Article
Combination anti-HIV antibodies provide
sustained virological suppression
https://doi.org/10.1038/s41586-022-04797-9 Michael C. Sneller1,10, Jana Blazkova1,10, J. Shawn Justement1, Victoria Shi1,
Brooke D. Kennedy1, Kathleen Gittens2, Jekaterina Tolstenko1, Genevieve McCormack1,
Received: 25 October 2021
Emily J. Whitehead1, Rachel F. Schneck1, Michael A. Proschan3, Erika Benko4, Colin Kovacs4,
Accepted: 25 April 2022 Cihan Oguz5,6, Michael S. Seaman7, Marina Caskey8, Michel C. Nussenzweig8,9,
Anthony S. Fauci1, Susan Moir1,10 & Tae-Wook Chun1,10 ✉
Published online: 1 June 2022
Check for updates
Antiretroviral therapy is highly effective in suppressing human immunodeficiency
virus (HIV)1. However, eradication of the virus in individuals with HIV has not been
possible to date2. Given that HIV suppression requires life-long antiretroviral therapy,
predominantly on a daily basis, there is a need to develop clinically effective
alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we
report the results of a two-component clinical trial involving the passive transfer of
two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074.
The first component was a randomized, double-blind, placebo-controlled trial that
enrolled participants who initiated antiretroviral therapy during the acute/early
phase of HIV infection. The second component was an open-label single-arm trial that
enrolled individuals with viraemic control who were naive to antiretroviral therapy.
Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks,
were well tolerated without any serious adverse events related to the infusions.
Compared with the placebo, the combination broadly neutralizing monoclonal
antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks)
after analytical treatment interruption, provided that no antibody-resistant HIV was
detected at the baseline in the study participants. Similarly, potent HIV suppression
was seen in the antiretroviral-therapy-naive study participants with viraemia carrying
sensitive virus at the baseline. Our data demonstrate that combination therapy with
broadly neutralizing monoclonal antibodies can provide long-term virological
suppression without antiretroviral therapy in individuals with HIV, and our experience
offers guidance for future clinical trials involving next-generation antibodies with
long half-lives.
Modern antiretroviral therapy (ART) enables the near-complete sup- or therapeutic agents that can eradicate the persistent viral reservoir,
pression of plasma viraemia in most individuals with HIV1. However, dif- long-term suppression of plasma viraemia by infrequent administra-
ficulties in adherence to a lifetime of medication, long-term side effects tion of long-acting antiretroviral drugs12–14 or broadly neutralizing
and the possibility for developing antiretroviral drug-resistant virus monoclonal antibodies (bNAbs)15–18 against HIV remains the most real-
have prompted intense research aimed at developing new therapies istic approach for achieving ART-free virological suppression. In this
to achieve sustained virological remission without the need for daily regard, passive transfer of single bNAbs in individuals with HIV in the
ART4. In this regard, considerable efforts have focused on eliminating context of analytical treatment interruption (ATI) has shown limited
the persistent HIV reservoir5,6—one of the major impediments to viral success in part due to the presence of pre-existing and/or emergent
eradication7–9—in individuals with HIV receiving clinically effective antibody-resistant virus19–22. To mitigate this shortcoming, a combina-
ART10. However, despite decades of research, it is becoming increasingly tion approach involving the use of two bNAbs that bind to different
clear that complete eradication of the persistent HIV reservoir in an indi- regions of the HIV Env glycoprotein has led to promising results15,23.
vidual with infection is not feasible using currently available approaches One such study used two bNAbs—one targeting the CD4-binding site
and therapies11. In the absence of an effective vaccine against HIV and/ on the HIV Env spike (3BNC117) and the other targeting the V3 loop and
1
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. 2Critical Care Medicine Department,
Clinical Center, NIH, Bethesda, MD, USA. 3Biostatistics Research Branch, NIAID, NIH, Bethesda, MD, USA. 4Maple Leaf Medical Clinic, Toronto, Ontario, Canada. 5NIAID Collaborative
Bioinformatics Resource, NIAID, NIH, Bethesda, MD, USA. 6Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. 7Center for
Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 8Laboratory of Molecular Immunology, The Rockefeller University, New York,
NY, USA. 9Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA. 10These authors contributed equally: Michael C. Sneller, Jana Blazkova, Susan Moir, Tae-Wook Chun.
