New Weapons Against HIV
New Weapons Against HIV
On April 23, 1984, Secretary of Health and Human Services Margaret Heckler announced that the virus that caused AIDS had been discovered and that scientists had perfected a process that enabled them to grow large quantities of the virus in order to study and characterize it. She also declared, "We … believe that the new process will enable us to develop a vaccine to prevent AIDS in the future. We hope to have such a vaccine ready for testing in approximately two years."21 Her final prediction was that "there will be a … cure for AIDS before 1990."22 Unfortunately, for the thousands of AIDS victims, families, and others who dealt with the human tragedy of the disease every day, Heckler's predictions were far too optimistic.
Two decades later, Heckler's words still echo as a constant reminder of how much more complicated HIV has proven to be than scientists first estimated. As of 2004, HIV vaccines were still in development, over 22 million people worldwide had died of AIDS, and there was no cure in sight.
In the years following Heckler's announcement, it became increasingly clear that finding a cure would not be the straightforward task she had outlined. Nevertheless, research into treatments moved forward, and by 1987, the first AIDS drug, AZT, was approved for use by the FDA. This was soon joined by many other drugs; as of 2004, almost two dozen medications had been approved to treat HIV infection. Though none of these drugs cure HIV, they greatly increase patients' survival time and improve their quality of life.
Stopping the Cycle
In 1985, Dr. Hiroaki Mitsuya of the NIH demonstrated that the drug AZT was able to inhibit the replication of retroviruses, the family of viruses that HIV belongs to, at least in laboratory cultures. Mitsuya believed that AZT could also be effective in human AIDS patients.
AZT represents the first of a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). These drugs control HIV by interfering with the action of proteins essential to the virus's life cycle. Since HIV is a retrovirus, all of its genetic information is stored as a single strand of RNA. In order for HIV to function, it has to convert its RNA into DNA. To accomplish this task, HIV uses chemical compounds, called nucleosides, found inside the cells it infects, as well as a protein called reverse transcriptase.
As part of its life cycle, a healthy cell normally makes DNA from nucleosides, which float freely inside the cell. Upon infection, HIV immediately begins to make the DNA it needs, using the cell's own nucleosides as the building blocks. Reverse transcriptase, using a strand of the virus's RNA as a template, determines the order in which to assemble those nucleosides to form a strand of DNA. When viral DNA is produced, HIV proteins can be made, leading to the production of new HIV particles. The new viral particles bud off the infected T cell and are released into the bloodstream.
Early studies suggested that AZT did indeed benefit HIV-positive patients. The drug interferes with reverse transcriptase's ability to convert viral RNA to DNA. When AZT enters a cell, it is transformed into a chemical compound that closely resembles a nucleoside—closely enough to fool reverse transcriptase. When the protein mistakenly tries to use this false nucleoside, however, DNA synthesis is halted, meaning that viral replication cannot continue. As a result, HIV cannot infect additional cells. According to Dr. Samuel Broder, director of the National Cancer Institute, who tested AZT in laboratory cultures of HIV-infected cells and demonstrated the drug's apparent interference with viral replication, "Attacking the virus by this unique enzyme has given us a foundation stone on which we can build new therapies and combination therapies, hopefully ultimately developing a cure for HIV infection."23
Despite the effectiveness of AZT, scientists said from early on that this drug was not the final answer to the HIV puzzle. Dr. Robert Windom of the Department of Health and Human Services urged in 1986 that people be cautious in their optimism: "This is not a cure. We don't want to overpromise to the thousands of people who have AIDS."24 Still, AZT offers many benefits to those infected with HIV. Because it greatly reduces the virus's ability to self-replicate, the decline of the immune system is slowed. Opportunistic infections, as a result, are greatly reduced. In addition, when taken during pregnancy, AZT reduces the risk of HIV transmission from pregnant mother to fetus. Studies have also shown that the earlier AZT is taken, the more effective it is. According to Dr. Jerome Groopman of the New England Deaconess Hospital regarding a 1989 study, "This is the first clear proof that early intervention makes a difference. It's exciting, and it's a finding of real importance."25
Scientists saw AZT as the basis for developing even more effective drugs. In 1989, for example, Broder said, "AZT is analogous to saying the Wright brothers can fly. The Wright brothers did not design the 747 that you can fly to Europe. AZT has made it possible to see that something can work against the retrovirus that causes AIDS."26 In the years since the successful trial of AZT, other NRTIs have been developed, including ddC, ddI, d4T, and 3TC. Though all the drugs work on the same principle, they each interfere with reverse transcriptase in a slightly different way.
Continuing research on NRTIs and other treatments was and remains vital. For one thing, the toxic side effects of these drugs on healthy cells are undeniable. To a certain extent, the drug interferes with the normal cellular processes in healthy tissue as well, which leads to tissue damage. For example, even in the earliest trials, patients suffered significant reductions in their red and white blood cell counts from damage to bone marrow. In fact, so severe are side effects like nausea, anemia, diarrhea, liver damage, nerve damage, and bone marrow damage that many patients—between 40 percent and 80 percent of AZT users—are forced to discontinue treatment.
