Speaker: Roy (Trip) Gulick, M.D., M.P.H., Cornell Clinical Trials Unit
The face of HIV therapy is constantly changing. October's community forum aimed at summarizing the current available antiretroviral (ARV) therapies, and where future ARVs stand in the clinical trial pipeline. Dr. Roy Gulick of New York Presbyterian Hospital/Weill Medical College of Cornell University provided the audience with information regarding the mechanics of HIV and how different classes of antiretrovirals attack the virus.
Life Cycle of HIV
Dr. Gulick first summarized the process by which HIV enters and infects an immune system cell. Cells are infected when the HIV protein, gp120, binds to a receptor on the surface of the T-cell (the T-cell receptor). This process is known as attachment. Attachment causes a rearrangement of HIV proteins, allowing binding to a second co-receptor (also called the chemokine receptor). Co-receptor binding causes a second HIV protein, gp41, to fold in itself, pulling the virus towards the surface of the cell. Once the virus and the cell are in contact together, a process called fusion occurs where the membranes of the HIV and the cell fuse together, allowing the genetic material of the virus to enter the cell. This process of attachment, co-receptor binding, and fusion are necessary for HIV to penetrate, and subsequently infect, the cell.
Once inside the cell, HIV is able to hijack the cell's internal machinery. This machinery serves HIV by allowing the virus to replicate (duplicate itself) and later infect more cells in the body. An enzyme called HIV reverse transcriptase converts the virus' RNA into DNA, which is compatible with the genetic material inside the nucleus of the cell. Once this process is completed, the modified form of the viral DNA is integrated into the cell's genetic material through the help of another HIV enzyme called integrase. It is possible for the virus to remain within the nucleus, in a dormant state, for many years. Upon activation, the viral DNA is transcribed into RNA and then used to make viral proteins. The newly formed RNA forms the genetic material of the next generation of viruses. The proteins and RNA assemble near the surface of the cell, preparing the next HIV. Among these proteins is the HIV protease enzyme, which serves to activate other viral proteins.
Antiretroviral medications act to interrupt or inhibit one or more stages of HIV's life cycle. For example, entry inhibitors, such as the fusion inhibitors, work at the first step in the life cycle by preventing the virus from entering the immune system cell. Entry inhibitors are not yet FDA approved medications. HIV reverse transcriptase inhibitors (RTIs) work to block reverse transcriptase earlier in the viral life cycle. HIV protease inhibitors (PIs) work to block the action of the protease enzyme late in the life cycle of the virus.
ARV Obstacle Course
There are many challenges facing antiretroviral therapy. ARV therapy most often involves the use of "drug cocktails" or the mixture of different medications over a 24-hour period. This presents problems for the patient such as the number of pills, the number of times the pills must be taken, food or water requirements, or unpleasant side effects. Problems with adherence often lead to further problems as the virus may develop resistance to medications. Resistance can also develop in patients with good adherence, although the risk is much lower. Toxicity is another problem, as these drugs may cause side effects, such as increasing cholesterol levels or liver function test levels, in some patients. Another challenge facing ARVs are their level of activity. ARVs need to drive the viral load down as much as possible or they simply aren't effective.
What Makes a Good ARV?
Dr. Gulick described the optimal qualities of an antiretroviral drug. Convenience is a factor in many regimens, as patients wish their therapy to be compatible with their work and personal activities. Ideally, this entails taking fewer pills, fewer times a day. Closely connected with this is the tolerability of the ARV. Will it cause an upset stomach? Will there be a loss of appetite? Such considerations must be made when selecting an antiretroviral. The concept of activity against the virus, mentioned earlier, also applies here. Not all medications reach all parts of the body, so it is necessary for ARVs to be selected that penetrate reservoirs of the virus such as the central nervous system or the genital tract. Those medications that are successful in these aspects will be able to drive the viral load down and this, in turn, will improve the T-cell count.
