26 January 2021 – Important advances in HIV prevention research were announced today at the 4th HIV Research for Prevention Conference (HIVR4P // Virtual), convened by IAS – the International AIDS Society.
Highlights included findings from a pair of trials evaluating whether infusions with a broadly neutralizing antibody (bNAb) can prevent HIV acquisition and positive interim results from a study of long-acting injectable pre-exposure prophylaxis (PrEP) in women. Other announcements included promising data from a study of islatravir as a once-monthly PrEP pill, a study warning that many African countries are not on track to meet key UNAIDS prevention targets, new data on global uptake of PrEP, and a promising new method to induce bNAbs that could help speed HIV vaccine development.
“COVID-19 has disrupted research around the world, so it’s especially exciting to see this new progress,” said IAS President Adeeba Kamarulzaman. “These research advances on options like broadly neutralizing antibodies and injectable PrEP could help significantly strengthen our HIV prevention toolkit.”
Studies provide proof-of-concept for bNAbs to prevent HIV acquisition
Lawrence Corey of Fred Hutchinson Cancer Research Center presented encouraging results from the Antibody Mediated Prevention (AMP) trials, which are evaluating whether a broadly neutralizing antibody (bnAb) directed at the CD4 binding site of HIV (VRC01) can prevent HIV acquisition. The study enrolled men and transgender persons who have sex with men (MSM/TG) in the Americas (HVTN 704/HPTN 085) and cisgender women in sub-Saharan Africa (HVTN 703/HPTN 081) into two parallel trials. Enrollees received 10 intravenous infusions at 8- week intervals of VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo. In vitro neutralization sensitivity of VRC01 for each acquired isolate (IC80) was measured by the TZM-bl assay.
VRC01 reduced acquisition of HIV isolates with in vitro sensitivity to the antibody of IC80 <1 μg/ml. Against this group of viruses, receipt of VRC01 achieved 75% protection over the 20- month study period in women at risk for HIV in sub-Saharan Africa exposed to subtype C variants and MSM/TG in South America, Switzerland, and the U.S. exposed to subtype B variants. Susceptibility to the antibody was the important determinant of antiviral activity. The incidence of HIV among isolates sensitive to VRC01 (IC80 <1 μg/ml) was 0.2/100 person-years in VRC01 recipients vs. 0.86 in control recipients (P<0.001) (estimated efficacy 75.4%).
VRC01 did not prevent the acquisition of isolates with IC80 >1.0 μg/ml. The AMP trials were designed conjecturing that strains with an IC80 <10 g/ml would be effectively inhibited by VRC01, an in vitro cutoff met for 65-81% of strains in contemporaneous subtype B and C panels. Because only 30% of control arm-acquired isolates had IC80 <1 μg/ml, overall prevention efficacy was 26.6% for HVTN 704/HPTN 085 and 8.8% for HVTN 703/HPTN 081 (P>0.10).
The authors concluded that these studies provide proof-of-concept for bnAbs to prevent HIV acquisition. The breadth and levels of a bnAb required for effective prevention are predicted by the in vitro neutralization sensitivity of the viruses circulating in the community as measured in the TZM-bl assay. These findings provide the guideposts for the development of combination bnAbs for the prevention of sexually acquired HIV. [Summary is based on submitted abstract; updated data may be presented at the conference.]
Abstract: VRC01 Antibody Prevention of HIV Session: Late-Breaking Trials at R4P
Further evidence that long-acting injectable cabotegravir safely and effectively prevents HIV infection in women
Final updated results from the blinded phase of the HPTN 084 trial, including new data on weight gain, pregnancy, and STI incidence, provide further evidence that a PrEP regimen of long-acting injectable cabotegravir (CAB) is safe and superior to daily oral tenofovir/emtricitabine (TDF/FTC) in preventing HIV among cisgender women in Africa.
The blinded phase of HPTN 084 was stopped early last year after an interim analysis by the trial’s data safety monitoring board.