✉e-mail:
Nature | Vol 606 | 9 June 2022 | 375
,Article
surrounding glycans (10-1074)—demonstrated that three infusions over Table 1 | Baseline characteristics of the study participants.
a period of 6 weeks significantly delayed plasma viral rebound in indi-
viduals with infection after ATI23. Furthermore, previous studies have Group 1 Group 2
suggested that, besides their ability to neutralize HIV, certain bNAbs Characteristic Antibody Placebo n=5
could potentially mediate the clearance of persistent viral reservoirs arm (n = 7) arm (n = 7)
and/or enhance host immunity against the virus24–27. Accordingly, we Sex, number (%) Male 7 (100) 7 (100) 5 (100)
conducted this study to further investigate the long-term effect of Median age (range) 40 (27–57) 34 (29–56) 44
treatment with a combination of the bNAbs 3BNC117 and 10-1074 on (years) (35–52)
the suppression of plasma viraemia and the dynamics of persistent Race or ethnic African American 1 (14.3) 0 1 (20)
viral reservoirs and their effect on immune parameters/responses in group, number (%)
individuals with HIV. Caucasian 4 (57.1) 5 (71.4) 3 (60)
Hispanic 1 (14.3) 1 (14.3) 0
Asian 1 (14.3) 1 (14.3) 0
Study design and participants
Mixed 0 0 1 (20)
Between September 2018 and January 2021, we conducted a phase 1
Antiretroviral NRTI 7 (100) 7 (100) –
clinical trial to assess the safety, tolerability and efficacy of the com-
regimen, number
bination of the bNAbs 3BNC117 and 10-1074 in individuals with HIV. (%)
This trial comprised two components: (1) a randomized, double-blind,
NNRTI 1 (14.3) 0 –
placebo-controlled study involving 14 participants in whom ART was ini-
PI/INSTI 1 (14.3) 0 –
tiated during the acute/early phase of infection and who subsequently
underwent ATI shortly after receiving the first infusion of bNAbs or INSTI 6 (85.7) 7 (100) –
placebo (group 1); and (2) an open-label study involving 5 individu- PK 2 (28.6) 2 (28.6) –
als with viraemic control who were naive for ART and had baseline Inclusion criteria Acute infection 5 (71.4) 2 (28.6) –
plasma viraemia of between 200–5,000 copies per ml (group 2) (Table 1, meta, number (%)
Extended Data Fig. 1 and Supplementary Table 1). The study participants Early infection 2 (28.6) 5 (71.4) –
were not prescreened for the sensitivity of their HIV to 3BNC117 and Reported 5 (71.4) 4 (57.1) –
10-1074 before enrolment (the study inclusion criteria are described seroconversion
in the Methods). The randomized controlled portion of the study had illness, number (%)
a planned enrolment of 30 study participants. However, the study was Median time 22 (0–50) 38 (9–76) –
prematurely halted in March 2020 owing to the increased safety con- between HIV
diagnosis and
cerns associated with ATI in the setting of the COVID-19 pandemic. start of ART (days)
The study participants in the antibody arm of group 1 and group 2 (range)
received 4–8 (median, 8) 3BNC117 (30 mg kg−1) and 10-1074 (30 mg kg−1) Median duration of 3.7 2.9 –
infusions— two in the first month and once monthly thereafter (Fig. 1a). suppressive ART at (2.6–12.6) (1.6–6.6)
The infusions of bNAbs were well tolerated, with most adverse events study entryb (years)
(range)
being mild-to-moderate (grade 1 or 2) transient symptoms, including
chills and/or fever (Supplementary Table 2). One study participant in Median CD4+ T cell 799 612 640
count (cells per (543–1,177) (426–832) (527–
group 1 (participant 01) experienced grade 1 fever and grade 2 rigors
mm3 at study entry) 1,011)
during the first 3BNC117 infusion and did not receive the first dose (range)
of 10-1074. Thus, this participant was effectively on antibody mono- a
See Methods for the acute and early infection inclusion criteria.
therapy for the first 2 weeks of the study. For subsequent infusions, b
Indicates the duration of uninterrupted suppression of plasma viraemia.