Pharmaceutical companies recognize the importance of these issues, Dr. Gulick reports, and have made efforts to incorporate some of these aspects into medications and treatment regimens. Nucleoside reverse transcriptase inhibitors (nRTI) have improved in convenience as many are now dosed twice a day, and several different medications have been combined into one pill. Tolerability has also been improved due to improvements in capsule coating. Improvements in non-nucleoside reverse transcriptase inhibitors (nnRTI) and protease inhibitors have been made to lower the number of pills patients are required to take.
New Medications in Existing Classes
The most recently approved class of drug is nucleotide analogue reverse transcriptase inhibitors. Like their cousins, nucleoside analogues, nucleotides are inserted into the growing viral DNA strand inside the cell. As a result, the strand terminates, resulting in a non-functional DNA viral strand. Tenofovir (trade name Viread) is a nucleotide analogue reverse transcriptase inhibitor. Only recently approved by the FDA, Viread has shown activity against hepatitis B in the test tube and against HIV in clinical studies. The drug is dosed as only one pill, once a day. Viread is targeted to those patients who have resistance problems, since it has shown activity against resistant virus.
Amdoxovir (DAPD) is a nucleoside analogue currently in clinical trials. Early data has shown activity against HIV in clinical studies and hepatitis B in the test tube.
Non-nucleoside reverse transcriptase inhibitors work by preventing the reverse transcriptase from binding to the RNA chain, and thus no viral DNA is produced. Sustiva (efavirenz) is a commonly-used nnRTI, and there are currently four different cousins of Sustiva in development. One, called DPC 083, shows early promise, as patients may be able to take it only once or twice a week.
Tipranavir, a non-peptide protease inhibitor currently in clinical trials, is found to have better levels when co-dosed with Norvir (ritonavir). It is currently being tested in patients with resistant virus.
Atazanavir (BMS- 232632), another protease inhibitor drug in clinical trials, has the advantage of being dosed once a day. Unlike other protease inhibitors, atazanavir may not lead to cholesterol and other lipid related abnormalities.
Medications in New Classes
Dr. Gulick explained the role of HIV integrase in HIV's life cycle. It is crucial in allowing the viral DNA to become part of the DNA of the immune system cell. S-1360 is currently the HIV integrase inhibitor furthest along in clinical trials. Currently in phase I studies, the drug is likely to be dosed two or three times per day.
Dr. Gulick discussed entry inhibitors briefly at the beginning of the forum, but delved into the issue at greater length. The term "entry inhibitor" is a broad category containing three subclasses: attachment inhibitors, co-receptor inhibitors, and fusion inhibitors. Attachment inhibitors prevent the gp120 protein from binding to the CD4 (T cell) receptor. Co-receptor inhibitors prevent binding to a co-receptor on the T-cell surface. Fusion inhibitors prevent the gp41 from drawing the HIV to the surface of the cell.
There are currently two fusion inhibitors available in clinical trials. T-20 is a polypeptide (short protein) consisting of about 30 amino acids. Because of this, the drug must be injected subcutaneously (under the skin); if swallowed, the stomach would digest and disable the drug. Due to a relatively short half-life, the drug is administered twice a day. T-20's main side effect appears to be injection site reactions. Another fusion inhibitor, T-1249, is structurally similar to T-20 and must be injected subcutaneously as well. It is believed to be two to 100 times more effective than T-20. Due to a longer half-life than T-20, T-1249 can be administered once a day. In the test tube, T-20 and T-1249 have distinct resistance patterns.
So Why All the Excitement?
New classes of drugs attack HIV differently than the FDA approved classes. As a result of the new strategy, HIV is unlikely to be resistant to the new medications. Patients who have tried several other regimens often turn to these new or experimental medications in order to combat their highly resistant strain of HIV. The two fusion inhibitors mentioned above have garnered additional attention because of their success in driving the viral load down in combination regimens in some patients.
Benefits and Risks
It is important to treat investigational drugs with skepticism, Dr. Gulick warns. Safety data regarding many of these medications is still being gathered and, as a result, all side effects are not fully known. Toxicity problems and other adverse events are still being discovered. These drugs may show a great deal of promise, but must be approached with cautious optimism. Participating in a clinical study requires a good sense of the possible risks (side effects, toxicities, resistance, etc.) and benefits (activity against resistant virus).