Structured Therapy Interruptions

Immune Decline During Therapy Interruption.

At the Resistance Workshop in June í99 Felipe Garcia first reported on a group of 10 chronicly infected individuals who interrupted therapy  twice 6 months apart. Garcia cautioned that therapy interruptions should only be attempted in controlled studies. In this study, viral load rebounded after each interruption but following the rebound in the second interruption 4/9 had their viral load spontaneously decline and a proliferative p24 response was detected in 2 of these 4 only after the second stop. The viral loads for these 4 people declined (0.8 to 2 log) but remained detectable. The viral loads ranged from above 1,000 to about 40,000 copies/ml. Therapy was re-started and they all declined to undetectable. No resistance was detected. A third interruption is planned.

Ten patients were initially included in the study with CD4 counts >500. They started therapy with D4T+3TC and either ritonavir or indinavir. After 1 year of treatment patients had a plasma viral load <20 copies/ml, volunteered to stop therapy, and had been below 20 copies/ml for at least 8 months. Just prior to the first stop, plasma viral load was <20 copies in all cases and below 5 copies/ml in 7/10 patients. CSF viral load was <20 copies/ml in all patients. Among the 6 patients with accessible tonsils, tonsillar tissue VL was <40 copies/ml of tissue in 5 and 485 copies/mg in the other patient. So this was a well suppressed group of patients. Nine patients reached the time point of the second stop. At week 28 (2nd stop), plasma VL was <20 copies/ml in all cases and below 5 copies/ml in 7/9.

A rebound in plasma VL occurred in all cases. After the first stop, one month after re-starting therapy VL dropped below 20 copies/ml again in all patients and remained <20 copies/ml after 6 months until the 2nd stop. However, after the second stop 4 patientsí viral load rebounded to similar levels of their baseline level but then dropped spontaneously (without therapy). The drops ranged from -0.80 log to -2.09 log. A  proliferative p24 response was detected in 2 of these 4 only after the second stop.

Although viral loads rebounded after both stops they did not detect RT and protease mutations known to be associated with resistance to RT inhibitors or protease inhibitors. They used the Visible Genetics System for genotyping. Garcia conducted an immunological study which showed some immune system decline after first interruption: the patientsí CD4s, naÔve CD4s and CD8s decreased. There was an increase in CD38+CD8 cells and of both memory CD4s and memory CD8s. Garcia reported that 6 months after restarting therapy patients regained these losses in the immune system back to where they were prior to the stop. After the second stop, which he characterized as lesser immune deterioration, CD4s decreased but CD38+ CD8 cells did not change and the naÔve and memory cells did not change. Several concerns have been raised about interruptions--what happens over long-term by allowing virus to re-seed tissues, such as lymph, after significant reductions due to HAART suppression? Long-term implications of interruptions are yet unknown. Although several individual reports appear promising it is too soon to discern who might respond well to STI and who might not. Although so far it appears that viral load declines back to undetectable after re-starting therapy research experience with this is limited.

STI in Chronic Infection. 

At Lisbon, Lydia Ruiz reported on 12 chronically infected individuals who interrupted therapy. They had viral suppression below 20 copies/ml for at least 24 months. They interrupted therapy for 30 days or until viral rebound above 3,000 copies/ml. Individuals had been infected for mean 7.7 years. These results are following 1 interruption as future interruptions are planned. Viral burden increased exponentially in 10 of the 12 patients during interruption period while 2 persons maintained levels below 20 copies/ml. In 5 of 10 patients, plasma viral load started to be detectable between 10-15 days, whereas in the 5 remaining individuals, viral load increase slowed to 18-21 days after interruption. The slope of viral load increase during interruption was similar in all patients except the 2. Ruiz said treatment was successfully resumed in all patients. No drug resistance mutations were found except in one person. Ruiz reported that in contrast with prior data, Ruiz did not observe flatter viral rebound slopes in those patients heterozygous for the 32 mutation in CCR5.

STI in Acute Infection: 1 year follow-up.