participant 01 was premedicated with ibuprofen and completed the INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibi-
remaining study infusions of both antibodies with minimal (grade 1) tor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PK, pharmacoki-
or no reactions. No participant discontinued study medications due to netic enhancer.
antibody-related adverse events. There was no grade 3 or higher adverse
event, including serious adverse events that were judged to be possibly,
probably or definitely related to the study drugs. The baseline median
CD4+ T cell counts for the antibody and the placebo arm of group 1 were participants, respectively (P = 0.001; Fig. 1c (left)). Notably, participant
799 and 612 cells per µl, respectively (Table 1). The baseline median 11, in the placebo arm, who did not meet criteria to restart ART, deviated
CD4+ T cell count of group 2 was 640 cells per µl (Table 1). from the protocol and surreptitiously resumed ART at study week 12
owing to concerns about rising plasma viraemia. Participant 14, in the
bNAb arm, reinitiated ART before meeting the restart criteria due to
Effect of bNAbs on virological parameters concerns associated with the COVID-19 pandemic. Thus, the data from
Three days after receiving the first infusion of 3BNC117 and 10-1074 or these participants were censored for end-point analysis.
placebo, the study participants in group 1 underwent ATI and plasma In an additional post hoc analysis, 5 out of the 7 study participants in
viraemia and CD4+ T cell counts were measured every 2 weeks (Fig. 1a). the bNAb arm of group 1 maintained suppression of plasma viraemia
For group 1, the protocol-predefined virological end point was the dif- (<40 copies per ml), whereas all of the study participants in the pla-
ference between the bNAb and placebo arms in the number of study cebo arm of group 1 experienced plasma viral rebound within the first
participants who experienced plasma viral rebound and met the cri- 8 weeks of ATI. The median duration of plasma viraemia suppression at
teria to restart ART before study week 28. As shown in Fig. 1b, c, 6 out <200 copies per ml in group 1 was 33.4 weeks (range, 7.4–43.3 weeks)
of the 7 study participants in the placebo arm experienced plasma and 3.4 weeks (range, 1.9–7.9 weeks) in the bNAb and placebo arms,
viral rebound and met the criteria to restart ART before study week respectively (P = 0.002; Fig. 1c (right)). Notably, two group 1 bNAb study
28 compared with none of the 7 participants in the treatment arm. participants (01 and 14), whose plasma viraemia rebounded by more
The median duration off ART was 39.6 weeks (range, 9.9–49.6 weeks) than 200 copies per ml within 8 weeks into ATI, carried bNAb-resistant,
and 9.4 weeks (range, 5.3–26 weeks) for the group 1 bNAb and placebo replication-competent HIV in their CD4+ T cells at the baseline (Fig. 2a).
376 | Nature | Vol 606 | 9 June 2022
, a
…………..
Screen W0 W2 W4 W8 W12 W16 W20 W24 F/U W4 F/U W12 F/U W24
Group 1 ART ATI + 3BNC117 and 10-1074 or placebo Follow-up/ART
ART stop ART restart
…………..
Screen W0 W2 W4 W8 W12 W16 W20 W24 F/U W4 F/U W12 F/U W24
Group 2 3BNC117 and 10-1074 Follow-up
b Group 1: bNAb arm Group 1: placebo arm
Plasma viraemia (copies per ml)
Plasma viraemia (copies per ml)
107 Participant 01 Participant 02 Participant 05 103 107 Participant 03 Participant 04 Participant 07
Levels of bNAbs in plasma
106 106
105 102 105
(μg ml–1)
104 104
103 101 103
102 102
0 8 16 24 32 40 48 56 64 72 80 0 8 16 24 32 40 48 56 64 72 80 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 0 8 16 24 32 40
Participant 06 Participant 08 Participant 13 103 Participant 09 Participant 10 Participant 11
Plasma viraemia (copies per ml)
107 107
Plasma viraemia (copies per ml)
Levels of bNAbs in plasma
106 106
105 102 105
104 (μg ml–1) 104
103 101 103
102 102
0 8 16 24 32 40 48 56 64 0 8 16 24 32 40 48 56 64 72 0 8 16 24 32 40 48 56 0 8 16 24 32 0 8 16 24 32 40 0 8 16 24
Participant 14 103
Plasma viraemia (copies per ml)
Plasma viraemia (copies per ml)
107 107 Participant 12
Levels of bNAbs in plasma
106 106
105 102 105
(μg ml–1)
104 104
103 101 103
102 102
3BNC117
10-1074
0 8 16 24 32 40 0 8 16 24 32
Group 2
Participant S2 Participant S4
Plasma viraemia (copies per ml)
107 Participant S1 Participant S3 Participant S5 103
Levels of bNAbs in plasma
106
105 102
(μg ml–1)
104
103 101
102
0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56
Time (weeks)
c Group 1: bNAb arm
d 107
P = 0.82
100 100
Suppression of plasma viraemia
Group 1: placebo arm
106
reinitiation (copies per ml)
(<200 copies per ml, %)
Participants remaining
Plasma viraemia at ART
80 P = 0.001 80 P = 0.002 Participant
01 03
off ART (%)
105 02 04
60 60
05 07
40 40 06 09
104 08 10
13 12
20 20
103 Geometric
mean
0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48
102
Time after ATI (weeks) Time after ATI (weeks) bNAb arm Placebo arm
Fig. 1 | See next page for caption.