Moreover, NRTIs are only able to slow replication of HIV, not stop it completely. This means that the virus is able to linger, waiting for an opportunity to strike. That opportunity often presents itself due to HIV's notorious adaptability.
As happens in all living things, random mutations arise whenever HIV's genetic material is copied. Usually, the mutations do not have significant effects, but every once in a while, a mutation will occur that changes HIV's ability to survive under adverse conditions. In the case of NRTIs, HIV's reverse transcriptase changes to the point where it is no longer fooled into using the false nucleoside during DNA synthesis. This means viral replication is able to continue, and in each replication cycle, the beneficial mutation is passed on to more viral particles. Eventually, a single NRTI by itself ceases to limit HIV replication.
A New Class of Drug
The limitations of NRTIs forced scientists to scramble to find something else to fight HIV. By 1994, researchers at pharmaceutical companies had found another class of potentially beneficial compounds, called protease inhibitors. These compounds interfere with the action of a protein called protease, which, like reverse transcriptase, plays an important role in the life cycle of HIV.
[Image not available for copyright reasons]
Protease inhibitors interfere with a later step in HIV's life cycle than NRTIs do, but the net effect is the same: The virus cannot replicate as efficiently. The first protease inhibitor, saquinavir, was approved for use by the FDA in December 1995. Since then, four other protease inhibitors have been approved: ritonavir, indinavir, nelfinavir, and amprenavir. Scientists initially thought that these drugs could do more than simply slow replication, as AZT and other NRTIs did, and stop HIV from replicating altogether. At first, the results looked promising. A 1996 study using ritonavir showed that over the seven months of the drug trial, the death rate due to AIDS was cut in half when ritonavir was administered. Unfortunately, the effects were temporary, just as they had proven to be for NRTIs. In fact, it often took less than a month for some resistance to these protease inhibitors to develop. The resistant HIV particles would then reproduce and continue to degrade the patient's immune system.
In addition, the side effects of protease inhibitors could be just as debilitating to patients as those of NRTIs. Nausea, abdominal pain, vomiting, and diarrhea are common; kidney toxicity, liver damage, pancreas problems, and headache can also be severe, sometimes even life threatening.
A Growing Arsenal
While protease inhibitors were being developed and tested, another class of drug also became available for use against HIV. Similar to NRTIs, these drugs also interfere with reverse transcriptase activity to prevent viral replication. Instead of mimicking nucleosides to fool reverse transcriptase, however, these drugs physically block reverse transcriptase. They are known as nonnucleoside reverse transcriptase inhibitors (NNRTIs).
The first NNRTI approved by the FDA in 1996 was called nevirapine. Once again, clinical trials showed that patients who took only nevirapine quickly developed drug resistance, and side effects similar to the other classes of anti-HIV drugs were also observed. Scientists, however, learned something new about anti-HIV drugs: When nevirapine was given to patients in combination with other anti-HIV medications, drug resistance took much longer to occur. One clinical trial, for example, showed that when nevirapine was combined with AZT and ddI, the treatment was significantly better at reducing HIV levels and increasing helper T cell counts than treatments using AZT and ddI only.
The realization that a single drug cannot control HIV as well as a multidrug approach can has proven to be a major breakthrough in AIDS research. When doctors attack HIV simultaneously with combinations of NRTIs, NNRTIs, and protease inhibitors, the virus is unable to mutate fast enough to develop resistance to all the drugs at once. Says Dr. Dani Bolognesi, chief executive officer of the pharmaceutical manufacturer Trimeris Corporation, "HIV so far has been able to resist anything. There are so many viral variants that the chance that one can overcome a specific inhibition is certainly there. We now combine a number of different inhibitors that operate under different mechanisms so the chance that HIV replicates and spawns a variant that is resistant to all are low."27
How patients respond to the cocktail therapies varies. Some patients on the new therapies have proven to be unable to tolerate the combination of powerful drugs; others get no benefit from the treatments. In a number of patients, however, the drug cocktail is so effective in eliminating HIV from the blood that doctors consider their patients in remission. According to Dr. Paul Volberding of San Francisco General Hospital, "We have seen patients whose viral load has gone below our ability to find it."28
Some successes with drug cocktail treatments are dramatic. For example, in July 1995, thirty-seven-year-old Dan Cusick was told that an AIDS-related illness would probably kill him by October. His doctors, however, prescribed a three-drug cocktail, and within weeks tests could no longer detect even trace amounts of HIV in Cusick's blood. Similarly, fifty-four-year-old John Rife's immune system was so weakened that opportunistic infections ranging from virulent pneumonia to AIDS-related cancers ravaged his body. Within a month of starting the drug cocktail, Rife's cancer was gone, and HIV levels in his blood were undetectable as well.
