Long term HIV suppression by new combination therapy

By Ajay V. Patil

Recent phase Ib clinical trial results from Nussenzweig and colleagues showed that, combination of broadly neutralizing antibodies, 3BNC117 and 10-1074 maintained long-term suppression in individuals with antibody-sensitive viral reservoirs.

Inconsistency in anti-retroviral medication in HIV patients poses the greatest risk of developing resistant variants of virus and also increases the likelihood of transmission. Current gold standard – anti retroviral therapy although effective, rely heavily on strict daily dosing to keep the virus latent. Due to this, it is difficult to control the disease in patients which do not have regular healthcare access. Hence, a lot of research is directed towards development of long lasting therapies.

Michel Nussenzweig and colleagues at The Rockefeller University, initially identified the antibodies, 3BNC117 and 10-1074, while studying “elite controllers” (people whose bodies fight better with HIV without the help of antiretroviral drugs). These antibodies are also called broadly neutralizing antibodies (bNAbs). Earlier studies carried out with the monotherapy of 3BNC117 or VRC01, showed suppression of virus in HIV-1-infected individuals undergoing ‘analytical treatment interruption’ (ATI) of antiretroviral therapy, but it was not long enough (10 weeks and 5.6 weeks of median suppression respectively). In recent phase Ib trials, Nussenzweig and colleagues investigated, whether the combination of 3BNC117 and 10-1074 (reportedly more potent than previous antibodies) can maintain longer viral suppression during ATI in HIV-1-infected humans.

Participants were following ATI for antiretroviral drugs and they were given three infusions of the two antibodies – 3BNC117 and 10-1074, over the course of six weeks. In the patient group of antibody sensitive viruses (to both antibodies) the treatment suppressed HIV for an average of 21 weeks, and over 30 weeks in some patients. Importantly, in the patient group of antibody insensitive viruses there was no development of resistance. The first trial was carried out with patients which did not show viremia (no virus in circulating bloodstream because of prior antiretroviral drug treatment). However in the second study, published in Nature Medicine, this combination treatment was also effective in treating viremic patients suppressing virus levels for up to three months.

Caskey and Nussenzweig say that combination therapy is very promising. Caskey said, “These two antibodies are not going to work for everyone, but if we start to combine this therapy with other antibodies or with antiretroviral drugs, it could be effective in more people and that’s something we hope to look at in future studies”. Previous studies in animal models have shown that, therapeutic efficacy of anti-HIV-1 antibodies is directly related to their half-life which can be extended by mutations enhancing Fc domain interactions with the neonatal Fc receptor. Nussenzweig claimed, “The expectation is that new versions of these antibodies will have three to four fold longer half-lives and we may be able to give the antibodies once or twice a year”.

Although there is considerable increase in the period of virus suppression, resistance post suppression period is still persistent. But this is a big step forward and it will provide important insights to solve the resistance puzzle in HIV research.

References

1. https://www.nature.com/articles/s41591-018-0186-4
2. https://www.nature.com/articles/s41586-018-0531-2
3. https://www.sciencemag.org/news/2018/09/powerful-antibodies-suppress-hiv-months-could-simplify-treatment
4. https://www.sciencedaily.com/releases/2018/09/180926140834.htm
5. https://www.the-scientist.com/news-opinion/antibody-combo-knocks-down-hiv-in-clinical-trials-64865

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