The median duration of suppression of plasma viraemia at below 200 in vivo. In group 2, 2 out of the 5 study participants whose baseline
copies per ml for the participants with sensitive virus was 35.4 weeks infectious HIV was sensitive to both antibodies maintained complete
(range, 31.7–43.3 weeks). There was no difference in the level of plasma suppression of plasma viraemia for an average of 41.7 weeks (Figs. 1b
viraemia before reinitiation of ART between the bNAb and placebo and 2a). Taken together, these results demonstrate that the combina-
arms in the group 1 study participants (P = 0.82; Fig. 1d), suggesting tion therapy with 3BNC117 and 10-1074 is highly effective in suppress-
that bNAb-mediated virological suppression may not necessarily alter ing HIV in the absence of ART for extended periods, provided that
the kinetics of plasma viral rebound after clearance of the antibodies antibody-resistant virus is not present at the baseline.
Nature | Vol 606 | 9 June 2022 | 377
Combination anti-HIV antibodies provide
sustained virological suppression
https://doi.org/10.1038/s41586-022-04797-9 Michael C. Sneller1,10, Jana Blazkova1,10, J. Shawn Justement1, Victoria Shi1,
Brooke D. Kennedy1, Kathleen Gittens2, Jekaterina Tolstenko1, Genevieve McCormack1,
Received: 25 October 2021
Emily J. Whitehead1, Rachel F. Schneck1, Michael A. Proschan3, Erika Benko4, Colin Kovacs4,
Accepted: 25 April 2022 Cihan Oguz5,6, Michael S. Seaman7, Marina Caskey8, Michel C. Nussenzweig8,9,
Anthony S. Fauci1, Susan Moir1,10 & Tae-Wook Chun1,10 ✉
Published online: 1 June 2022
Check for updates
Antiretroviral therapy is highly effective in suppressing human immunodeficiency
virus (HIV)1. However, eradication of the virus in individuals with HIV has not been
possible to date2. Given that HIV suppression requires life-long antiretroviral therapy,
predominantly on a daily basis, there is a need to develop clinically effective
alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we
report the results of a two-component clinical trial involving the passive transfer of
two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074.
The first component was a randomized, double-blind, placebo-controlled trial that
enrolled participants who initiated antiretroviral therapy during the acute/early
phase of HIV infection. The second component was an open-label single-arm trial that
enrolled individuals with viraemic control who were naive to antiretroviral therapy.
Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks,
were well tolerated without any serious adverse events related to the infusions.
Compared with the placebo, the combination broadly neutralizing monoclonal
antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks)
after analytical treatment interruption, provided that no antibody-resistant HIV was
detected at the baseline in the study participants. Similarly, potent HIV suppression
was seen in the antiretroviral-therapy-naive study participants with viraemia carrying
sensitive virus at the baseline. Our data demonstrate that combination therapy with
broadly neutralizing monoclonal antibodies can provide long-term virological
suppression without antiretroviral therapy in individuals with HIV, and our experience
offers guidance for future clinical trials involving next-generation antibodies with
long half-lives.
