New developments in affordable antiretroviral therapy: intermittent treatment

16 August 2000. Related: Conference reports, Treatment strategies, World AIDS 13 Durban 2000.

Calvin Cohen, for HIV&hepatitis.com

A few years ago the focus of interest in HIV-treatment research was the search for regimens that could ultimately lead to eradication of HIV from the body. In the past year, however, there has been pessimism about the likelihood of this outcome, given how long HIV persists in some of the body’s cells.

Recent estimates suggest the possibility that it could take 60 years of continuous control of HIV replication to expect eradication to occur. Therefore, more research has started to focus on “stalemate,” e.g. what can be done to augment the immune system and its capacity to control HIV itself, with fewer meds, or even no meds at all.

While some research, particularly in those very recently exposed to HIV (“acute infection”), has shown some promise, it is increasingly noted that immunologic control of HIV is difficult to recreate in more than a small percentage of those who are treated some months to years after seroconversion (“chronic infection”). This has led to the next potential phase of HIV treatment research; namely to define ways to both control HIV and the damage it causes, while using the least amount of medications to accomplish this, even if immunologic control isn’t feasible.

One novel approach, presented here, is to use short cycles of medication in an attempt to control HIV with medication, but allow regular time off of antivirals. This is done partly to conserve resources in resource-poor countries, and partly in the hope that pauses will limit the cumulative side effects of medications. These pauses are done for short periods of time to prevent damage done to the immune system when medications are stopped and viral load rebounds.

One observation that underlies some of this work comes from studies which stopped antivirals in a NIH-sponsored trial presented last year. After about two weeks, virtually all participants saw a rebound in their viral load. However, for those with a viral load below detection who then stopped meds, it was noted that during the first week off meds there was very little if any return of detectable HIV. While it is virtually certain that there is some growth going on in that first week, the amount that is growing is so low as to not result in any obvious damage to the immune system. These observations have led to the following clinical studies.

Two studies from the NIH were presented with preliminary observations on just a few participants, and was presented by Dr. Mark Dybul. All study participants had a viral load suppressed to below 50 copies on a standard antiviral regimen. Starting with those who have viral load suppression is a key to this research, since stopping meds with a higher viral load potentially increases the risk of developing drug resistance to some of the antivirals. Three cycles of times “on/off” antivirals were studied. One was a cycle of two months on, one month off. Second was one week on, one week off. Third was a two-day on, five days off. Each had theoretically interesting reasons why it was worth further investigations.

The two day on/five day off cycle had only three participants studied before that approach was discontinued. It was found that there was some risk in not quickly re-establishing control of replication when going back on treatment using this schedule, and thus no further work is planned with this short cycle. The one week on/one week off cycle also had just a few (four) participants with information about their response out to about three months. To date, however, all were successful in re-establishing a suppressed viral load while on medication, and there was no loss of CD4 cells noted with this approach. While of great interest, it is cautioned that this approach should not be tried outside of research settings before more results are presented since there were significant concerns that these multiple rapid cycles might risk the development of medication resistance, and thereby threaten the longer term success of using antivirals.

The results of the Swiss/Spanish study are out to just about one year, and provide some of the best available data about the longer-term outcomes of an intermittent therapy approach. The cycle starts, as with all of these studies, after they first establish suppression of HIV to below 50 copies with standard antiviral combinations. Then, the cycle is to go off medication for two weeks, followed by eight weeks back on treatment. At one year, there was little evidence that continuous pulsing off meds with this schedule leads to immunologic control, as they showed that during the one month time off, the 122 participants continued to have viral load returns during each “off” cycle. On average, the viral load came up to about 1,000 copies during each of the two-week cycles off medication, and didn’t show a declining trend in the one-year period of the study. (It was also noted that during the first two-week interruption, about 12% had a viral load rebound over 100,000 copies.) However, while there was no evidence for decreasing peaks in the viral load over time in the majority of participants, there was a suggestion that in perhaps 20% of participants, there was some possible decline in the peak viral load off medication over the one-year period. Of those who successfully did re-establish virologic control, the CD4 counts were stable in this group for the entire one-year period, maintaining a mean of just over 700 cells/mm over this one-year period.

However, the study was not uniformly successful for all of those enrolled. Of concern is that about 15% of the group did not get a viral load back down to <50 copies after the eight-week re-treatment period, a finding which happened to about 5% of participants after each two-week interruption. Finally, they reported in one person that drug resistance to the medications taken did develop.

So where do these studies bring us? The larger Swiss study suggests that at best perhaps 20% of those who start treatment years after seroconversion might – through these cycles – have some improvement in immunologic control of HIV that leads to lower viral loads when off medication. In the remaining 80%, this cycle was not fully successful in that 15% did not get a viral load back down to <50 in the eight-week period back on medications. In addition, one person did develop drug resistance.

Perhaps if the re-treatment period were longer than eight weeks, more participants would be successful in meeting this goal. This may be important to accomplish since interruptions of medications may be riskier in those with higher levels of HIV growth, since in the time period that the medications are leaving the body, there is more of a chance that some of the virus will develop resistance to the medications. Alternatively, as in the NIH studies, the period of time off of medications could be shortened to just one week as a way to decrease the degree of viral rebound.

It is also important to emphasize that, except for the decrease in the amount of antivirals actually taken in these studies, it remains completely unknown which if any of these schedules might result in fewer long-term complications than what is seen in those who take antivirals daily. Thus, active ongoing research will be needed in order to provide guidance to those living with HIV infection and their providers about how to apply these initial observations.

References:

Unless stated otherwise, references are to the Programme and Abstracts of the XIII International AIDS Conference, 9-14 July 2000, Durban, South Africa.

1. Dybul M., Yoder C., Belson M. et al. Drug Interruptions, Holidays and Pauses: an overview of outcomes. A randomised, controlled trial of intermittent versus continuous highly active antiretroviral therapy (HAART). Lb0r11.
2. Dybul M., Yoder C., Belson M. et al. Short cycle intermittent HAART: a pilot study. Lb0r12.
3. Hirschel B., Fagard C.,. Lebraz M et al. The Swiss-Spanish Intermittent Trial (SSITT). ThOrB747.