Remarkable progress has been made in developing HIV treatments, considering that the human immunodeficiency virus, or HIV, was a complete mystery until the mid-eighties. Not only has the virus that causes AIDS been identified and dissected gene by gene, but drugs that work at many different stages of the HIV replication cycle have been developed. Today, people with HIV-at least in developed nations-can expect to live well beyond what was possible in the early days of the HIV epidemic. Indeed, the precipitous drops in documented HIV- related illnesses and new cases of AIDS in developed nations are the direct result of highly active anti-retroviral therapy-or HAART, according to keynote speaker, Dr. Martin Hirsch, Massachusetts General Hospital and Harvard Medical School, Boston. Dr. Hirsch reviewed the evolution of antiretroviral therapy of HIV infection and highlighted current challenges and future directions.

Essential advances in the treatment of HIV infection were the development of potent antiretroviral drugs and the recognition that these drugs need to be used in combination to suppress HIV replication to below the detection limits of sensitive assays of levels of HIV RNA in the plasma (so-called viral load assays). Current HAART regimens employ at least three drugs. The selection of number and types of drugs to be included in a HAART regimen for a given patient needs to include consideration of the patient's treatment history. For patients who have not been treated previously with antiretroviral drugs (so called "antiretroviral naive"), studies lasting as long as three years suggest that the use of two nucleoside reverse transcriptase inhibitors, such as zidovudine (Retrovir®) and lamivudine (Epivir®), in combination with either a protease inhibitor such as indinavir sulfate (Crixivan®), or a non-nucleotide reverse transcriptase such as efavirenz (Sustiva®), can result in durable benefit in terms of immune system preservation and viral suppression.

Another recent, popular regimen for antiretroviral naive patients is the combination of zidovudine, lamivudine, and abacavir sulfate (Ziagen®), all three of which have been formulated into a single drug, Trizivir® (a request for approval of this combination formulation has been filed with the United States Food and Drug Administration). Results from one study reported at the meeting suggest that this simplified regimen achieves the same degree of viral suppression as regimens containing a protease inhibitor. With the three drugs combined in a single pill, the regimen is easier for patients to follow. Many other potent anti-HIV combinations exist, and all of them seem able, if used appropriately, to achieve excellent control over the virus. The sobering fact is that all regimens, even when initially effective, will fail in some patients, most commonly due to either non-adherence or to pre-existing antiviral drug resistance engendered during prior unsuccessful antiretroviral treatment. When treatment regimens fail, the virus takes over, and the immune system begins to fail. As effective as HAART regimens are, none of them can stop viral replication completely, and none of them are able to eradicate the infection. They are only able to contain it for as long as potent antiviral suppression is maintained. Because HIV is capable of mutating at lightning speed, any changes that the virus makes allows it to evade multiple anti-HIV drugs. In other words, the virus becomes "resistant" to treatment-not only to one drug, but commonly to many or all drugs within the same class of agents, Dr. Hirsch indicated.

HIV patients are also required to follow demanding drug regimens that can be associated with difficult side effects. When people with HIV fail to take their drugs regularly, virus replication is insufficiently suppressed, and the virus is very likely to become resistant to the drugs used. As a result, not only will the specific regimen used fail, but because of cross-resistance observed between different antiviral drugs, the ability of alternative available regimens to achieve adequate virologic suppression will be compromised. "We have come to appreciate that drug toxicities and drug resistance are important confounders of our therapeutic progress," Dr. Hirsch confirmed.

One of the toxicities that people with HIV find enormously troubling is the so- called "fat redistribution syndrome" or lipodystrophy. This syndrome consists of central obesity (often referred to as the "protease paunch"), fat deposits at the base of the neck (the so-called "buffalo hump"), and loss of subcutaneous fat in the limbs and the face, leaving the face gaunt and lined.

Other metabolic disturbances reported to be associated with HAART include high cholesterol and triglyceride levels in the blood, abnormal glucose metabolism, lactic acidosis, hepatitis, pancreatitis, and osteoporosis. Driven by the need to resolve these issues, scientists are making a great effort to come up with new drugs and new treatment strategies that will be more effective and user-friendly and less toxic.

The newest drug-on-the-block is a second-generation protease inhibitor (PI), lopinavir, which is structurally related to ritonavir (Norvir®). This agent is formulated in combination with ritonavir to prolong its half-life and increase the blood levels achieved. The combination of lopinavir/ritonavir is called Kaletra®, and it has just been approved for the treatment of HIV by the United States Food and Drug Administration.

The lopinavir/ritonavir combination has ten times more anti-HIV activity under test situations than ritonavir alone, and, due to its pharmacologic properties, can be used in twice-daily dosing. In addition, lopinavir/ritonavir remains potent against viruses that have become resistant to other PIs, Dr. Hirsch observed.

