One of the most provocative and controversial questions to come out of the XI International Conference on AIDS in Vancouver is, "Can HIV Infection Be Eradicated?" Numerous presentations and much discussion outside the meeting rooms at the conference dealt with this issue. That such a radical notion could be seriously entertained at an international AIDS conference is the remarkable outgrowth of three important developments over the past two years. These advances are:
- An improved understanding of HIV pathogenesis and viral kinetics.
- The ability to quantify HIV RNA levels in plasma.
- Development of potent, combination antiretroviral regimens.
Work done by David Ho, George Shaw and others in the past two years has greatly elucidated the dynamics of HIV replication and pathogenesis. Studies by these investigators have demonstrated that HIV is not a "slow virus," as previously thought, but instead replicates at an extraordinary pace, with billions of virions produced daily in patients with advanced disease. By carefully evaluating patients receiving potent protease inhibitors and measuring plasma HIV viral RNA levels, it has become clear that the half life of HIV is extremely short (6 hours) and that as many as 10 billion new virions may be produced daily. Moreover, with such rapid replication, mutations in viral DNA can be expected that will confer a selective advantage to viral phenotypes that are drug-resistant in patients on antiretroviral regimens that do not completely halt viral replication.
While controlling a virus that replicates and mutates so rapidly is a daunting prospect, these kinetic data also raise the possibility that effective viral suppression might allow the infection to "burn out" after a prolonged period of intense therapy. In a presentation at the closing session of the Vancouver AIDS Conference, Dr. Ho presented a mathematical model of how long it might take to eradicate HIV. This model considered the various compartments of the body where HIV is found, including plasma, activated lymphocytes, persistently-infected cells, and lymph nodes. Ho hypothesized that it could be possible to eradicate HIV infection with an extremely potent antiretroviral regimen in 18 to 36 months. Ho cautioned that these estimates are calculated guesses based on an imperfect understanding of the life cycle and replication kinetics of the virus. Nonetheless, exercises such as this model provoke a profound change in our thinking about treatment for HIV infection.
Three clinical trials presented at the Vancouver AIDS Conference further elevate the hope that HIV infection might be put into remission, if not eradicated. A study by Julio Montaner and colleagues found that in patients treated with the three-drug regimen of nevirapine (a non-nucleoside reverse transcriptase inhibitor), AZT and ddI, 60 percent had undetectable plasma HIV RNA after one year of therapy. A trial presented by Roy Gulick and associates reported follow-up data on patients with previous long-term AZT exposure who were treated with indinavir, AZT and 3TC. After an average of one year of treatment, 83% of patients had undetectable plasma HIV RNA and sustained improvements in CD4 cell counts. Finally, in a small study conductedby Marty Markowitz and coworkers, twelve patients who were within 90 days of HIV seroconversion were treated with ritonavir, AZT and 3TC. After up to ten months of treatment with this potent regimen, all patients continuing therapy had undetectable plasma HIV RNA levels, all had improved CD4 cell levels and normalized CD4:CD8 ratios. In addition, several patients were reported to have lost antibody response to some HIV antigens (i.e., they were seroreverting). These dramatic and exciting results are still quite preliminary and represent a very select group of highly motivated patients. Nevertheless, the data from these three studies suggest that potent antiretroviral therapies can suppress HIV replication below the current limits of detection and induce what might be considered a remission. It is premature to speculate that any patient may have been cured of HIV infection, as it is not known what will happen when antiretroviral therapy is stopped in these individuals.
The implications of these findings for clinical practice are profound. The figure shows the idealized response of plasma HIV RNA levels to several antiretroviral therapies. With AZT alone, viral load is reduced by about 0.5 log for up to six months and then returns to baseline levels. AZT therapy prolongs life for one to two years, despite a more transient effect on viral load. Combination nucleoside analogue therapy with AZT and 3TC or ddI reduces plasma HIV RNA levels by 1.5 logs, and this effect is more sustained than with AZT monotherapy. The survival advantage conferred by this treatment is superior to that of AZT. With triple combination therapy that includes a protease inhibitor, viral load can be reduced below the limits of detection. This therapy is obviously superior to treatment with one or two nucleoside analogues, but the long term implications remain unclear. Patients with sustained responses may be considered to be in remission as long as their therapy is continued, but what would happen if therapy is stopped? It is still not known if patients will experience immediate or delayed rebounds in viremia after prolonged suppression of HIV replication.
Triple combination therapy is extremely demanding for patients, requiring up to 20 pills per day. Additionally, such therapy is very costly and may be out of the reach of many patients. But in making treatment decisions with our patients, we are now faced with a troubling question: should we prescribe combination nucleoside analogue therapy that will partially suppress viral replication and prolong life, but which is ultimately doomed to fail because the virus will continue to replicate and develop resistance? Or, should we only prescribe "remission-inducing" triple combination therapy, despite its expense and complexity, in the hopes of completely shutting down HIV replication and preventing resistance from developing? There is no clear answer to this dilemma. A compromise position is to give triple combination therapy to those patients who are truly committed to taking it, and to stage treatment for other patients, using drug combinations that will not preclude more effective therapy in the future if drug resistance occurs and HIV disease progresses.