Antibodies and AIDS
and John S. James
This most recent World AIDS Day saw President Obama, joined by Presidents Clinton and Bush, speaking about an “AIDS-free generation”.
Experts and advocates believe this may be achievable because we now know that treating HIV infected people dramatically reduces the risk they will pass it on to others.
The development of rapid tests for HIV that are easy to use, the success of post and pre exposure prophylaxis, the partial success of a microbicide, the fact that condoms and circumcision reduces transmission give us the tools to create High Impact Prevention—public health programs with the realistic potential to get transmission low enough to end the epidemic.
In practical terms however, the existing tools we have may be too expensive and too cumbersome to succeed. Only 5 million out of some 40 million infected people have access to antiretrovirals, only 29% of people in the United States with HIV have their viral load suppressed, and people like Bill Gates and others have warned that the costs of universal access to antiretrovirals may be unsustainable if we do not stop the transmission rate which would keep us financing worldwide HIV programs to the tune of many billions of dollars for the foreseeable future.
While we hope and wait for better AIDS vaccines to be developed, there is one new weapon we can add to the arsenal that makes the goal even more realistic:
Among the obstacles in implementing a successful program to end AIDS are:
* Needing a prescription to get an HIV test or having to go to a hospital or clinic rather than having direct access to 10 minute home tests which are available;
* Having a treatment regimen that is not useful for people unable to maintain a 95% adherence rate ( for example the Fenway Health finds that 17% of its patients on ARV’s are not able to sustain the effort to keep viral load fully suppressed);
* Addictions to alcohol and drugs, which makes it likely that there will be episodes during which people are not taking medicine;
* A percentage of people who are having difficulty with side effects from existing drugs;
* Cultural problems with circumcision;
* The inability to use condoms either because of cost or because they cause in older men difficulties maintaining erections;
* Failure of short sighted rich countries to pay for medicines. (For example, the latest round of Global AIDS Fund monies was skipped, causing serious problems in some countries. And as of February 2012, over 4600 people are on waiting lists for medicines in the United States, which means of course that they are infectious.);
* Erratic supply chains in many parts of the world;
* Failure to even test significant numbers of people who have HIV. (In the United States, fewer than half the people between 18 and 64 years old have been tested; and about a third of them were diagnosed in later stages of the illness, which means they were infectious for years before having access to medicines);
* A continued barrage of denialist propaganda, fear, laws criminalizing HIV in the United States and elsewhere, police use of possession of condoms as evidence of prostitution, politicians blocking clean-needle programs, and many other stigma-based policies that increase HIV transmission;
* PREP (pre-exposure prophylaxis) in international real-world studies showed only a 43% success rate, which could be 97% except for the difficulty people have in practice sticking with the drugs. (When only people in the studies whose blood showed they were on drug are considered, the power of protection was at least 97%, better than condoms in studies.)
These are among the impediments toward a successful end to the epidemic.
A New Tool: Monoclonal Antibodies
There are three current efforts to use ‘monoclonal antibodies’ as therapy for HIV and to prevent HIV -- one under the leadership of David Ho, one developed by the company Progenics, and one by the company Cytodyn.
We have reason to believe each of these may be of help in ending HIV, giving us a new tool that is different from all others and which may avoid many of the problems listed above targeted at ending AIDS.
In 1897, Paul Ehrlich proposed that something in the blood serum we now call ‘antibodies’ are responsible for immunity. Ehrlich, with his friend Emil von Behring, developed an antibody therapy against diphtheria. However, for a hundred years a problem stopped this type of therapy from being used for anything but very short periods of time.
This is because the human body reacts to antibodies not produced by the body by getting either immune to them, in which case the antibodies stop working, or getting a powerful allergic reaction to them, in which case they stop working and also the person using them gets very sick. This sickness is called ‘serum sickness’ because the first time antibodies were used as therapy, it was called using ‘serum’ from animals or other people.
By 1975 several scientists had discovered how to reproduce an antibody using a cancer cell, like zeroxing it, so that you could have one specific molecule to work with rather than a swarm of different although similar ones. These carbon copy antibodies were called ‘monoclonal’ because they all came from one (mono) copy (clone). This made it possible to be a lot more precise in using antibodies as medicines. But it did not stop the monoclonal antibodies (usually made in mice) from causing an immune reaction which made them lose power over a short amount of time.