Modern antiretroviral therapy (ART) enables the near-complete sup- or therapeutic agents that can eradicate the persistent viral reservoir,
pression of plasma viraemia in most individuals with HIV1. However, dif- long-term suppression of plasma viraemia by infrequent administra-
ficulties in adherence to a lifetime of medication, long-term side effects tion of long-acting antiretroviral drugs12–14 or broadly neutralizing
and the possibility for developing antiretroviral drug-resistant virus monoclonal antibodies (bNAbs)15–18 against HIV remains the most real-
have prompted intense research aimed at developing new therapies istic approach for achieving ART-free virological suppression. In this
to achieve sustained virological remission without the need for daily regard, passive transfer of single bNAbs in individuals with HIV in the
ART4. In this regard, considerable efforts have focused on eliminating context of analytical treatment interruption (ATI) has shown limited
the persistent HIV reservoir5,6—one of the major impediments to viral success in part due to the presence of pre-existing and/or emergent
eradication7–9—in individuals with HIV receiving clinically effective antibody-resistant virus19–22. To mitigate this shortcoming, a combina-
ART10. However, despite decades of research, it is becoming increasingly tion approach involving the use of two bNAbs that bind to different
clear that complete eradication of the persistent HIV reservoir in an indi- regions of the HIV Env glycoprotein has led to promising results15,23.
vidual with infection is not feasible using currently available approaches One such study used two bNAbs—one targeting the CD4-binding site
and therapies11. In the absence of an effective vaccine against HIV and/ on the HIV Env spike (3BNC117) and the other targeting the V3 loop and
1
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. 2Critical Care Medicine Department,
Clinical Center, NIH, Bethesda, MD, USA. 3Biostatistics Research Branch, NIAID, NIH, Bethesda, MD, USA. 4Maple Leaf Medical Clinic, Toronto, Ontario, Canada. 5NIAID Collaborative
Bioinformatics Resource, NIAID, NIH, Bethesda, MD, USA. 6Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. 7Center for
Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 8Laboratory of Molecular Immunology, The Rockefeller University, New York,
NY, USA. 9Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA. 10These authors contributed equally: Michael C. Sneller, Jana Blazkova, Susan Moir, Tae-Wook Chun.
✉e-mail:
Nature | Vol 606 | 9 June 2022 | 375
,Article
surrounding glycans (10-1074)—demonstrated that three infusions over Table 1 | Baseline characteristics of the study participants.
a period of 6 weeks significantly delayed plasma viral rebound in indi-
viduals with infection after ATI23. Furthermore, previous studies have Group 1 Group 2
suggested that, besides their ability to neutralize HIV, certain bNAbs Characteristic Antibody Placebo n=5
could potentially mediate the clearance of persistent viral reservoirs arm (n = 7) arm (n = 7)
and/or enhance host immunity against the virus24–27. Accordingly, we Sex, number (%) Male 7 (100) 7 (100) 5 (100)
conducted this study to further investigate the long-term effect of Median age (range) 40 (27–57) 34 (29–56) 44
treatment with a combination of the bNAbs 3BNC117 and 10-1074 on (years) (35–52)
the suppression of plasma viraemia and the dynamics of persistent Race or ethnic African American 1 (14.3) 0 1 (20)
viral reservoirs and their effect on immune parameters/responses in group, number (%)
individuals with HIV. Caucasian 4 (57.1) 5 (71.4) 3 (60)
Hispanic 1 (14.3) 1 (14.3) 0
Asian 1 (14.3) 1 (14.3) 0
Study design and participants
Mixed 0 0 1 (20)
Between September 2018 and January 2021, we conducted a phase 1
Antiretroviral NRTI 7 (100) 7 (100) –
clinical trial to assess the safety, tolerability and efficacy of the com-
regimen, number
bination of the bNAbs 3BNC117 and 10-1074 in individuals with HIV. (%)
This trial comprised two components: (1) a randomized, double-blind,
NNRTI 1 (14.3) 0 –
placebo-controlled study involving 14 participants in whom ART was ini-
PI/INSTI 1 (14.3) 0 –
tiated during the acute/early phase of infection and who subsequently
underwent ATI shortly after receiving the first infusion of bNAbs or INSTI 6 (85.7) 7 (100) –
placebo (group 1); and (2) an open-label study involving 5 individu- PK 2 (28.6) 2 (28.6) –
als with viraemic control who were naive for ART and had baseline Inclusion criteria Acute infection 5 (71.4) 2 (28.6) –
plasma viraemia of between 200–5,000 copies per ml (group 2) (Table 1, meta, number (%)