Another drug that may soon receive FDA approval is tenofovir, and inhibitor of the HIV reverse transcriptase. A member of the new nucleotide analog class of reverse transcriptase inhibitors, tenofovir can be given once a day, and it appears to remain active against HIV strains that have developed resistance to nucleoside analogs, he added.

Inhibition of the HIV envelope-mediated membrane fusion process, or the interaction of the viral envelope with chemokine coreceptors, might provide highly selective strategies to block the virus from attaching and gaining entry into the cell. Novel agents that inhibit these essential processes in the HIV life cycle are currently undergoing clinical evaluation in HIV-infected persons.

In addition, clinical HIV researchers are now exploring combinations of these agents, each of which acts at a different sequential step as the virus makes its way into the inner sanctuary of the CD4 cell. One of these compounds is T-20, a short sequence of amino acids that blocks the fusion of the virus to the cell membrane. In work done by Dr. Hirsch and colleagues, researchers observed a "strong synergy" between T-20 and a CCR5 chemokine receptor inhibitor, another compound which acts at a different point of viral attachment and entry into the CD4 cell. "Whether this synergy between the agents will translate into clinical benefits needs to be studied in the context of clinical trials," researchers caution. A promising additional antiviral target is the HIV integrase enzyme that catalyzes integration of the newly copied viral genome into the host cell chromosome-an essential step in virus replication. Candidate integrase inhibitors are now in pre-clinical development.

As Dr. Hirsch suggested, combinations of these novel types of agents may eventually give physicians new approaches to treat HIV infection more conveniently, more effectively, and more durably. A central pathogenic feature of HIV infection is the ability of the virus to damage the immune system, resulting in patients' inability to fight infection with other opportunistic pathogens and to control HIV infection itself. If the body's own immune responses against HIV could be strengthened, "[it might] greatly reduce the need for anti-retroviral therapy in patients who are already infected with HIV," Dr. Hirsch suggested. Researchers at the National Institutes of Health in Bethesda, Maryland, have already shown that HIV patients who are treated with an immune- stimulant in the form of interleukin-2 (IL-2) respond with increases in their CD4 cell counts over time.

Researchers also observed that the use of IL-2 in combination with effective anti-retroviral agents has no negative effect on activation of HIV replication itself. However, Dr. Hirsch cautioned that IL-2 has "considerable toxicity", and more studies are needed before it is known whether this approach can actually improve clinical outcomes and be recommended in standard care of HIV-infected persons. "Hopefully, it will represent an important future addition [to our therapeutic options]," he said.

The use of so-called "structured treatment interruptions", or STIs, where patients enjoy structured "drug holidays" from their anti-HIV regimen, is now generating considerable interest. As Dr. Hirsch explained, in order for people to maintain active immune responses against HIV, their immune systems appear to require ongoing stimulation by the presence of measurable amounts of HIV antigens. "When patients are on anti-retroviral therapy for long periods of time, they lose their detectable immune responses to the virus," Dr. Hirsch explained. If people give their immune systems "a break" by stopping treatment in a structured way over specific intervals of time, they might potentially "wake up" their immune systems when the same therapy is re-introduced, thus keeping the virus under better control for a longer period of time. In one study of STIs cited in a separate presentation at ICAAC, starting and stopping therapy in specific cycles led to an increase in viral replication in some patients, which is a dissuasive finding.

In other studies, viral levels stayed the same or decreased as treatment was serially re-introduced over the study interval. Critically, concerns that this approach might make HIV less susceptible to anti-retroviral therapy did not appear to be borne out-researchers observed very little new drug resistance. Further studies need to be done in this area, Dr. Hirsch indicated. If further studies confirm that patients can take drug holidays from chronic anti-HIV therapy without jeopardizing the function of their immune systems and without creating more resistance to anti-HIV drugs, physicians may be able to start therapy when a patient's immune system is still strong and without worrying as much about long-term toxicity problems such as the fat redistribution syndrome. "Structured treatment interruptions are risky, and whether they will be any better than boosting the immune system with other antigens such as a therapeutic vaccine [should one become available] is not clear," said Dr. Hirsch. But, he added, people with HIV can look forward to the day when the prescribed regimen involves only a small number of pills taken once a day, to more potent and, therefore, more effective anti-HIV drugs, and to treatment plans that are tailored to match the susceptibility of the virus they personally harbor.

"My hope is that in the year 2001 and beyond, we will see the mature era of anti-HIV therapy where we have safe and effective regimens that lead to prolonged HIV suppression, minimal toxicity, and ultimately, to viral eradication," said Dr. Hirsch.