Nukes? Or No Nukes?
While specific drugs have fallen in and out of favor, the basic structure of anti-HIV therapy -- called HAART -- has changed very little since the late 1990s. Almost all regimens include one highly potent drug -- either a boosted protease inhibitor (PI) or an NNRTI -- along with two NRTIs. While there's no doubt that this has proven very successful, it comes with many side effects associated with taking two NRTIs. As two new important classes of drugs launch onto the market, it may now be the time to begin questioning the conventional wisdom of HAART. One area that seems most ripe for it is the widespread use of NRTIs (nucleoside/nucleotide analog reverse transcriptase inhibitors).
As of this writing there are 20 unique anti-HIV drugs. When fixed dose combinations are included, there are 27 different products to treat HIV disease currently sold in the US. When discontinued drugs and reformulations are added into the count, over 30 products have come to market in less than 20 years. That is a remarkable achievement and credit is due to everyone who made this unparalleled accomplishment, including the scientists, researchers, activists, pharmaceutical companies and especially the people with HIV who participated in the studies.
While the list of available drugs is large, the truth is that many of them are not widely used. Some, like Rescriptor (delavirdine), were never widely used while others like Zerit (stavudine, d4T) and Crixivan (indinavir) were once quite popular but are now rarely used.
NRTIs are the oldest and most widely used class of anti-HIV drugs. This class is quite large and diverse. It includes the oldest drugs, like Retrovir (zidovudine, AZT), Videx (didanosine, ddI) and Epivir (lamivudine, 3TC); newer drugs like Viread (tenofovir, TDF) and Emtriva (emtricitabine, FTC); as well as the fixed-dose combination pills like Epzicom and Truvada.
In the nine years between the approval of Retrovir in 1987 and the beginning of the HAART era in 1996, NRTIs (sometimes called "nukes") were the only drugs available to treat HIV. At first they were given alone, called monotherapy. This was followed in the late 1980s and early 1990s by the first generation of combination therapy, using two NRTIs. When PIs came along, they proved much more potent. NRTIs then took on a supporting role in therapy. This paradigm continued as a third class of drugs, called NNRTIs (non-nucleoside reverse transcriptase inhibitors), joined PIs as the potent agents.
As the third decade of anti-HIV therapy approaches, there are good reasons to start examining the role of NRTIs. These reasons fall into two categories: concerns over long-term toxicity and the basic question of whether they're needed to be used all the time any more. While it's premature to make a blanket call for major changes in how we treat HIV, the sheer variety of anti-HIV drugs now available may give us the chance to re-evaluate when and how to use NRTIs.
The main concern about NRTIs is their safety, especially with long-term use. This stems from two concerns. The first is the real world community experience of these drugs. Almost as soon as the first NRTIs became available, the first major problems began to appear. They ranged from annoying (like nausea) to painful (like peripheral neuropathy) to life-threatening (like pancreatitis).
As newer NRTIs came out, some improvements were noted. The second generation, like Epivir and Zerit, appeared less toxic than the fist. However, problems persisted -- some quite difficult. As the HAART era took hold, the role of NRTIs in a newly recognized syndrome (to be named lipodystrophy) started to become apparent. All NRTIs, some more so than others, are involved in the loss of fat in the arms, legs, buttocks and face (lipoatrophy). Even the newest and best tolerated NRTIs draw concern from some, due to possible but so far unproven bone and kidney problems.
While there are very real differences in safety and tolerability among the NRTIs, there's concern about how they work that affects the whole class. NRTIs work by blocking the synthesis of HIV DNA -- a process called reverse transcription. It is also known that they can sometimes interfere with the synthesis of another kind of DNA that exists inside the cell. This kind is called mitochondrial DNA, or mtDNA, and is different from the DNA inside a cell's nucleus. Mitochondria are small cell structures (called organelles) that generate energy to help the cell to function. Mitochondrial DNA is much more sensitive to damage than our genetic DNA.
It is widely thought that many of the side effects of NRTIs are due to their interference with the normal function of mtDNA. In some cases, the link is unclear. In others, like pancreatitis and lactic acidosis, the connection is well understood. All NRTIs have the potential to damage mtDNA but some, like Zerit, are more likely to do so than others. It may also be the case that some people are more prone to mtDNA damage than others. This could explain, at least in part, why some people have severe problems taking NRTIs while others have little or no problems, even with long-term use. (For more information on this topic, read Project Inform's publication, Mitochondrial Toxicity and Lactic Acidosis.)
If this is a problem for the whole class of drugs, why are they so widely used? In part the explanation lies in the time when many of them were approved. In the 80s and early 90s, effective therapy for HIV was measured in its ability to extend a person's life by weeks or months. Any gain in survival was welcomed. However, when PIs ushered in the HAART era, successful treatment was measured by extending lives by years, thus raising the threshold of what should be expected of a new drug.
Now, we have moved to thinking in terms of decades. Many people think that a person living with HIV, with access to an experienced HIV medical provider and adequate therapies, should expect to live a normal life span. While this is a tremendous achievement, it also requires adjusting the way we evaluate the drugs used to treat HIV. Side effects and toxicities that used to be "acceptable" may become unacceptable when the new time frame now is years or decades.
The other central factor leading some to re-evaluate NRTIs is the other kinds of anti-HIV drugs. By the end of 2007 there should be six unique types, or classes, of anti-HIV drugs. It will take time, research and real-world use to figure out the best ways to use them. The time might not be too far off that it won't be necessary to use NRTIs -- or other commonly used drugs -- in all or even most anti-HIV regimens.
There's little doubt that NRTIs have contributed greatly to the remarkable advances in HIV care and treatment over that past 20 years. However, the balance between their potency and their toxicity seems less favorable than the other classes. This doesn't necessarily mean they should all be abandoned and relegated to medical history but their role in the future of HIV treatment is uncertain.
As we move into the next decade and beyond, the difficult work of constantly re-examining our basic assumptions must be done. Even those assumptions that have served people with HIV well should be open to scrutiny. We have done quite well, but it is time now to ask how we could do better.
Some pharmaceutical companies could become obstacles to this process since these drugs are also important revenue streams for them. Without profits from the sale of older drugs, less money will be invested to search for new and better anti-HIV drugs. Of course, the well-being of people living with HIV is more important than any company's bottom line, but there's a link between profits and continuing research and development. However, that link is also challenged by other factors, including the length of time these drugs have been on the market. One NRTI -- Retrovir (AZT, zidovudine) -- has already lost its patent protections and others are soon to follow. Thus, their value in turning a profit is limited anyway.
Times have indeed changed. Where once activists called loudly for ddC to be approved, there's little doubt it wouldn't get support from the activist, scientific or medical communities if it were developed today. The overriding goal of treatment advocacy is to facilitate and ensure the development of the very best treatments for HIV/AIDS. With new classes of drugs close on the horizon, this goal might be advanced by calling not for more drugs, but for fewer and better ones. It is truly a testament to how far we've come that this discussion is even possible.
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