HIV Meds: The Latest in Treatment & What’s Ahead
Infection with the HIV wreaks havoc on the body’s natural defense system and has the potential to cause death from a variety of other infections, which are not commonly seen in the general population. As a result, it became imperative for the medical science community to develop drugs that could block the activities of HIV and prolong survival.
In 1987, only three years after the structure of HIV was identified, the first anti-retroviral medication, azidothymidine (AZT), was discovered. Over the next 23 years, more than 20 new medications have been discovered to thwart the virus’ ability to destroy the human body.
HIV is a retrovirus, meaning that it needs to convert its normal genetic material -- ribonucleic acid (RNA -- into deoxyribonucleic acid (DNA), our normal genetic material, using its own enzyme, called reverse transcriptase (RT), in order for it to exert its effects. A virus is not considered "alive," as it does not have the inherent ability to reproduce more copies of itself; it requires assistance, notably in the form of our normal cellular machinery.
The only way this can happen, though, is for the virus to gain access to the inside of our cells. So the virus has proteins on its surface that allow it to dock onto and fuse with specific cells, called CD4+ cells, in order to insert itself into the cell. Once inside, the viral genetic material makes its way to the nucleus of the cell and integrates itself into our DNA with the help of a viral enzyme called integrase.
Through a series of biochemical reactions, the viral DNA ultimately gets interpreted by our cell and initiates the process of making new copies of the virus. The viral proteins need to be cleaved by a protease enzyme, thereby creating smaller particles which then assemble to form new viruses which escape the cell by stealing some of our cell membrane. This entire process takes approximately two days, on average, to complete. Ultimately, continued replication of new viruses will cause death of the cell.
The purpose of designing antiretroviral drugs is to block the ability of HIV to make new copies of itself and thus infect other cells, further destroying the immune system. In an ideal world, these drugs would kill the virus, but they only stop the virus from making new copies. The virus is still present in the DNA in the cells it infects. Also, ideally the drugs would work all the time without fail.
A Rapidly Mutating Virus
The virus, however, can mutate to attempt to escape inhibition by the antiretrovirals. For some medications, only one simple mutation renders the drug -- or sometimes even the entire class of drugs -- ineffective; and for some other medications, multiple mutations are required.
This is partly why the standard therapeutic regimen includes at least three different medications, but not necessarily different classes of medications.
AZT was the first medication in the class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTIs). This class of drugs specifically binds to the RT enzyme in the exact same spot that the normal genetic building blocks bind, thereby blocking the replication of new viral DNA. If the virus cannot make new DNA, then the virus cannot make new copies of itself.
Other drugs that have been designed in this class include didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), tenofovir (TDF), and emtricitabine (FTC). There are certain available preparations that are combinations of two or three of these NRTIs, notably Truvada (FTC and TDF), but also Epzicom (3TC and ABC), Combivir (3TC and AZT), and Trizivir (3TC, AZT, and ABC).
The next class of antiretroviral medications to be discovered was the protease inhibitors (PIs), with saquinavir (SQV) being the prototype found in 1995. These drugs block part of the assembly of new virus particles. If the larger viral proteins cannot be broken down into smaller ones required for assembly, then no new viruses can be made from that cell.
Other PIs include: indinavir (IDV), ritonavir (RTV), nelfinavir (NFV), amprenavir (APV), lopinavir (LPV), fosamprenavir (FPV), atazanavir (ATV), tipranavir (TPV), and darunavir (DRV). Ritonavir was initially designed as a direct antiretroviral; however, the side effects and toxicities nearly prohibited its use. It was subsequently discovered to serve as a "booster" for the other PIs, since it acts on the liver to inhibit the metabolism of the other PIs.
This allows for lower dosages and improved dosing schedules for the PIs, thereby minimizing side effects and toxicities. Only one of these medications is currently available as a co-formulation: Kaletra (lopinavir-ritonavir).
New Class of Drugs Improves Survival Rates