At ICAAC, Marty Markowitz reported on 4 individuals who started HAART between 7 and 90 (median 52 days) days within the onset of symptoms of acute infection and chose to stop therapy. They were part of 14-person study. Patients were on therapy about 3 years at the time of discontinuation (median days 1049). They now had normal CD4 counts and CD4/CD8 ratios. Their median CD4s increased to 977 from 488 at baseline and their median CD4/CD8 ratio had improved to 1.25. Levels of culturable residual virus ranged from 0.03 to 0.25 (median 0.11) IUPM (infectious units per million) CD4+ T-cells. At discontinuation, all 4 patients had maintained undetectable viral load and had <50 copies/ml. After stopping therapy the time to detectable virus (> 50 copies/ml) was 23, 26, 14, and 24 days, respectively). On day 25, the person with 6 million baseline viral load had their viral load peak at 32,000 and decided to resume therapy. Their viral load peaked sooner and higher than the other 3 patients. After re-starting therapy their viral load went back down to <50 copies/ml. In the other 3 persons peak plasma virus reached 21,965, 20,150, and 14,391 copies/ml on days 38, 193, and 77 after stopping therapy. Without resuming therapy these individuals remain with plasma virus of 2102, 3400, and 4700 copies/ml after 252, 222, 154 days, respectively. All 3 patients had detectable HIV-specific CTLs at the time of therapy discontinuation. In 2 of 3 patients, the levels of CTLs appeared to increase suggesting stimulation from virus after stopping therapy and/or partial virus control. In the third person the CTL levels decreased and then increased after stopping therapy.

3 Therapy Interruptions: CTL & HIV-Specific CD4 responses.

At IDSA, Eric Rosenberg reported on 2 individuals who had interruptions. Both individuals experienced partial but not complete control of HIV replication following interruptions. Subject one interrupted therapy 3 times. The first interruption was planned and it took about 3 weeks for virus to begin to replicate, whereupon it went up to 17,000 copies/ml. After restarting therapy (protocol mandated restarting therapy at 10,000) viral load promptly went back down to undetectable and stayed there. Due to acute hepatitis A the person had an unplanned second interruption. Again, it took 2 weeks for virus to return whereupon virus shot up to 37,000. He was still too ill to restart therapy and within 72 hours fell to 6,000. 48 hours later his viral load was 400. Over the next 2-3 weeks slowly viral load started creeping up (it was still below 10,000) and therapy was restarted because it wasnít a planned interruption. Viral load rapidly declined to below detection after restarting therapy. The second person had two interruptions. The first interruption lasted 2-3 weeks during which he had low viral load but then it rebounded to 116,000 copies/ml. Therapy was re-started and viral load was kept below limits of detection. When therapy was discontinued a second time the person went 4 months consistently with viral load below 5,000 copies/ml. Despite being below 5,000 the person elected to restart therapy at the 4-month period "to try for a better result". Both subjects experienced improved CTL response in breadth and magnitude. As well both experienced improved stimulation index which measured the HIV-specific CD4 response. Subject one had a SI of 80 prior to first interruption (above 10 is considered significant) which went to over 800 after second interruption. Subject two had a SI of 20 at baseline that improved to 120 after first interruption.

Can Drug Holidays Reverse Resistance? 

Veronica Miller and her German colleagues gave patients a drug holiday of 2-3months followed by Mega HAART (>5 drugs) for salvage therapy. These were very treatment experienced individuals who were failing therapy. After a drug holiday 26/39 had their virus return to wild-type. Drug resistance was not detectable. This surprised a number of resistance researchers. In 13/39 they did not revert to wild-type. The reverters received a Mega HAART regimen of at least 5 drugs or more. Baseline susceptibility was associated with a virological response (achieving and maintaining VL<500 c/ml). 67% of responders had viral populations which were sensitive to at least 4 of the drugs in their regimen; whereas, 70% of patients of failing regimens (never achieving <500 c/ml) had viral populations which were sensitive to a maximum of 3 drugs in their regimen. During drug holidays viral load increased by a median of 0.71 log and CD4s declined by a median of 89 cells. Treatment with drug regimens resulted in a median week 8 VL reduction of 2.9 log for patients with shift to wild-type and 0.78 log in patients without a shift to wild type. Researchers reported CD4s increased subsequent to restarting therapy but slowly. 19/24 patients with shift to WT reached <500c/ml within 24 weeks compared to 1/9 without shift to WT. Miller concluded complete treatment interruptions may lead to shifts in the viral population, with a change to WT as the dominant variant in some patients. These changes in susceptibility may be associated with better treatment responses. However, CD4 counts need to be closely monitored during drug holidays. The German group also said that if a person did not respond to the drug holiday and Mega HAART the first time they would give them a second drug holiday and try another Mega HAART regimen. They said this worked for some.

A number of researchers think that although undetectable resistance to the drugs is present. And that eventually it will emerge. However, viral load reduction for a period of time may offer clinical benefit. I personally spoke with the German researchers and they have an ongoing program utilizing the drug holiday approach, and they have confidence that the approach works for some individuals. Bare in mind this approach is used for people who are failing therapy who have resistance to drugs they are using.  Additional studies will explore this question.