NATAP ICAAC Report 9

Jules Levin, NATAP

Martin Markowitz reported on 4 of 14 individuals treated with HAART between 7 and 90 (median 52 days) days within the onset of symptoms of acute infection and chose to stop therapy. They were treated with indinavir or ritonavir. and AZT+3TC. Their baseline viral loads were 49,000 (541 CD4), 6300 (916 CD4), 87,000 (433), and 6 million (227) copies/ml. Their baseline CD4/CD8 ratios were reversed with a median ratio of 0.58.

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, 25, and 24 days, respectively). Markowitz said the time to detectable virus was significantly longer than in prior studies. 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 drug. Rebound in viral load appears later than in that seen in individuals who stopped therapy after starting during chronic infection. Without resuming therapy these individuals remain with plasma virus of 2102, 3400, and 4700 copies/ml after 252, 222, 154 days, respectively. The CD4 responses after stopping therapy was variable: 1 person’s CD4s and naïve and memory cells declined; a second person’s remained about the same; while in the third person the CD4 count increased but the other values remained about the same. 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.

In summary Markowitz said—there was a rebound in plasma virus which was delayed compared to published cohorts. The delay likely reflects lower residual virus and residual number of HIV infected cells. Initial doubling time comparable in 3/4 subjects and published data. Virus is now being partially controlled and Markowitz suggests it’s presumably due to immunologic effects. The effects of early therapy on virologic set point awaits outcome of further follow-up. The levels of lymphocyte proliferation to Gag vary considerably during rebound sand partial control of virus.

Commentary-- Several other very small preliminary studies on stopping therapy have been discussed at conferences. Three individuals remain undetectable after starting therapy during acute infection with HAART, and this includes the "Berlin Patient". In data so far reported, generally individuals starting therapy during chronic infection experience viral load rebound fairly quickly. It appears as though viral load can usually be re-suppressed after restarting therapy following a discontinuation. However, if a person is taking a drug with a long half-life such as efavirenz or nevirapine drug can remain in blood after stopping the regimen. It’s been discussed that this may cause a problem with resistance after restarting the drug. An additional concern about stopping therapy is that upon viral load rebound HIV reservoirs and tissues can be re-seeded with HIV after having reduced their levels due to HAART. No one knows the long-term implications of this.

Several studies are planned to explore stimulating immunity with immune-based therapies and therapy interruptions. Remune, IL-2 and the Pastuer vaccine are all included in these studies, some of which include combinations of these IBTs.

Remune+HAART. Italian investigators Rizzardi and Pantaleo reported preliminary data at ICAAC on an ongoing study (n=34) comparing HAART to HAART+IL-2 and HAART+Remune. Patients receive one of two bid HAART regimens: abacavir 300mg+nelfinavir 1250mg+Fortovase 1200mg bid or abacavir+nelfinavir+amprenavir 1200mg. Subcutaneous IL-2 was given as 8 5-day cycles every 4 weeks and every 6 weeks after 3^rd cycle. Remune was given 10 ug/ml p24 every 3 months. Patients were treatment-naïve with mean baseline CD4 and viral load of 623 and 53,000 copies/ml. After 48 weeks (n=14), there was a 4 log reduction in viral load when using a sensitive boosted Amplicor test measuring to 5 copies/ml. The reduction was 2 log using the standard Amplicor 400 copy test. Investigators reported there were no virological differences between the three arms as they were all well suppressed: at week 48 (n=18), 70% < 50 copies/ml, 60% <5 copies/ml, ITT. The CD4 increases in the IL-2 arm were significantly more than in other two arms at week 48 (about 750 cells at wk 48). Although the data at this point is preliminary with small numbers, investigators said 100% of patients in Remune arm had significant lymphocyte proliferative responses to HIV antigen at about week 36 whereas 50% did so over time in the IL-2 arm. About 60% (n=8) in Remune arm at week 33 developed positive HIV-DTH response. The clinical benefit of improved lymphocyte proliferative responses due to Remune have yet to be established. The study investigators said individuals will be offered to stop therapy after about 5 more months. It is at that time investigators said we will be able to observe if Remune plays a role in controlling HIV when taken with HAART.

Patient D resumed therapy 25 days after stopping therapy and peaking at 32,000 copies/ml and returned to <50 copies/ml.