The trial enrolled 3,224 HIV-negative, sexually active cisgender women in sub-Saharan Africa. Participants were randomized to either active CAB plus TDF/FTC placebo or active TDF/FTC plus CAB placebo. They received five weeks of the daily oral product followed by intramuscular injections every eight weeks after an initial four-week interval load, alongside daily oral pills.
According to presenter Sinead Delany-Moretlwe of the University of the Witwatersrand, these updated data confirm CAB as the first safe and effective injectable HIV prevention agent for cisgender women. Highlights:
- CAB and TDF/FTC were both highly effective in preventing HIV. A total of 40 HIV infections were observed (4 in the CAB group; 36 in the TDF/FTC group) over 3,892 person-years; pooled HIV incidence was 1.03 per 100 person-years. However, CAB was superior to TDF/FTC; women in the CAB group had an 89% lower risk of HIV infection compared to the TDF/FTC group, likely because of the adherence advantage conferred by 8 weekly injections
- Both products were safe and well-tolerated, with few differences in Grade 2+ adverse events by arm – apart from injection site reactions, which were higher in the CAB group but generally mild. An immediate increase in body weight (about 0.4 kg) was observed in the CAB arm, but it was small compared to the weight gain in both arms over the course of the study (+2.4 kg/year in the CAB arm; +2.2 kg/year in the TDF/FTC arm).
- Pregnancy incidence per 100 person-years was 1.3 total (1.5 in the CAB group, 1.1 in the TDF/FTC group); no congenital anomalies were reported.
- The incidence of chlamydia and gonorrhea was similar in both study arms; using these STIs as a marker of risk compensation, there was no evidence of differences in risk by arm.These results complement those from HPTN 083, which reported last year that long-acting injectable CAB was superior to daily oral TDF/FTC in preventing HIV among cisgender men and transgender women who have sex with men. [Summary includes updated information that is not in the submitted abstract but will be presented at the conference.]Abstract: Long-acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women: interim results from HPTN 084
Session: Late-Breaking Trials at R4P
Abstract: Trial design, enrollment status, demographics, and pharmacokinetics (PK) data from a blinded interim analysis from a phase 2a trial of Islatravir once monthly (QM) for HIV pre-exposure prophylaxis (PrEP)
Session: PrEP via novel mechanisms of delivery: Into the unknown
African countries not on track to reach 2030 targets for HIV testing and condom use
An analysis of data from 38 African countries predicts that few, if any, are on track to reach key UNAIDS targets for HIV testing and condom use by 2030. The study, presented by Phuong Nguyen of St. Luke’s International University, is based on 114 nationally-representative datasets representing more than 1.4 million sexually active people.
The study team estimated coverage of annual HIV testing and condom use at last higher-risk sex for each country and year to 2030, and the probability of reaching UNAIDS testing and condom use targets of 95% coverage by 2030.
The team calculated that overall, the probabilities of reaching the 2030 targets were very low for both HIV testing (0% to 28.5%) and condom use (0% to 12.1%). They predict that the countries with the highest coverage of annual HIV testing in 2030 will be Eswatini with 92.6%, Lesotho with 90.5%, and Uganda with 90.5%, and the countries with the highest proportion of condom use will be Eswatini with 85%, Lesotho with 75.6%, and Namibia with 75.5%.
Based on these projections, the study concludes that there is currently “little prospect of reaching global targets for HIV/AIDS elimination,” and calls for “more attention to funding and expanding testing and treatment” in Africa. [Summary includes updated information that is not in the submitted abstract but will be presented at the conference.]
Abstract: Progress toward HIV elimination goals: Trends in and projections of Treatment as Prevention strategy in 38 African Countries
Session: Epidemiology: Using the basic science of implementation
Global PrEP uptake has increased but falls far short of UNAIDS target
A study from AVAC finds that while global PrEP uptake has increased significantly over the past four years, it still falls far short of the UNAIDS target.
