduction targets by the sub-populations most at risk, rather than focusing on PrEP numbers, as a way to focus on impact.
Elizabeth Irungu argued that prevention efforts are indeed mobilized by setting high targets (which 56% of the audience selected in the poll). Dr. Irungu agreed that PrEP is needed alongside treatment to eliminate incidence, citing UCSF’s Dr. Koss and the SEARCH study’s finding of reduced HIV incidence among PrEP users, and that PrEP targets help everyone working in the system operationalize the goal of reduced incidence. Using Kenya as an example she described how PrEP targets help engage every player in the PrEP delivery system, including the facility, the health care workers, and counselors, and has promoted creativity around PrEP delivery centers. The goal of meeting targets during the COVID pandemic has driven the PrEP providers to be even more innovative, leading to improved efficiency in the system. And importantly, she argued that PrEP targets demonstrate global commitment and motivate providers.
Both experts agreed that a successful PrEP strategy will be community-driven and client directed, rather than healthcare provider or clinic driven.
Oral Abstract Session: Tuberculosis and Hepatitis
RIFAPENTINE +/– MOXIFLOXACIN FOR PULMONARY TUBERCULOSIS IN PEOPLE WITH HIV
Shorter treatments for tuberculosis are badly needed, and there has been great interest in the potential of rifapentine (a rifamycin related to rifampin with a longer half-life) and fluoroquinolones to allow for treatment shortening. Study 31/A5349 assessed whether two 4-month rifapentine-based treatment regimens were non-inferior to the standard 6-month regimen for drug-susceptible pulmonary TB. This presentation reviewed outcomes among the subset of HIV+ participants in the trial. Out of 2,516 participants, 214 (8%) were HIV+, with a median CD4 count of 344 cells/uL. ARV regimens were efavirenz-based.
As in the overall study population, among participants with HIV, a 4-month treatment based on rifapentine and moxifloxacin was found to be non-inferior to standard 6-month therapy, although a 4-month regimen without moxifloxacin did not meet the noninferiority criteria. If these results are confirmed, the burden of TB treatment on patients and health systems will be lightened. Drug interactions with rifapentine have not been as well-characterized as for rifampin. Bictegravir is not recommended to be given with rifapentine, although data with dolutegravir are encouraging.
HIGH-DOSE RIFAMPICIN FOR HIV-ASSOCIATED TB MENINGITIS: A PHASE II RANDOMISED TRIAL
Tuberculous meningitis (TBM) remains associated with substantial morbidity and mortality, particularly among persons with HIV. Although there is great interest in host-directed therapies to modulate the immune response in TBM, efforts have also focused on optimizing antimicrobial therapy. Of the standard first-line TB drugs, rifampin (RIF) achieves relatively poor levels in CSF and the doses chosen historically for TB were drive more by cost concerns. Consequently, there has been interest in studying substantially higher doses of RIF in TBM. In this phase 2 RCT, Cresswell and colleagues randomized persons with suspected TBM (n=60, 92% HIV+) to standard 4 drug therapy (RIF 10 mg/kg/day), high dose PO RIF (35 mg/kg/day), or initial IV RIF (20mg/kg/day x 14days followed by PO 35 mg/kg/day). High dose RIF was well-tolerated. Whereas standard dosing of RIF was associated with undetectable CSF RIF levels in 56% of participants, RIF 35 mg/kg/day was associated with RIF levels >MIC in CSF among ~95% of participants. No differences in 24-week mortality were seen, though larger studies are underway.
A SIMPLE AND SAFE APPROACH TO HCV TREATMENT: FINDINGS FROM THE A5360 (MINMON) TRIAL
Directly-acting antivirals for hepatitis C have revolutionized treatment of this disease. However, efforts to streamline laboratory testing & clinician monitoring would help make treatment more widely available, particularly in resource-limited settings. In the MINMON study, 399 participants with active hepatitis C (HCV viral load >1000 IU/ml) and without prior HCV treatment received 12 weeks of the pan-genotypic regimen of sofosbuvir/velpatasvir. Persons with decompensated cirrhosis were excluded. No baseline HCV genotyping was done, except for persons with HIV co-infection (n=166, 42%). In contract to typical US practice, the entire 84 dose course of treatment was dispensed at study entry, and there were no scheduled in person visits or labs during the course of therapy. Participants had remote visits scheduled at week 4 of therapy and then at week 24. Genotype testing on banked specimens indicated that 62% were genotype 1, 7% were genotype 7, and 20% were genotype 3. Treatment response was excellent (95%), and treatment was well-tolerated as expected with this regimen. The results of this study suggest that among persons with compensated liver disease and hepatitis C, excellent outcomes can be achieved with minimal clinical monitoring and laboratory testing thereby increasing access to HCV therapy.