Although much research is currently exploring the extent to which neutralizing antibodies can help prevent, treat or cure HIV, some scientists believe that without significant improvements in their performance, antibodies may have a limited future role in treating HIV.
The authors of a recent opinion piece published in the journal Clinical Infectious Diseases note that several hurdles remain to be overcome before antibody therapy can become a viable alternative to existing antiretroviral therapies.
Laura Waters, PhD, president of the British HIV Society, José Arribas, PhD, former chair of the European AIDS Clinical Society HIV Treatment Guidelines Group, and colleagues co-authored the review. Specifically, they argue that the lack of clarity around the appropriate combination of antibodies, the need for resistance testing, and the difficulty of penetrating anatomical reservoirs combine to make broadly neutralizing antibodies less practical than antiviral therapy.
Several years after initial HIV infection, 10% to 30% of people living with the virus produce broadly neutralizing antibodies that are active against a variety of viral strains. These antibodies can surround or neutralize the virus and prevent it from infecting other cells. They bind to and interact with different parts of the HIV virus, thereby affecting their effectiveness in preventing further transmission of the virus in the body. Likewise, the interaction of antibodies with immune cells affects how long they last in the body. Because it can take weeks for the concentration of antibodies in the blood to drop by half, their lifespan may be more favorable than daily oral antiretroviral medication. The
antibodies 3BNC117, 10-1074, VRC01 and PTG121 showed the highest ability to suppress HIV in the absence of antiretroviral therapy. However, as monotherapy (one antibody at a time), several studies have shown that the duration of viral suppression is relatively short, between approximately 3 and 10 weeks, depending on the antibody tested and the dose given. In addition, when viral load rebounded, the virus almost always became resistant to the antibody tested. Therefore, this group of authors believes that combination therapies consisting of multiple broadly neutralizing antibodies hold the most promise for attacking different sites of the HIV virus.
According to the authors, the combination of 3BNC117 and 10-1074 was the most widely tested mixture. In one test, three-quarters of those who responded to treatment did not develop sustained viral undetectability, but those with the lowest viral loads at the start of the study (less than 1,000 copies) maintained viral loads of less than 20 copies for more than eight weeks. All participants in this study developed varying degrees of resistance to one of these two antibodies. In another trial, 17 people received up to seven injections of the same two antibodies, and 13 of them maintained viral suppression for 20 weeks without antiretroviral therapy, and some for much longer.
In summary, some antibody therapies have been shown to delay viral rebound in the absence of antiretroviral therapy, but none have completely prevented viral rebound (although one person maintained an undetectable viral load in the absence of antiretroviral therapy for four years after receiving the antibodies). Waters and her colleagues also note that other studies have shown that broadly neutralizing antibodies have no significant effect on reducing the size of the latent reservoir, which is necessary to truly eradicate HIV from the human body. The
authors concluded that it is unclear how many antibodies could constitute the ideal combination to attack HIV from multiple angles. In addition, they add that pre-screening is needed to determine whether patients have HIV strains that are already resistant to one or more antibodies in a particular therapy:a key predictor of virologic failure with this therapy. Resistance testing is a major obstacle to treating HIV with broadly neutralizing antibodies because it is "technically difficult, time-consuming, expensive, and difficult to implement widely," the group of authors write. The
authors suggest that perhaps broadly neutralizing antibodies and antiretroviral therapy could be combined to provide a long-lasting therapy. The European Commission recently approved lenacapavir (Sunlenca) as a twice-yearly injectable antiretroviral drug. However, those taking it will still usually need to use it in conjunction with a daily pill, as no other HIV treatment lasts as long. A long-acting, broadly neutralizing antibody may be a better partner for lenacapavir, but the authors note that the often high cost of new drugs may keep new therapies out of reach for many people. The
authors also suggest that antibody therapies may be more relevant to populations that are typically excluded from clinical trials, such as pregnant women, children and adolescents, and transgender populations. This will, of course, depend on additional clinical trials that include these groups, as well as results that show beneficial outcomes.
Although beyond the scope of their article, the authors note that broadly neutralizing antibodies may play a more important role as a form of long-term PrEP. Injectable cartigravir (cabotegravir) has shown the value of long-acting PrEP in alleviating adherence problems caused by daily tablets. Because cabotegravir can persist in the body for months, insufficient integrase inhibitor concentrations may persist for some time after patients stop taking it. HIV infection during this period may lead to viral resistance to such drugs, which are commonly used as first-line antiretroviral therapy. The authors concluded that if broadly neutralizing antibodies become effective as long-term PrEP, a significant benefit would be that stopping it would not risk limiting HIV treatment options.
Finally, this group of authors concludes that, given the current standard of antiretroviral therapy, broadly neutralizing antibodies are unlikely to be used as first-line treatment for HIV without eliminating the need for resistance screening and overcoming the barriers to maintaining long-term viral suppression. Because the effectiveness of antiretroviral therapy is so high and the virological failure rate among those taking it so low, Waters and her colleagues write that it is currently "virtually impossible" to demonstrate superior efficacy in neutralizing antibodies.
Waters L et al. Broadly Neutralizing Antibodies for HIV Treatment: Broad in Theory, Narrow in Reality. Diseases, online ahead of print, 28 October 2022.