Extended Data Fig. 1 and Supplementary Table 1). The study participants Early infection 2 (28.6) 5 (71.4) –
were not prescreened for the sensitivity of their HIV to 3BNC117 and Reported 5 (71.4) 4 (57.1) –
10-1074 before enrolment (the study inclusion criteria are described seroconversion
in the Methods). The randomized controlled portion of the study had illness, number (%)
a planned enrolment of 30 study participants. However, the study was Median time 22 (0–50) 38 (9–76) –
prematurely halted in March 2020 owing to the increased safety con- between HIV
diagnosis and
cerns associated with ATI in the setting of the COVID-19 pandemic. start of ART (days)
The study participants in the antibody arm of group 1 and group 2 (range)
received 4–8 (median, 8) 3BNC117 (30 mg kg−1) and 10-1074 (30 mg kg−1) Median duration of 3.7 2.9 –
infusions— two in the first month and once monthly thereafter (Fig. 1a). suppressive ART at (2.6–12.6) (1.6–6.6)
The infusions of bNAbs were well tolerated, with most adverse events study entryb (years)
(range)
being mild-to-moderate (grade 1 or 2) transient symptoms, including
chills and/or fever (Supplementary Table 2). One study participant in Median CD4+ T cell 799 612 640
count (cells per (543–1,177) (426–832) (527–
group 1 (participant 01) experienced grade 1 fever and grade 2 rigors
mm3 at study entry) 1,011)
during the first 3BNC117 infusion and did not receive the first dose (range)
of 10-1074. Thus, this participant was effectively on antibody mono- a
See Methods for the acute and early infection inclusion criteria.
therapy for the first 2 weeks of the study. For subsequent infusions, b
Indicates the duration of uninterrupted suppression of plasma viraemia.
participant 01 was premedicated with ibuprofen and completed the INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibi-
remaining study infusions of both antibodies with minimal (grade 1) tor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PK, pharmacoki-
or no reactions. No participant discontinued study medications due to netic enhancer.
antibody-related adverse events. There was no grade 3 or higher adverse
event, including serious adverse events that were judged to be possibly,
probably or definitely related to the study drugs. The baseline median
CD4+ T cell counts for the antibody and the placebo arm of group 1 were participants, respectively (P = 0.001; Fig. 1c (left)). Notably, participant
799 and 612 cells per µl, respectively (Table 1). The baseline median 11, in the placebo arm, who did not meet criteria to restart ART, deviated
CD4+ T cell count of group 2 was 640 cells per µl (Table 1). from the protocol and surreptitiously resumed ART at study week 12
owing to concerns about rising plasma viraemia. Participant 14, in the
bNAb arm, reinitiated ART before meeting the restart criteria due to
Effect of bNAbs on virological parameters concerns associated with the COVID-19 pandemic. Thus, the data from
Three days after receiving the first infusion of 3BNC117 and 10-1074 or these participants were censored for end-point analysis.
placebo, the study participants in group 1 underwent ATI and plasma In an additional post hoc analysis, 5 out of the 7 study participants in
viraemia and CD4+ T cell counts were measured every 2 weeks (Fig. 1a). the bNAb arm of group 1 maintained suppression of plasma viraemia
For group 1, the protocol-predefined virological end point was the dif- (<40 copies per ml), whereas all of the study participants in the pla-
ference between the bNAb and placebo arms in the number of study cebo arm of group 1 experienced plasma viral rebound within the first
participants who experienced plasma viral rebound and met the cri- 8 weeks of ATI. The median duration of plasma viraemia suppression at
teria to restart ART before study week 28. As shown in Fig. 1b, c, 6 out <200 copies per ml in group 1 was 33.4 weeks (range, 7.4–43.3 weeks)
of the 7 study participants in the placebo arm experienced plasma and 3.4 weeks (range, 1.9–7.9 weeks) in the bNAb and placebo arms,
viral rebound and met the criteria to restart ART before study week respectively (P = 0.002; Fig. 1c (right)). Notably, two group 1 bNAb study
28 compared with none of the 7 participants in the treatment arm. participants (01 and 14), whose plasma viraemia rebounded by more
The median duration off ART was 39.6 weeks (range, 9.9–49.6 weeks) than 200 copies per ml within 8 weeks into ATI, carried bNAb-resistant,
and 9.4 weeks (range, 5.3–26 weeks) for the group 1 bNAb and placebo replication-competent HIV in their CD4+ T cells at the baseline (Fig. 2a).
