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bNabs Combination Study new reports & antibody-resistance
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Triple & Double bNAbs Studies - NATAP
CROI 2022 Feb 11-16 ... HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple.......
A single infusion of 20 mg/kg of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a mean of -2.04 Log10 HIV RNA drop by day 7 copies/ml, however, viral rebound occurred within a median of 20 days post nadir (range 13 and 70).
Despite decades of intensive research, the prospects of achieving an HIV cure as manifested by eradication of the virus remain elusive2. A more realistic alternative to a cure may be through immune-based therapies aimed at achieving maximal virological suppression without the need for life-long and predominantly daily ART and without the need to eliminate the persistent HIV reservoir in individuals with infection32,33
However, the combination bNAbs was ineffective in maintaining suppression of plasma viraemia in 2 out of 7 study participants in our small cohort in whom replication-competent HIV exhibited resistance to one or both antibodies at the baseline. This will potentially pose a substantial challenge for the treatment of individuals with HIV with bNAbs on a large scale.
It also remains to be fully elucidated whether additional benefits of bNAbs, aside from their ability to neutralize HIV and maintain viral suppression in the absence of ART, can ultimately alter the course of infection (that is, long-term suppression of plasma viraemia in the absence of both bNAbs and ART) after clearance of the antibodies in vivo. Although a larger study involving multiple infusions of bNAbs and extended periods of follow-up will be necessary to address this question, our data strongly suggest that the virus will ultimately rebound after bNAb clearance after 24 weeks of bNAb therapy. In this regard, future trials may need to incorporate a prespecified ART initiation shortly after the last infusion of bNAbs to prevent the emergence of antibody-resistant virus in study participants.
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Combination anti-HIV antibodies provide sustained virological suppression
June 2022 Nature
Abstract
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.
In an additional post hoc analysis, 5 out of the 7 study participants in the bNAb arm of group 1 maintained suppression of plasma viraemia (<40 copies per ml), whereas all of the study participants in the placebo arm of group 1 experienced plasma viral rebound within the first 8 weeks of ATI. The median duration of plasma viraemia suppression at <200 copies per ml in group 1 was 33.4 weeks (range, 7.4–43.3 weeks) and 3.4 weeks (range, 1.9–7.9 weeks) in the bNAb and placebo arms, respectively (P = 0.002; Fig. 1c (right)). Notably, two group 1 bNAb study participants (01 and 14), whose plasma viraemia rebounded by more than 200 copies per ml within 8 weeks into ATI, carried bNAb-resistant, replication-competent HIV in their CD4+ T cells at the baseline (Fig. 2a).
In group 2, 2 out of the 5 study participants whose baseline infectious HIV was sensitive to both antibodies maintained complete suppression of plasma viraemia for an average of 41.7 weeks (Figs. 1b and 2a). Taken together, these results demonstrate that the combination therapy with 3BNC117 and 10-1074 is highly effective in suppressing HIV in the absence of ART for extended periods, provided that antibody-resistant virus is not present at the baseline.
Discussion
Despite decades of intensive research, the prospects of achieving an HIV cure as manifested by eradication of the virus remain elusive2. A more realistic alternative to a cure may be through immune-based therapies aimed at achieving maximal virological suppression without the need for life-long and predominantly daily ART and without the need to eliminate the persistent HIV reservoir in individuals with infection32,33. To date, one of the most promising and realistic approaches for accomplishing these outcomes is by infrequent passive infusions of combination HIV-specific bNAbs15,16,17,18. Numerous HIV-specific bNAbs have been isolated in recent years16,17,34,35 and more than a dozen of them, either as single or combination therapies, have been tested in humans for safety and therapeutic efficacy15. However, although certain bNAbs have been shown to be highly effective in neutralizing HIV in vitro by standardized assays involving large panels of HIV Env-pseudotyped viruses35, it is becoming increasingly clear that durable and ART-free virological suppression will require a combination of two or more antibodies together with screening for bNAb resistance to the pre-existing virus in individuals with infection19,22. The data obtained from our clinical trial, a randomized study involving participants in whom ART was initiated during the acute/early phase of infection with a long duration of follow-up, clearly demonstrated that complete and sustained virological suppression is achievable with intermittent administration of combination bNAbs. However, the combination bNAbs was ineffective in maintaining suppression of plasma viraemia in 2 out of 7 study participants in our small cohort in whom replication-competent HIV exhibited resistance to one or both antibodies at the baseline. This will potentially pose a substantial challenge for the treatment of individuals with HIV with bNAbs on a large scale. Nonetheless, our findings revealed several positive outcomes. Over the course of 24 weeks of virological suppression in the study participants who received the combination bNAbs, there were no significant immunologic or virological alterations, such as increases in immune activation and exhaustion or the size of HIV reservoirs. A recent study has demonstrated that combination bNAbs could further augment T-cell responses against HIV in individuals with infection while suppressing their plasma viraemia27. Although we did not observe any significant changes in the frequency of HIV-specific polyfunctional CD8+ T cells in our study, further studies with early and frequent time points27, as well as detailed assessments of virus-specific proliferative and cytotoxic effector functions36, may be needed to fully delineate the role of T cells in bNAb therapeutic agents. It is also plausible that the marked virological suppression mediated by the bNAbs in our study cohort (those who initiated ART during the acute/early phase of infection), combined with their relatively low HIV reservoir burden at baseline, may have prevented the formation of immune complexes18 and/or the residual levels of viral expression needed for the induction of robust antiviral T-cell responses33,37. It also remains to be fully elucidated whether additional benefits of bNAbs, aside from their ability to neutralize HIV and maintain viral suppression in the absence of ART, can ultimately alter the course of infection (that is, long-term suppression of plasma viraemia in the absence of both bNAbs and ART) after clearance of the antibodies in vivo. Although a larger study involving multiple infusions of bNAbs and extended periods of follow-up will be necessary to address this question, our data strongly suggest that the virus will ultimately rebound after bNAb clearance after 24 weeks of bNAb therapy. In this regard, future trials may need to incorporate a prespecified ART initiation shortly after the last infusion of bNAbs to prevent the emergence of antibody-resistant virus in study participants.
One of the major confounding factors of this study is the small sample size and it is therefore essential to conduct a much larger study involving study participants in whom ART was initiated during the acute/early phase of infection to confirm our findings. Other major caveats of our study include the lack of lymphoid tissue analyses and the limited number of infusions (up to eight). Nonetheless, our findings offer clear evidence that combination bNAb therapy in individuals with HIV is safe and well tolerated and, for those with antibody-sensitive virus, offers marked virological suppression without any significant or unforeseen immunologic and virological anomalies. As the next generation of bNAbs with increased breadth and prolonged half-lives (>60 days)15,17,35 become available, there is a reason to believe that the infrequent administration (that is, twice a year) of such antibodies, possibly along with a long-acting injectable antiretroviral drug12,13,14, could lead to ART-free HIV suppression for extended periods (years) in individuals with infection.
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