First, let's look at the way the drug itself contributes to failure. At the simplest level, the most common reason for drug failure is because HIV develops resistance to them. How easily and quickly this happens is at least partially determined by the design of the drug. The most effective drugs remain stable in the blood for long periods. As a result, the level of the drug in the blood rarely falls below the amount needed to sustain full suppression of the virus, and thus, there is little opportunity for the growth of resistant forms of HIV. In contrast, some drugs are quickly flushed out of the body. As a result, the level of drug in the blood is constantly rising and falling as people take their daily doses. This often creates periods in which the level of drug in the blood is too low to fully suppress the virus, and this is precisely the condition which encourages the development of resistance, and thus, drug failure.
Next let's look at how the drug's user can contribute to the problem. The key issue here is adherence -- how carefully the user follows the instructions on taking the drug. This is particularly critical with drugs that are quickly flushed out of the body. The only way to make such drugs work well is to constantly replenish the drug supply in the bloodstream. For some drugs, this means taking them on a precise time schedule two or three times a day. The worse the drug is at maintaining a high, steady level in the bloodstream, the more important adherence becomes. Yet, we are all human and it's hard to expect people to adhere to their drug regimens' perfectly year after year.
New research suggests the startling conclusion that not everyone using a 3-drug regimen is actually getting the effect of three drugs. A new study, conducted by Drs. Robert Redfield, Charles Davis and Alonso Heredita, reported in the Journal of Human Virology (Vol. 4: pages 113-122), shows that another variable, called cell-cycle dependency, is also at work and affecting the outcome of anti-HIV therapy.
Simplistically, there are two basic states for every type of cell, including the cells that are infected by HV. In the ACTIVE state, a cell is engaged in the process of replication, or making copies of itself. In the RESTING state, a cell is quietly awaiting a signal to turn itself on. The cells, however, can produce copies of HIV or become infected in either state. What makes this an issue for anti-HIV therapy is that some drugs only work in ACTIVE cells, some work only in RESTING cells and some work in both cell states. Ideally, a drug should work without regard for the cell cycle. Drugs that work only in one state of the cell are said to be CELL-CYCLE DEPENDENT. Drugs that work regardless of the state of the cell are said to be CELL CYCLE INDEPENDENT. In contrast, HIV can infect cells in either the active or resting state.
|Drug works in:|
|Drug||active cells||resting cells|
|ritonavir boosted lopinavir (Kaletra)||yes||no|
The implications of this appear to be highly significant. Unless all three drugs in a combination are CELL-CYCLE INDEPENDENT, the person using the combination is not really on a three-drug combination all the time. If the combination includes one drug that doesn't work in resting cells, the user is for all intents and purposes only on a two-drug combination in regard to resting cells. Some combinations even use two drugs that have little or no effect in resting cells.
Most, but not all, drugs work in active cells. The exception is ddI, which works mostly in resting cells. The biggest differences occur in the effect of drugs on resting cells. Here, two of the most common nucleoside analogue drugs, AZT and d4T, and all protease inhibitors have little effect in resting cells. Fortunately, there are a number of drugs that work well in both cell states. The chart (previous page) summarizes the activity of various drugs in the two different activity states.
This data raises many important questions that can only be answered by human trials. On the surface, though, these findings may help explain why some people experience drug failure despite good adherence.
Can any conclusions be drawn while awaiting further research? Possibly. For example, it seems reasonable to want to make sure that every combination include at least two (if not three) drugs that are effective against cells in both the ACTIVE state and the RESTING state. In some cases, this might require using more than three drugs in total, or at least carefully selecting three.
Looking at the chart, it is clearly possible to meet the goals implied by this data. For example, any of the following combinations would provide full coverage in both cell states:
|Any two from column A|
plus one from column B:
Other factors, however, would also have to be considered in a typical situation, such as a person's drug history, any known resistance to individual drugs, relative potency, etc. In most situations, there won't be simple solutions like those implied above. Any protease inhibitor, for example, lacks effectiveness against resting cells. Thus, care should be taken when selecting a regimen based on a protease inhibitor to include at least two drugs that are effective in RESTING cells.
In the long term, these observations must be factored into the search for new drugs, so that ideally, new therapies that work in both ACTIVE and RESTING cells might be given priority.