I recently wrote about an unintended consequence of the discovery of highly effective AIDS drugs. They are so effective that those who are HIV-positive — and would have most likely died within a few years as recently as the early 1990s — now are living much longer. The antiretroviral drugs that people all over the world are now taking have succeeded in inhibiting the replication of HIV, to the point where the virus becomes undetectable (aka, a low viral load).
The outcomes we have seen from very low viral loads would have been unimaginable only two decades ago. Not only are HIV-infected people living much longer, but they do not even transmit the infection nearly as efficiently. Sometimes not at all.
Perhaps even more astounding is that it's now possible for individuals to remain uninfected (1) — even if they practicing unsafe sex. And, another major factor of the continuing spread of the virus — mother to fetus transmission — has been greatly suppressed. It has been eliminated entirely in Cuba, Thailand, Belarus, Armenia, and Moldova.
By any measure, the progress against HIV has been a remarkable success. There is, however, a catch. Truvada, a very effective two-drug combination (2), has been the mainstay in the war against HIV. But, although it is fairly well tolerated (3), it is not devoid of potentially serious toxicity (4), especially when taken for many years .
This paradox was discussed in a recent Bloomberg article, entitled "Drugs That Saved HIV Patients Now Threaten Them in Old Age." The piece contrasts the short- and medium-term benefits of Truvada with long-term adverse effects.
So, what to do? The answer is: Be thankful that HIV research did not stop, even when highly effective drugs were finally available. The most important focus of HIV research continued to be finding drugs that inhibited HIV in different ways. This approach has been quite successful, and now may become crucial in managing long-term HIV infection.
In order to understand what "different ways" means, you need to know a little about the life cycle of HIV. For replication to take place, a series of steps must occur. Otherwise new, viable viruses will not form. In drug discovery, these individual steps are referred to as targets. Here is a simplified version of how HIV works. (See diagram below)
- HIV attaches to host cell via specific receptors. The host cells for HIV are called T4 lymphocytes (aka CD4 white blood cells, T-helper cells) — a crucial component of our immune systems.
- Following attachment, the virus "chemically dissolves" (a process called fusion) the CD4 cell membrane and enters the cell (5). Then the virus breaks open, releasing its contents. Some of the viral components enter the nucleus of the host cell. This is where the real damage is done.
- An enzyme called reverse transcriptase is responsible for making multiple copies of viral genetic material so that replication can take place. It does this by converting viral RNA into its corresponding DNA — an unusual biochemical transformation that is limited to so-called retroviruses. This is the sole function of reverse transcriptase, which makes it an attractive target for inhibition by drugs.
- Then, an enzyme called integrase takes the newly formed viral DNA and stitches it into the DNA genome of the host cell (6), thus creating a very different cell — one that is now programmed to make many copies of the virus. The cell becomes a factory for HIV, and is now genetically different from its uninfected counterpart. It has been estimated the one T-helper cell can produce between 1,000 and 10,000 new HIV particles.
- All the newly formed viral components are assembled into an immature viral particle, which migrates to the cell membrane.
- HIV protease processes immature HIV particles into viable viruses, which leave the host cell (budding) and start the cycle again (7).
This is illustrated in the diagram below:
Of the six steps (8), five can be specifically blocked by five different classes of AIDS drugs. These are marked by the yellow stars. The last novel drug to be approved was the integrase inhibitor Elvitegravir. The interval between the discovery of HIV and the approval of Elvitegravir was 33 years.
This massive amount of research has provided us with choices that would have been otherwise unavailable. One such choice, which was mentioned in the Bloomberg article is another integrase inhibitor called Tivicay (GlaxoSmithKline, 2013). It will be combined with a (yet undetermined) second drug (9) to form a two-drug cocktail, presumably having a better safety profile than Truvada or Atripla.
Tim Horn of Treatment Action Group (an HIV activist group that was formed in 1991) summed up today's challenges in battling HIV. He said, “Depending on when you test positive for HIV, you could be looking at up to eight decades of treatment. ... We need drugs that are gentler, kinder, better and cheaper.”
Good thing that research continued.
(1) This number for ranges from 50-to-100 percent, depending upon patient compliance in taking the drugs.
(2) Truvada is frequently combined with a third drug, efavirenz.
(3) Some of the most common side effects include gastrointestinal problems, depression and itching.
(4) More serious side effects include kidney toxicity, and decreased bone density.
(5) Although attachment and fusion are distinct processes, they are often classified together as "entry inhibitors."
(6) Integrase is the hallmark of retroviruses. Unlike other viruses, retroviruses alter the genome of the host cell by inserting their own DNA. This is one reason why it has been impossible to entirely rid the body of HIV.
(7) Although maturation is blocked by protease inhibitors, the maturation is distinct from the action of HIV protease. I have chosen to combine them, however, maturation itself is another target that is being investigated.
(8) Some of these steps have been subdivided. The "current" number is about 10.
(9) Tivicay is already being sold as part of a three drug combination therapy called Triumeq, which received FDA approval in 2014. GlaxoSmithKline's goal is to combine it with only one other drug to further improve its safety profile.