By the 1980’s however, scientists figured out how to ‘humanize’ antibodies—make them look like they belong in your body—and in the 1990’s this led to the availability of humanized antibodies for experimentation.
Finally in 2002, adalimumab became the first human monoclonal antibody to be approved by the US Food and Drug Administration (FDA). By 2008 adalimumab was approved by the FDA for the treatment of rheumatoid arthritis and some other types of arthritis and Crohn’s disease.
By 2012 the FDA had approved 30 monoclonal antibodies for cancer and various autoimmune diseases.
It was not until quite recently that using monoclonal antibodies to treat HIV has been attempted.
Three New Medicines for HIV
Antibodies to treat HIV has been talked about among scientists and papers have been written about the idea since at least 2003. But the first three antibodies actually used in people are Ibalizumab, PRO-140, and Cytolin.
Ibalizumab is a monoclonal antibody against CD4 which stops HIV from fusing with the cell, stopping it from getting into the cell by blocking both CXCR4 and CCR5. In small clinical trials it has shown the largest viral load drop using a single drug of any of the 25 approved FDA antiretrovirals, well over 90% [?? reduction in viral load?] lasting 2-4 weeks.
PRO-140 is directed against CCR5, the co receptor which M-tropic virus (the main type of HIV) needs to use to get into a cell. It blocks this virus well over 90% of the time, with one dose lasting for more than two weeks. [??- 90% of the time, or 90% viral load reduction?]
Cytolin is a monoclonal antibody which attaches to LFA-1 at CD11a. It most likely directly attaches to the LFA-1 that HIV steals from a human cell, and because of this Cytolin is thought to be especially unlikely to stop working because of resistance; HIV does not have genes which it can mutate that impacts LFA-1 since it is part of a human cell, not the virus. It had been used prior to 1996 by doctors on some patients who did not use antivirals and who experienced significant reductions in viral load.
Advantages of the New Therapies
Monoclonal antibodies as therapies to HIV have several advantages over all existing medicines:
* They are administered once a week, two weeks or possibly once a month. For people having trouble sticking with once a day every day medicines for any reason, they have an extraordinary advantage. Especially as they are so forgiving: missing a dose by a few days would not mean much. Also, infrequent dosing means a more realistic effort in resource-limited settings is possible; getting medicine to someone once a month is much easier than getting medicines in a cocktail to millions of people every day on time. DOT (directly observed therapy, so important in tuberculosis treatment) may become possible for HIV.
* These antibodies are not likely to have many serious side effects.
* HIV will have trouble becoming resistant to Cytolin and possibly to the other two as well (although virus that uses the CXCR4 co-receptor will get through PRO-140). However, this type of virus is relatively rare, especially in early HIV infection.
* HIV has never seen any of the monoclonal antibodies and this means they would all be able to stop the virus even in people whose medicines are no longer working. They also could be used to get full suppression in people whose cocktails are not fully suppressing the virus, thus protecting the cocktails from the emergence of resistance.
* They are likely effective at prophylaxis, given how infrequently they need be used. They might be especially successful for PEP and PREP.
* Until a vaccine is invented, the monoclonal antibodies may be the best chance we have at putting an end to HIV -- because they can be used as a type of ‘vaccine,’ perhaps once a month, and could significantly reduce transmission.
* Finally, and not least importantly, if the once every two week or once a month dosing is sufficient to drop viral load to undetectable, the 24 times a year as opposed to 365 times a year dosing means cost savings that may make it much more realistic to sustain a long effort economically and globally.
Very few people are working on monoclonal antibodies for HIV. Progenics has dropped its program and is looking for someone to adopt the antibody and finish testing it. Ibalizumab is in its second generation of effort, having been dropped by companies before, and has been stagnant for the past two years. Cytolin is the only drug being developed by a company still determined to see a monoclonal antibody become a tool for our community to use to fight HIV.
We need to support the effort, push the NIH into exploring all the antibody therapies for HIV, and be loud about our determination to see that the scientific community has the money and the encouragement it needs to test the antibodies and develop the delivery systems and other supports needed, to make sure the new therapies are available and used by the world community.
This may be our best chance to add a significant new medicine to the arsenal that could help us put an end to AIDS.