The study, presented by Kate Segal, analyzed data from AVAC’s Global PrEP Tracker to identify global and regional PrEP initiation trends from the third quarter of 2016 through the second quarter of 2020. The study team found that global PrEP uptake increased six-fold in approximately four years, from 102,446 initiations in 2016 to 651,586 in 2020. However, annual growth has slowed over time, from 104% from 2017-2018 to 55% from 2018-2019 to 18% from 2019-2020.
At the regional level, Oceania had the highest rate of change, with total PrEP initiations increasing from 318 to 29,093, driven largely by Australia. Sub-Saharan Africa substantially expanded PrEP access, from 4,154 initiations in 2016 to 290,981 by mid-2020, comprising 44% of the global total. Brazil led PrEP uptake in Latin America and the Caribbean, accounting for two-thirds of initiations, and Thailand comprised 51% of initiations in Asia. The U.S. had the most cumulative initiations at 203,837, about one-third of the global total, but saw comparatively modest growth rates. According to the study team, shared traits in many of these settings are “early adoption [of PrEP], national commitment to scale-up, and programs tailored to populations at high risk offering rights-based services and linkages to social support.”
The study concludes that “while PrEP initiations have grown exponentially in several countries, global uptake falls far short of UNAIDS’ target of 3 million users, indicating a need for sustained demand creation where PrEP programs exist and scale up where PrEP is provided by demonstration projects with limited reach.” [Summary is based on submitted abstract; updated data may be presented at the conference.]
Abstract: The Evolution of Oral PrEP Access: Tracking trends in global oral PrEP use over time Session: PrEP is here: Considerations to achieve continued use
Promising new method to induce bNAbs could help speed HIV vaccine development Emilie Seydoux of Fred Hutchinson Cancer Research Center discussed the development of a new VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies – an advance that could help accelerate the development of an HIV vaccine.
VRC01-class antibodies are among the most broad and potent broadly neutralizing antibodies (bNAbs) known; they target the CD4-binding site on the HIV envelope protein (Env) and use a unique combination of VH1-2*02 VH gene paired with light chains expressing rare 5 amino acid long CDRL3 domains. Precursor VRC01-class bNAbs display no reactivity to recombinant Env, which lead to the development of germline-targeting immunogens to engage and stimulate naïve VRC01-class precursor B cells. However, these immunogens also present off-target epitopes that could hinder the maturation of VRC01-class bNAbs.
As an alternative, this study developed a panel of monoclonal anti-idiotypic antibodies (ai-mAbs) that can target and potentially activate putative VRC01-class precursors with high affinity. In B cell sorting experiments, none of the ai-mAbs were able to reliably engage VRC01-class precursor B cells. The study team engineered a bispecific molecule (iv4/iv9) derived from two ai- mAbs (iv4 and iv9), from which the iv9 arm is specific for VRC01-class heavy chains and the iv4 arm for VRC01-class light chains. Compared to the parental ai-mAbs, iv4/iv9 could bind ex vivo B cell receptors comprised of a germline VRC01-class heavy or light chain, but it preferentially crosslinked and activated B cells expressing both VRC01-class heavy and light chains. When used as an immunogen, the bispecific ai-mAb was more efficient at engaging and expanding putative VRC01-class precursor B cells in vivo than either iv4 or iv9 Fabs.
These results are relevant not only to the development of an HIV vaccine aimed at eliciting VRC01-class antibodies, but to general efforts to activate specific B cell lineages that produce protective antibodies, and further suggest that ai-mAbs-derived immunogens may have general utility as germline targeting immunogens against diverse B cell targets. [Summary is based on submitted abstract; updated data may be presented at the conference.]
Abstract: Development of a novel VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies
Session: Building better bNAbs
About the IAS
IAS – the International AIDS Society – leads collective action on every front of the global HIV response through its membership base, scientific authority and convening power.
Founded in 1988, the IAS is the world’s largest association of HIV professionals, with members in more than 170 countries. Working with its members, the IAS advocates and drives urgent action to reduce the impact of HIV. The IAS is also the steward of the world’s most prestigious HIV conferences: the International AIDS Conference, the IAS Conference on HIV Science, and the HIV Research for Prevention Conference (HIVR4P).