Chapter 6
The Future of AIDS

Research into HIV and AIDS has yielded many effective drugs and holds the promise for effective vaccines in the coming years. Experts fear, however, that the progress has resulted in one great disadvantage. The success of HAART and other treatment regimens in extending the lives of patients in developed countries has led to a complacency about HIV and AIDS. Says John Siegfried of the drug company industry group the Pharmaceutical Research and Manufacturers of America (PhRMA), "The fact that the death rate dropped 80 percent (in the United States) and the fact that people are living much longer is misinterpreted by many, many people as meaning AIDS is no longer a threat in the United States."⁴⁶ The problem of complacency is not limited to the United States. Said Derek Bodell, director of the National AIDS Trust in the United Kingdom, "I think we've now got a whole new generation who think that HIV is not the issue that it was for the generation before them."⁴⁷

The truth, however, is that there is still no known cure for HIV infection, and even the drug regimens that have enjoyed a great deal of success have limitations. Between the potentially intolerable side effects and the possibility of a patient developing drug resistance, the current drug regimens are not universally effective. As far as the research has come since the beginning of the worldwide crisis, scientists continue to push forward down new avenues to contain and treat the disease. Some research is focused on the development of new classes of HAART drugs and new vaccines, while other studies aim to use gene therapy to treat HIV.

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In addition, HIV education and prevention remain central issues, and many groups are trying to change the perception of HIV and the AIDS crisis around the world.

New and Better Antivirals

Through a global effort, the HAART drugs that have been successful in developed countries are now available in limited quantities in the developing world, with increased availability to come. Nevertheless, these drugs do not cure HIV infection or AIDS; in addition, up to 40 percent of HIV-positive individuals have either developed resistance to current multidrug cocktails or have had no success with the existing options. Said Ho, "Developing regimens that include anti-HIV drugs designed to attack the virus in new ways is one of the most pressing unmet medical needs in HIV therapeutics today."⁴⁸

To that end, new classes of antiretroviral drugs are in development. One such class in particular, comprising drugs called entry inhibitors, shows the most promise. During HIV infection, the virus must first attach, or fuse, to a host cell. By preventing this fusion event, entry inhibitors block HIV from getting into cells and therefore prevent the infection from spreading.

The first drug in the entry inhibitor class is called Fuzeon, or T20. Fuzeon works by interfering with a protein called gp41, which is used by HIV to attach itself to proteins on the surface of a T cell. Normally, gp41 extends out from a virus particle to anchor the virus to the T cell's surface proteins. When Fuzeon is present, however, it binds those T cell surface proteins itself, thereby preventing gp41 from finding available targets and from entering the cell.

In July 2000, the results of a clinical trial of Fuzeon on seventy patients were revealed. HAART no longer worked in these patients, but of the forty-one who survived through the entire clinical trial, twenty-three of them saw their HIV levels cut to levels below detection. The drug's side effects also seemed tolerable, a major advantage over the toxicity of HAART. Later clinical trials that involved close to one thousand HIV-positive individuals worldwide confirmed Fuzeon's beneficial clinical effect. By March 2003, Fuzeon was approved by the FDA for use in the United States.

Though Fuzeon is beneficial to HIV-positive individuals at all stages of the disease, the drug is usually reserved for use after the immune system has become greatly damaged or other drug regimens have failed. A partial reason is that the drug requires high doses and patients can still suffer from such adverse side effects as injection site reactions, which both can lead to decreased patient compliance. The main reason, however, to hold off on Fuzeon is the drug's cost: According to Fuzeon's manufacturer, Roche Pharmaceuticals, the price of Fuzeon in the United States and Europe will exceed twenty thousand dollars annually per patient. This makes it the most expensive antiretroviral drug by far, and out of reach of many people even in the developed world. HIV victims in the developing world have little hope of being able to afford Fuzeon. Still, the drug represents success in a new area of HIV treatments and has already been joined by other prospective drugs in the same class. Experts hope, as with previous HIV drugs, that the cost can be reduced with time and that entry inhibitors will become widely available, even in the developing world.

Turning HIV Against Itself

Entry inhibitors are but one of the new frontiers of HIV research. For the first time since AIDS was labeled a crisis, scientists have tools to use against HIV that promise significant breakthroughs—tools that were also completely unknown in the 1980s. For example, with the advent of advanced biotechnology, a new path to treat, and possibly cure, HIV infection has emerged in the form of gene therapy.

Gene therapy aims to treat illnesses by altering the genetics of diseased cells. The original goal of gene therapy was to treat diseases caused by specific defective genes by stimulating the body into incorporating new, working copies of the genes. However, VIRxSYS Corporation of Gaithersburg, Maryland, announced in 2003 that it would begin trying a drug called VRX496 that would work not by replacing a defective gene but by introducing a new gene that would neutralize one of HIV's key genes.

