VRC01 antibody only prevents minority of HIV infections: AMP study results

24 February 2021. Related: Conference reports, HIV prevention and transmission, R4P 2021 Virtual.

Simon Collins, HIV i-Base

Introduction

Some of the most important news from the virtual R4P conference this year included early results from two large HIV transmission studies using a monoclonal antibody (mAb) called VRC01. This antibody, that showed strong cross-clade neutralisation, was identified in 2009 in an HIV positive slow progressor in the US NIH cohort. It was then isolated and manufactured into a treatment in a collaboration involving many leading public health laboratories.

Even though the studies didn’t reduce HIV transmission overall, they showed that VRC01 worked in a subset of participants. Results were presented as a late-breaker oral abstract by Lawrence Corey, study co-chair. Further aspects of this research discussed other aspects of this important research in the last roundtable symposium of the meeting. [1, 2]

Between Spring 2016 and Autumn 2018, the two AMP studies (Antibody Mediated Prevention) randomised over 4600 participants (1:1:1) to receive VRC01 (either 10 mg/kg or 30 mg/kg), or to a matched placebo. Infusions were given every two months (total ten per person) with follow-up over two years.

Entry criteria defined risk of HIV as having anal sex without a condom at least once over the previous six months, or having anal sex with two or more partners over six months. Participants had to be between 18 to 50 years old. Exclusion criteria included some pre-existing health complications including BMI >40.

AMP-1 (HVTN 704/HPTN 085) enrolled 2699 gay men and transgender women, in the US (n=1381), Peru (n=1131), Brazil (n=151) and Switzerland (n=36). Of these, 899 received 10 mg, 897 received 30 mg, and 903 received placebo. Roughly 90% identified as male, 5% as transgender female, 2% as female, and 1% each as gender queer, gender non-conforming, or transgender male. Just over half were aged 21 to 30 with another 11% aged 18  to 20. Median number of partners in the previous two months was three and STIs were common at baseline, including 13% with syphilis.

AMP-2 (HVTN 703/HPTN 081) enrolled 1924 heterosexual women in seven countries in sub-Saharan Africa, mostly in South Africa (n=1019), Zimbabwe (n=434), Malawi (n=180) and Botswana (n=150). Of these, 642 received 10 mg, 645 received 30 mg and 637 placebo. Median age was 25 (IQR: 22 to 30) with 42% <25 years old. Condom use was generally low (55% sometimes, 17% never). Median number of partners in the previous two months was 2 (range: 0 to 300) and 17% reported transactional sex. Approximately 25% had a treatable STI at baseline, mostly asymptomatic (16% chlamydia, 7% trichomoniasis, 2% syphilis).

Efficacy results

The efficacy results from the AMP studies are based on the primary endpoint of HIV infections after 80 weeks and safety results were based on follow up at week 104. This was the first time a mAb has been used in large HIV prevention studies.

In combined results, 175 people became HIV positive (98 in the American and 77 in the African study). Neither dose of VRC01, compared to placebo, had any significant impact on reducing HIV transmission. See Table 1.

However, a subgroup of participants were protected by VRC01 – if this virus was sensitive to the antibody. The lack of effect in the study overall, is related to factors about dosing, formulation and use of mAb monotherapy, some of which were suspected before the studies started.

Table 1: New HIV positive diagnoses (dx) in AMP studies

Dx: diagnoses; CI: Confidence Interval; HT: heterosexual; TGW: transgender women.

Explaining antibody responses

In the AMP studies, a broad panel of potential viruses were categorised by the IC80 values. Three predefined IC80 categories were <1, 1 to 3 and >3 ug/mL In this analysis, the pooled VRC01 arms were approximately 74% less likely to lead to infections against the most sensitive viruses with IC80 <1 ug/mL. compared to placebo. This subgroup reported 9 vs 19 infections in the pooled VRC01 vs placebo arms respectively: prevention efficacy (PE) 75.4 (95%CI: 44.5 to 88.9). No other factors had an impact on efficacy including gender, population, clade, region or dose.

In explaining these results, there are three main characteristics that are needed for a mAb to be effective.

One is that the virus has to be sensitive to the individual mAb. This is a little like a virus being drug resistant for someone using oral PrEP.

When designing the study, researchers tested VRC01 sensitivity in vitro to a global panel of clade B /C viruses and estimated that 60 to 70% of strains would be sensitive at a target mAb concentration of <10 ug/mL. Note though that this accepted that 30% of viruses would not be sensitive, so that protection would never be as high as with oral PrEP.

If sensitive, the related second issue is to use a dose (or titre) that will give high enough levels of the mAb – a little like testing drug levels with oral PrEP. The VRC01 doses were chosen to inhibit (ie stop) 80% of viral replication – called the IC 80 (Inhibitory Concentration).

In practice, the estimated sensitivity to VRC01 was accurate: 47/64 viruses (73%) from the placebo participants who became HIV positive were sensitive with an IC80 <10 ug/mL. However, the researchers underestimated the in vivo sensitivity and only 30% were sensitive at IC80 level <1 ug/mL, that had also been selected for the studies.

Finally, a third issue relates to using VRC01 as monotherapy. Just as with HIV treatment, a single mAb can be easily overcome in people who become HIV positive. This was known before AMP and was also observed in the results. [3]

Participants who became HIV positive in the active arms developed approximately 2.4 fold greater IC80 compared to those in the placebo arm (p=0.003). Sensitivity to VRC01 (<1 ug/mL) also resulted in lower post-infection viral load in the treatment arms.

