By Jason Faulhaber, M.D. -
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
Shortly after saquinavir came out, a new class of medications was also discovered. This class was similar to the NRTIs because these drugs also blocked the RT enzyme; however, they did not bind in the same spot as the NRTIs. These drugs bound in a separate location, and therefore they are called the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). These drugs are nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), and etravirine (ETR).
There was significant improvement in the survival rates of people infected with HIV after the third class of antiretrovirals had been discovered. But there were still people who had been infected for over a decade who were not benefiting as much because of mutations in the virus. So, scientists continued toiling to find other ways of blocking the virus.
The class of entry inhibitors was then discovered. This class includes those medications which can block the entry of the virus into the specific CD4+ cells. Currently, there are only two types of drugs in this class: enfuvirtide (ENF) and maraviroc (MVC). Enfuvirtide was the first of the class to be identified, and it was considered a breakthrough medication as it was a completely new class which should affect resistant viruses.
One major drawback to the medication, though, is that it is only available as an injectable medication, not in pill-based form. A few years later, maraviroc became available. Maraviroc blocks a specific receptor used by certain HIV particles to gain access to the cell; so, it is not necessarily useful for everyone infected with HIV.
The newest class of antiretrovirals, the Integrase Inhibitors (IIs), only became available over the last three years.
Raltegravir (RAL), the prototypic drug, blocks the enzyme that allows incorporation of the viral DNA into our DNA. This class was also considered to be a major breakthrough because, again, it was blocking a whole different step of the viral life cycle, and therefore it should still be effective even in resistant viruses.
The current guidelines for treatment recommend using at least three "active" drugs in the regimen. The "active" refers to whether or not the virus has resistance to any of the medications. A resistance test should be performed prior to starting any regimen.
As of today, there is only one regimen that is one pill once a day. It is a combination pill that has three drugs within it, Atripla. Other recommended regimens have no choice but to increase the number of pills taken: three pills once a day, four pills once a day, or five pills once a day.
There are other regimens, depending on the resistance of the virus, that do require taking the pills twice a day. Also, some of the medications need to be taken with food, and some need to be taken on an empty stomach. Anyone with HIV needs to consult with a health-care provider to determine which is the best regimen, based on the resistance, side effects, and ability to take the medications.
The future holds promise for newer medications and new ways of improving the current set of antiretrovirals. Within the year, there is a plan to have another once-a-day pill that uses a non-ritonavir boosting agent. Although this is exciting and important, we still do not have a cure for HIV infection.
With continued research and support, we hope to find the cure.. The sooner the better.
A Comprehensive List of Currently Available Medications
What follows is the latest, most up-to-date list of HIV and AIDS drugs, listed by type, followed by the name of each drug, the trade name, and the recommended dosing schedule.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Zivovudine (AZT) Retrovir Twice daily
Didanosine (ddl) Videx Twice daily
Didanosine (ddl) enteric coated Videx EC Once daily
Lamivudine (3TC) Epivir Once or Twice daily
Stavudine (d4T) Zerit Twice daily
Abacavir (ABC) Ziagen Once or Twice daily
Zalcitabine (ddC) Hivid Three times daily
Emtricitabine (FTC) Emtriva Once daily
Nucleoside analog Reverse Transcriptase Inhibitors (NRTI)
Tenofovir (TDF) Viread Once daily
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Nevirapine (NVP) Viramune Once or Twice daily
Efavirenz (EFV) Sustiva Once daily
Delavirdine (DLV) Rescriptor Three times daily
Etravirine (ETR) Intelence Twice daily
Protease Inhibitors (PIs)
Ritonavir (RTV) Norvir Varies
Saquinavir (SQV) Invirase Once or twice daily
Indinavir (IDV) Crixivan Two or three times daily
Nelfinavir (NLF) Viracept Twice daily
Fosamprenavir (fAPV) Lexiva Once or twice daily
Lopinavir/ritonavir (LPV/r) Kaletra Once or twice daily
Atazanavir (ATV) Reyataz Once or twice daily
Tipranavir (TPV) Aptivus Twice daily
Amprenavir (APV) Agenerase Once or twice daily
Darunavir (DRV) Prezista Once or twice daily
Enfuvirtide (T-20) Fuzeon Twice daily
Maraviroc Selzentry Twice daily
Raltegravir Isentress Twice daily
AZT + 3TC Combivir Twice a day
ABC + 3TC Epzicom Once a day
AZT + 3TC + ABC Trizivir Twice a day
TDF + FTC Truvada Once a day
TDF + FTC + EFV Atripla Once a day
New Medications on the Horizon (& How Far Along)
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Elvucitabine Late Phase II
Racivir Early Phase II
Amdoxivir Phase I
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Rilpivirine Phase III
Elvitegravir Phase III
Cobicistat Nearly complete
Dr. Faulhaber is a graduate of Tulane University in Psychology and Cellular and Molecular Biology and received his medical degree from the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School. He performed his residency training in Internal Medicine and Pediatrics at Saint Vincent’s Hospital in Manhattan, where he then served as a Chief Resident in Internal Medicine. He completed his fellowship in Infectious Diseases at New York University, where he specialized in HIV/AIDS, Hepatitis, and fungal infections. Since fellowship, he has been working as an Internal Medicine/Infectious Diseases physician at Fenway Community Health in Boston. He is a Clinical Instructor in Medicine at Harvard Medical School, and he is affiliated with Beth Israel Deaconess Medical Center. He has been the lead author or co-author of several journal articles and textbook chapters on infections with HIV, other viruses, bacteria, and fungi. He is also accredited by the American Academy of HIV Medicine.