VRX496's developer, Dr. Boro Dropulic, realized that HIV's ability to integrate its own DNA into that of host cells meant that gene therapy might also work against this virus. His approach with VRX496 was to use a genetically engineered form of HIV in which the normal viral gene sequences were replaced by antisense DNA—sequences of DNA that are exactly opposite what they are in the normal virus—as well as DNA that coded for proteins called ribozymes. These ribozymes act like molecular scissors, cutting up and destroying genetic material from normal HIV but nothing else.

For VRX496 to work, T cells are harvested from a patient's body and infected with the therapeutic virus in the laboratory. T cells treated this way undergo the same processes as with HIV infection, except that VRX496 does not cause a disease. Eventually, the DNA of VRX496 is integrated into the host cells' DNA, and a VRX496 reservoir is created, just as it would be for HIV.

In theory, the presence of VRX496 turns T cells into "Trojan horses" that are ready to fight HIV. When these cells are returned

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to the patient's body, some also get infected with HIV. Both the virus and VRX496 begin to replicate, one making normal HIV genetic material, and the other producing ribozymes to destroy that genetic material. As the process continues, HIV particles never properly form, and the disease progression is halted, perhaps permanently.

In trials in animals, VRX496 was proven safe, and scientists were able to deliver the therapeutic virus consistently to more than 90 percent of T cells harvested from humans. When the VRX496-infected T cells were tested in the laboratory, scientists observed a greater than 99 percent reduction in the replication of HIV.

In August 2003, VRX496 was administered to the first patient. By September, an independent data safety monitoring board declared that no adverse effects from the drug were detected in early clinical trials. Dropulic is optimistic and said in 2003 that "with the correct dose, it may be possible to cure patients with AIDS by creating an army of T cells that can inhibit and resist HIV infection."⁴⁹ Nevertheless, VRX496 faces many more hurdles and clinical trials before it can be used on a large scale. As seen with earlier therapies such as AIDSVAX, positive results from early trials do not guarantee success in large-scale clinical trials.

The Promise of Microbicides

Though Fuzeon and VRX496 are promising new therapies, the future of AIDS is not just about new treatments. As was true from the beginning, prevention and education remain vital to the efforts to contain this disease. The problem in much of the developing world remains that treatment with drugs does not prevent the transmission of HIV. This means that without changes in sexual behavior, HIV's spread will continue. The solution, at least in terms of reducing infection in women and therefore MTCT, seems to lie in developing preventive measures that are entirely within the control of women, who are at the greatest risk for contracting HIV. Said Gatell, "Prevention and therapy are no longer a dichotomy. They are complementary and should be implemented together and everywhere."⁵⁰

One of these preventive measures, the female condom, has proven successful in some portions of the world in protecting women against HIV infection. Nevertheless, although it is an effective means of protection and can be obtained and used by women, the female condom still requires male cooperation in its use. Researchers have found that the same social and cultural barriers that prevent male condom use often come into play with female condoms.

To avoid the necessity of obtaining male cooperation, many researchers have turned to microbicides as a potential way to prevent HIV infection. Just as spermicides are topical solutions that kill sperm, microbicides work in similar ways to kill viruses and bacteria that cause a number of sexually transmitted diseases, including HIV.

Microbicides can be inserted into the vagina or rectum by women, and therefore do not require active cooperation from male partners. This is an advantage in societies where women lack the power to demand that their partners use protection. In addition, though spermicides by definition are contraceptives, many of the microbicides in development do not kill sperm. Women and couples who wish to conceive therefore need not risk HIV infection in order to have children.

Research into microbicides has yielded over fifty different products in various stages of clinical testing. Though the approach shows promise, some experts estimate that a $500 million investment will still be required to bring an effective microbicide to market. Moreover, extensive educational campaigns will be required to use the products successfully. The challenge for the future will be to provide these products to high-risk women in easy-to-use and affordable forms.

Combining Prevention and Therapy

Experts estimate that by 2010 there could be as many as 45 million additional people throughout the world who are HIV positive. The need for anti-HIV efforts therefore becomes even more pressing. In fact, by implementing safe sex practices and education about the virus, it is estimated that 29 million of these infections can be prevented. Says former American president Bill Clinton:

It's pretty hard to justify or explain how we are on the verge of the worst epidemic in human history, that is preventable, where we have medicine that helps, replete with examples where the epidemic has been turned back. Some of the questions have to be answered by science, with continued progress in treatment therapies and the development of vaccines and cures. But the other questions have to be answered by politics and citizen action.⁵¹

Scientists urge that new forms of prevention must be actively investigated. For example, when sexually transmitted diseases other than HIV are aggressively treated, HIV infection rates seem to drop, as seen in the case of Tanzania where this approach has resulted in a 40 percent decrease in HIV infection. By simply giving people in rural areas of Tanzania access to a clinic with a trained staff and regular supply of drugs to treat STDs and encouraging people to visit the clinic regularly to receive health education, doctors were able to slow significantly the spread of HIV. Experts believe that similar programs in other areas are likely to achieve similar results.