The PK limitations of VRC01 meant that mAb levels had peaks and troughs where protection would be more likely early in the dosing schedule but that would wane during the second month. Long-acting formulations – notably VRC01-LS, also have more consistent PK levels throughout.

This supported early concerns raised about the AMP studies about using monotherapy.

Before the AMP studies started it was already known that VRC01 would only cover about 90% of circulating viruses. So maximum efficacy would likely be less than 90%, perhaps significantly so if resistance developed during low concentration of monotherapy. In fact, the protocol was based on VRC01 having perhaps 60% efficacy. So, even before the first participant were enrolled the researchers knew this intervention would be less effective than oral PrEP (with good adherence).

As PrEP became available in different countries during the study it was added as an option as part of the standard of care. Although few data were presented on PrEP use, approximately 40% of AMP-1 used oral TDF/FTC, with no information given for PrEP use in AMP-2.

Overall retention was also incredibly high with <10% and 5% drop out in AMP-1 and AMP-2 respectively, This is an important logistical achievement given the intensity of the treatment. It also provides a timely example for COVID-19 that mAb infusions are feasible and acceptable to thousands of participants who are not hospitalised, and in a wide range of countries.

These studies also involved a considerable amount of community involvement and education. This engagement can have positive health effects including increasing participant confidence in this aspect of their health. This is probably what was referred to by participant quoted in various presentations. For example: “Wow, I am so pleased to learn how successful the study has been thus far and I am excited to see what life-changing medicines will come of it” – suggests these were from people who remained HIV negative.

The congratulatory tone of some of the talks would perhaps have been more appropriate if the study did in fact provide overall protection. Only Michel Nussenzweig, a leading antibody researcher at the Rockefeller University, while acknowledging the logistical achievement, clearly said that the overall results were disappointing, based on issues linked to early modelling and given the knowledge that monotherapy would not suppress infection. [4, 5]

Myron Cohen, the other study co-chair, replied that “at least the train has left the station” – supporting the proof-of-principal of mAbs to prevent infection. Also, recognising that the AMP studies were able to use the accumulated 82 kg of VRC01 (a staggering amount of antibody) even though monotherapy with this compound was not going to produce the results that everyone wanted.

The symposium discussion – recommended to understand many of the details – also commented on the potential for continued treatment to mask HIV infections by suppressing seroconversion (similar to PEP). Also, the general surprise that results were similar for men and women.

The AMP studies were run jointly by the HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network (HPTN).

The American study was run in Brazil, Peru, Switzerland, and the US and the African study was run in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe.

comment

It is important to recognise the lack of overall benefit from the AMP studies – and this doesn’t negate the significant achievement of running large preventions studies against a background of changing research. But it also raises the overlap between ethical and practical questions.

As with other prevention studies, all participants were counselled about HIV risk and given information about how to reduce risks. However, the AMP studies were designed to reduce the risk of HIV transmission and participants probably joined the studies in the hope that they would not become HIV positive. Therefore, informed consent also incuded the possibility of limited protection and that this was an experimental option.

The proof of principle that VRC01 reduced the risk of HIV transmission in a subgroup of participants is also important. It supports future research continuing, using mAbs with greater potency and breadth in combinations (including bispecific and trispecific mAbs), that use LS formulations – and ideally only require 6-monthly dosing.

The R4P conference also included results from using VRC07-523LS (a long-acting version of VRC01) to protect infants during breastfeeding, reported below. [6]

In the context of COVID-19, the AMP studies also showed that mAb infusions were an acceptable long-term treatment for thousands of people who were not hospitalised, including in low-income settings.

References

1. Corey L. The AMP studies: phase 2b proof-of-concept trials designed to test the efficacy of VRC01 antibody to prevent HIV acquisition. HIVR4P virtual conference 2021. Late breaker oral presentation HY 0101LB.
   https://virtual.hivr4p.org/media-434-hy01—late-breaking-trials-at-r4p  https://ampstudy.org/assets/docs/AMP-Trials-Efficacy-Results-Community-Slides_01OCT2020.pdf (PDF)
2. Antibody Mediated Prevention trial: Where to from here? HIVR4P virtual conference 2021. Roundtable symposium RT03.
   https://virtual.hivr4p.org/media-500-rt03—antibody-mediated-prevention-trial-where-to-from-here
3. Bar K et al. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N Engl J Med 2016; 375:2037-2050. DOI: 10.1056/NEJMoa1608243. (24 November 2016).
   https://www.nejm.org/toc/nejm/375/21
4. Cohen YZ et al. Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against clade B clinical isolates produced in peripheral blood mononuclear cells. Journal of Virology, 92(5)e01883-17. (March 2018).
   https://jvi.asm.org/content/jvi/92/5/e01883-17.full
5. Lorenzi CG et al. Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against primary African isolates. Journal of Virology, 95(5)e01909-20. (March 2021).
   https://jvi.asm.org/content/95/5/e01909-20.full
6. Clayden P. Long-acting bNAb is safe and well tolerated and achieves target concentrations in newborns (VRC07-523LS). HTB (24 February 2021).
   https://i-base.info/htb/39941