October 24, 1999
Dr. Youle reviewed many of the difficult decisions involved when deciding whether to initiate therapy at all, as well as attempting to make the best decision about which approach to use. His primary emphasis for his talk is a note of caution about potential side effects of treating HIV, and all involved must be mindful of not only current side effects, but be observant for new ones that may arise in our future. Nonetheless, like all speakers at the conference he agreed that the benefits of antivirals can be substantial in preventing all of the illness and death associated with untreated or poorly treated HIV infection -- the difficult part is still defining the best way to intervene in that process.
The arguments in favor of treating as soon as possible, including a special recognition for the need to recognize people who are newly infected, e.g. within the first six months of seroconverting (which is the term for making an immune response against HIV infection). The hope is that intervening this early would preserve cells directed against HIV specific proteins, and these cells, if rescued by antiviral therapy, might allow more people to become long term slow progressors. Unfortunately, it remains unlikely that the initial HIV illness is seen and diagnoses during this time period are less likely, although progress has been made in early recognition. After seroconversion, there is much more debate about when is the optimal time to initiate antiviral treatment, although even the most skeptical agree that there is a rationale to initiate medication well before HIV related illnesses might occur -- how long before this point is where there is ongoing debate.
One current concern with using PI's has been the occurrence of symptoms all known as lipodystrophy. While this may have multiple causes, there are data that suggest that at least some of the manifestation may improve with interventions, such as exercise, dietary changes, and medications including metformin and human growth hormone. Thus, Dr. Youle noted that the incidence of these side effects might not warrant avoiding PI's for treatment.
As it is one of the first triple combination trials, the most durable suppression of any regimen has been the clinical trial using indinavir with AZT and 3TC. At three years, about two thirds of people who started this combination continue to show viral suppression to below 50 copies. Flexibility of the choice of nucleosides has been shown with two studies known as START. These studies used indinavir in combination with either AZT plus 3TC, d4T plus 3TC or d4T plus ddI. All have shown comparable success rates. These results have been confirmed by an Australian study known as OzCombo, which compared the same three regimens and showed similar results. One potential difference between the arms is the increase in CD4 cell counts, with a small advantage noted in the d4T/3TC arm of the START study at the end of one year compared with the AZT/3TC arm. One improvement in the use of ddI that has become more standard since the START studies is the use of ddI dosed just once a day. That ddI can be successfully dosed once a day has been shown in several studies, including one which compared d4T, ddI and nelfinavir to AZT/3TC/nelfinavir. This study, recently presented at ICAAC, showed similar outcomes in terms of viral load drops, viral suppression below 400 copies, and the percent of those who stopped their regimen.
What is the role of dual PI's? There have been several studies over the past few years using dual PI's and these have shown impressive success rates in a range of patients. While many of the initial studies have relied on the combination of ritonavir and saquinavir, recent studies have used ritonavir with indinavir. In general, studies using dual PI's with one or two nucleosides have shown very impressive results, including a similar rate of viral suppression at all baseline viral loads. One study was reviewed which used the four-drug combination of d4T, 3TC, and ritonavir/indinavir. The results show that, at the end of week 24, about 80% have a viral load below 80 copies. The newest PI to be studied is ABT 378/ritonavir. In combination with d4T and 3TC, this PI combination has been very impressive in those who are antiviral na&imul;ve. In PI experienced patients, a significant majority of patients achieve viral suppression with 378/r, regardless of PI treatment history, when starting it with nevirapine and two nucleosides.
Finally, Dr. Youle briefly reviewed the data on the use of hydroxyurea as a medication that can not only increase the suppression seen with d4T and ddI, but also potentially contribute to enhancing immunologic control of HIV. Three patients have undergone a series a treatment starts and stops and the results were reviewed. All three were given the combination of hydroxyurea, ddI and either a PI or d4T. Some time after viral suppression was achieved, the regimen was interrupted and the patient monitored for the return of viral replication. When the viral load hit 5000 copies, the regimen was restarted. What was noted was that the first interruption results in return of viral load within one week. The second interruption showed a slower rise, hitting 5000 by about 2-3 weeks. The third interruption took longer still, hitting 5000 by about 4-7 weeks. This studies, and others like it, have inspired a number of studies targeting the potential for treatment interruptions to provoke an enhanced immunologic response.