376 | Nature | Vol 606 | 9 June 2022
, a
…………..
Screen W0 W2 W4 W8 W12 W16 W20 W24 F/U W4 F/U W12 F/U W24
Group 1 ART ATI + 3BNC117 and 10-1074 or placebo Follow-up/ART
ART stop ART restart
…………..
Screen W0 W2 W4 W8 W12 W16 W20 W24 F/U W4 F/U W12 F/U W24
Group 2 3BNC117 and 10-1074 Follow-up
b Group 1: bNAb arm Group 1: placebo arm
Plasma viraemia (copies per ml)
Plasma viraemia (copies per ml)
107 Participant 01 Participant 02 Participant 05 103 107 Participant 03 Participant 04 Participant 07
Levels of bNAbs in plasma
106 106
105 102 105
(μg ml–1)
104 104
103 101 103
102 102
0 8 16 24 32 40 48 56 64 72 80 0 8 16 24 32 40 48 56 64 72 80 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 0 8 16 24 32 40
Participant 06 Participant 08 Participant 13 103 Participant 09 Participant 10 Participant 11
Plasma viraemia (copies per ml)
107 107
Plasma viraemia (copies per ml)
Levels of bNAbs in plasma
106 106
105 102 105
104 (μg ml–1) 104
103 101 103
102 102
0 8 16 24 32 40 48 56 64 0 8 16 24 32 40 48 56 64 72 0 8 16 24 32 40 48 56 0 8 16 24 32 0 8 16 24 32 40 0 8 16 24
Participant 14 103
Plasma viraemia (copies per ml)
Plasma viraemia (copies per ml)
107 107 Participant 12
Levels of bNAbs in plasma
106 106
105 102 105
(μg ml–1)
104 104
103 101 103
102 102
3BNC117
10-1074
0 8 16 24 32 40 0 8 16 24 32
Group 2
Participant S2 Participant S4
Plasma viraemia (copies per ml)
107 Participant S1 Participant S3 Participant S5 103
Levels of bNAbs in plasma
106
105 102
(μg ml–1)
104
103 101
102
0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56
Time (weeks)
c Group 1: bNAb arm
d 107
P = 0.82
100 100
Suppression of plasma viraemia
Group 1: placebo arm
106
reinitiation (copies per ml)
(<200 copies per ml, %)
Participants remaining
Plasma viraemia at ART
80 P = 0.001 80 P = 0.002 Participant
01 03
off ART (%)
105 02 04
60 60
05 07
40 40 06 09
104 08 10
13 12
20 20
103 Geometric
mean
0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48
102
Time after ATI (weeks) Time after ATI (weeks) bNAb arm Placebo arm
Fig. 1 | See next page for caption.
The median duration of suppression of plasma viraemia at below 200 in vivo. In group 2, 2 out of the 5 study participants whose baseline
copies per ml for the participants with sensitive virus was 35.4 weeks infectious HIV was sensitive to both antibodies maintained complete
(range, 31.7–43.3 weeks). There was no difference in the level of plasma suppression of plasma viraemia for an average of 41.7 weeks (Figs. 1b
viraemia before reinitiation of ART between the bNAb and placebo and 2a). Taken together, these results demonstrate that the combina-
arms in the group 1 study participants (P = 0.82; Fig. 1d), suggesting tion therapy with 3BNC117 and 10-1074 is highly effective in suppress-
that bNAb-mediated virological suppression may not necessarily alter ing HIV in the absence of ART for extended periods, provided that
the kinetics of plasma viral rebound after clearance of the antibodies antibody-resistant virus is not present at the baseline.
Nature | Vol 606 | 9 June 2022 | 377