As effective as the drug cocktails have proven against HIV, some scientists hope for more—that combination therapy can completely eliminate HIV. One such scientist is the previously mentioned Ho. As early as 1994, Ho tested his theory that patients who were treated early on in HIV infection—during clinical latency—could benefit more from combination therapy than the patients who usually receive these treatments—those who had already developed AIDS. For his study Ho chose twelve men whose helper T cell count had dropped below five hundred cells per milliliter of blood, but was still higher than the count of two hundred that signifies the onset of full-blown AIDS. He then treated these patients with a combination of AZT, 3TC, and a protease inhibitor, either indinavir or ritonavir. Three of the participants had to withdraw from the trial early due to adverse reactions to the drugs. At the 11th International Conference on AIDS, however, Ho revealed that the nine men who remained on the therapy showed no evidence of HIV in their blood within three months of commencing treatment. As Ho explained to the conference attendees, his results prove that it is "time to hit HIV, early and hard."29
The Possibility of Eradication
The effectiveness of combination therapy, now referred to as highly active antiretroviral therapy (HAART), offers some hope that the Holy Grail of AIDS research, a cure, may be in sight. As studies were conducted that followed patients' progress as they underwent combination therapy, it became clear that HAART remains effective for years rather than months, as is the case when single drugs are administered. Many scientists, including Ho, propose that effective HAART could lead to the eradication of HIV from an infected individual's body. However, HIV's ability to remain hidden in reservoirs continues to be problematic. As Ho explained in a 1997 interview:
The available therapies have helped us eliminate over 99 percent of the virus in infected individuals. But we are learning about additional viral compartments. In our patients who have been treated very early and very hard, and have received this treatment two years now, we are still finding a residual pool of virus resting in certain CD4 cells, in a very quiescent way. This poses a new obstacle to deal with.30
Since even single copies of the virus can infect new cells to produce thousands of additional viral particles, anything less than 100 percent elimination cannot be considered a cure.
Adding to the challenge is that HAART often has severe side effects, making it impossible for many patients to continue taking the drugs indefinitely. In addition, scientists have not completely identified the effects of prolonged HAART on killer T cells. Although in the short term the treatment is clearly beneficial, evidence has surfaced about the toxicity of HAART on other immune system components. Finally, there is the possibility that, as toxic as HAART treatments are, they might need to be strengthened in order to keep working. One of Ho's collaborators, Dr. Linqui Zhang, noted, "It is sobering to realize that the so-called highly active antiretroviral therapy is actually not always active enough. As we strive to eradicate HIV-1 infection or induce a remission, we must focus on the possibility of further intensifying antiretroviral treatment, even though current therapies are already toxic, costly and complex."31
The Road Ahead
Researchers continue to strive for refinements to HAART. One such refinement is reducing the complexity of HAART regimens, making it easier for people to adhere to them. For example, in Zerit XR, which received FDA approval in 2002, a day's worth of therapy is contained in a single pill. Though Zerit XR must be combined with other anti-HIV drugs to be effective, many others are becoming available in once-daily or twice-daily formulations.
The success of HAART, however, has in some ways hurt efforts to prevent the spread of HIV. According to Dr. Jessie C. Gruman, executive director of the Center for the Advancement of Health, "Because HIV/AIDS is no longer an assured death sentence, new issues in disease management have arisen—cost and adherence. The success of new treatments presents an additional challenge, helping patients keep from returning to risky behaviors that could spread the disease anew."32
Living with HIV
Even with powerful HAART drugs, there is a considerable amount of variability among AIDS patients in the way the disease affects their quality of life. Some are so debilitated by the disease that holding a job or performing household chores becomes impossible, whereas others may go for long periods of time where they function normally, only to succumb to a single severe opportunistic infection.
Still, many HIV-positive individuals find HAART invaluable. People, such as San Francisco hairdresser Puck, who had been given months to live, now look forward to much longer lives. Puck was once in search of a way to pay his final medical bills; after he began HAART treatment, however, his disease came under control and his thoughts turned from final expenses to saving for his retirement.
As the lives of people with AIDS have been extended by HAART, a new dilemma has emerged: where to find the funds to pay for the expensive treatments. In many cases, health insurance policies do not cover HAART, and patients have had to go deep into debt to pay for the medications they need. In 1990, Congress created the AIDS Drug Assistance Program (ADAP) to subsidize the cost of HIV and AIDS treatment. However, as the demand for treatment increases, people are turned away because of budget constraints. In 1996, ADAP had set aside $188.5 million; by 2002, the budget had increased to $878.6 million, and still, there are insufficient funds to help all who applied. There is, however, hope that economics will no longer be an issue for patients who seek HAART. Since 2000, the cost of HAART in the United States has dropped from ten thousand dollars per patient annually to approximately three hundred dollars. The challenge going forward will be to provide effective anti-HIV treatment to people around the world, especially in developing countries, where even today's relatively modest prices make AIDS drugs completely unaffordable.