Studies have also shown that promoting male circumcision reduces the risk of HIV infection by half. This is because the tissues of the foreskin include a type of cell that is particularly susceptible to HIV, and in an uncircumcised male, may provide an additional entry point for the virus. A similar situation exists among women, in that the cervix is particularly susceptible to HIV. In fact, cervical tissues are much more vulnerable to HIV than vaginal tissue; therefore, experts contend that women should be encouraged to use diaphragms as a protective measure against infection.

Current HAART drugs may also play a role in prevention of HIV infection, and these roles need to be investigated further. Some studies have suggested that the administration of certain antiretroviral drugs after an individual has been exposed to HIV might inhibit infection. In essence, HAART drugs could be administered as a sort of "morning after" treatment after HIV exposure. Other studies are ongoing to determine whether antiretroviral drugs could block HIV transmission preemptively. According to Dr. Helene Gayle, director of the HIV-AIDS program for the Bill and Melinda Gates Foundation, "HIV infection rates will drop when we implement programs based on sound scientific research and when prevention has the full backing of national leaders and is funded with adequate resources.… We must maintain a balance between biomedical options and behavioral prevention."⁵²

Challenges

Part of the challenge that surrounds the AIDS crisis is to convince the world that the problem is not merely a medical issue or a public health issue—it has major implications on the economy, on crime, and on society. For example, 80 percent of those dying of AIDS are between twenty and fifty years old, the age group that normally holds the jobs, earns the money, and raises the families. As Bill Clinton says:

In some nations, teachers, doctors, and nurses are dying faster than they can be trained, undermining health and education. In some places farmers and farm laborers are dying, cutting food production. Factory workers dying leads to reduction in productivity and growth. Police and military personnel dying undermines public order and safety. And most important, the mothers and fathers dying in droves undermines the fabric of families, social life, and civilization itself.⁵³

The worldwide commitment to solving the problem of AIDS grows every day. Faced with the fact that as of 2003, only four hundred thousand people in developing countries had access to life-saving antiretroviral drugs, on December 1, 2003, the World Health Organization (WHO) announced its "3 by 5" initiative, a commitment to provide antiretroviral treatments to 3 million additional people in developing countries by the year 2005. Initiatives of this magnitude would not be possible without the help of governments, private foundations, pharmaceutical companies, and researchers. Said Dr. Jack Chow, assistant director-general of WHO for HIV/AIDS, Tuberculosis, and Malaria, "The 3 by 5 framework is a plan for action by a broad alliance of nations, institutions, and committed people, including those living with HIV/AIDS. We urge all concerned to work to reach the 3 by 5 target as rapidly as possible."⁵⁴

A key element of the 3 by 5 plan is that tens of thousands of community health care workers will be recruited to help with the administration of HIV drugs. By acknowledging that community involvement is vital for the success of an anti-HIV initiative, experts hope for greater adherence to treatment regimens and for more success in HIV prevention. In addition, the clear presence of HIV counselors in communities will presumably reduce the stigma for people living with the virus.

Still, it is important to keep in mind that though the 3 by 5 plan is an important step in achieving control over the AIDS crisis, it is not a complete solution. In 2003, the estimated number of people who needed but were not getting antiretroviral treatment was 5.9 million—nearly double the number covered by the WHO's plan. That number may even rise significantly by 2005. Furthermore, antiretroviral treatments must be taken for life, so the 3 by 5 plan cannot stop in 2005. As the WHO states in a 2003 report, "3 by 5 is just the beginning of antiretroviral therapy scale-up and strengthening of health systems."⁵⁵

Where Does the Solution Lie?

Even with the large amount of HIV research being conducted, it is still unclear whether any of the existing avenues of investigation will result in a definitive cure for this deadly disease. As experience has shown, even the most promising treatments may fail to realize their goals. Furthermore, many scientists feel that the AIDS crisis will get worse before it gets better and that this modern plague will remain deadly for several more generations.

The story of AIDS does not yet have an ending. Scientific authorities and global leaders continually work toward containing the spread of this disease and treating the victims more effectively. No one knows which approach will finally cure HIV infection or how long it will take to eradicate the disease; nevertheless, there is a great deal of hope in the twenty-first century that a cure for AIDS is not far off. Said Piot on World AIDS Day 2003, "There are few moral causes more important in the world today than to build the momentum which transforms scattered examples of success into a massive global movement to overcome AIDS.… We cannot delay."⁵⁶