Structured Treatment Interruption in Chronically HIV-1 Infected Patients After Long Term Viral Suppression

By Jules Levin, NATAP

Lidia Ruiz reported on small group who interrupted therapy. I don't know if this is different cohort than she previously reported on at Resistance Workshop. At Resistance Workshop Martinez, from same Spanish group, reported on individuals who interrupted twice and all rebounded. After 2nd interruption 2 individuals I think had spontaneous reduced viral load but not to undetectable. The full report is on NATAP web site in Resistance Workshop reports.

In Lisbon report, 12 chronically infected adults with long virus suppression for at least 24 months (below 20 copies/ml), and CD4/CD8 ratio above 1 (for a minimum of 12 months) during median of 22 months, interrupted therapy for 30 days or until viral load rebound above 3000 copies/ml. The same prior ART regimen was resumed after interruption. Kinetics of plasma viral rebound was evaluated every 2 days during treatment interruption. Genotype resistance was assessed at the time of treatment resumption. Flow ctometry and cell proliferation assays were performed before and after interruption. The primary endpoint was the time elapsed until viral rebound was detected. Secondary endpoints were the degree of CD4 T cell reduction during the interruption and the HIV-1 specific responses reached at the end of interruption.

Plasma viral load was evaluated at day 1 and then 3 times weekly during interruption. At resumption of therapy plasma samples obtained at day 1 and once weekly for next 2 months. Ruiz characterized CCR5 deletion. 26 patients qualified for study and were randomized to interrupt or continue treatment. 12 patients agreed to interrupt therapy according to study design.

At baseline, patients had HIV infection for 7.7 years (2-13), 3 male-9 female, mean age 34 (27-42). Five patients contracted HIV through heterosexual contact, 2 homosexual contact, and 5 IVDU. Mean CD4 count was 1200 and CD8 965, CD4/CD8 ratio 1.4, and prior time with viral load below 20 copies/ml was 28.5 months (range 24-48 months). Patients therapy prior to interruption was either initial or ubsequent therapy.

Results
These results followed 1 interruption. Additional interruptions are planned. Ruiz reported no adverse events occurred during interruption. In 2 patients there was no viral rebound above 20 copies/ml after 30 days of treatment interruption. In 5 of the remaining 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. In the 10 viral load rose exponentialy with a mean half-life time of 1.6 days (0.8-2.5 days range).

Ruiz said treatment was successfully resumed in all patients. No drug resistance mutations were found except in one person. AZT resistance mutations D67N, T215Y/C, and K219Q were detected in this patient who showed detectable plasma HIV-RNA (801 copies/ml) at the time of initiation of HAART. The remaining patients who received sequentially different anti-retroviral regimens did not show any drug-resistance mutations. Of note, when these patients switched their anti-retroviral treatment to HAART their plasma viral load was below 20 copies/ml.

Four patients were heterozygous for the CCR5 deletion.

The mean percentage in CD4+ and CD8+ lymphocytes (56 and 41) did not vary during the interruption compared to baseline (54 and 42). CD4/CD8 ratio remained stable at 1.4. No changes in naive and memory (CD45RA+CD62L+ and CD45R0+) CD4 and CD8 T cells were observed when anti-retroviral treatment was discontinued.

The level of expression of T cell activation marker antigen CD38 on CD8+ T cells increased significantly in response to viral rebound from 64 to 70. However, the percentage of CD8+ T cells that express HLA-DR did not significantly differ from the mean baseline value (15 to 14). The percentage of CD8+CD28+ T cells decreased significantly compared to baseline values (60 to 53, p=0.003).

Four patients improved LPA responses to tuberculin and 2 patients to tetanus toxoid. Overall, none of patients showed a remarkable specfic CD4 T cell response to candida and CMV at baseline and at end of interruption. A modest p-24 specific response was detected in 2 patients after interruptio--one had a stimulation index of 6 and the other had an index of 15.

Ruiz concluded--the structured therapy interruption of HAART in chronically HIV infected patients with long-lasting viral suppression is not associated with clinical or immunological impairment. In this study, a slightly longer period in the viral rebound was observed than in other previous reports. However, once plasma viremia is detectable, the rebound slopes are similar to those shown by previous studies. In contrast with prior data, Ruiz did not observe flatter viral rebound slopes in those patients heterozygous for the 32 mutation in CCR5. No clinical disturbances or events were seen during interruption. To achieve stronger HIV-specific responses may require more cycles of interruption. (Jules Levin's comments--longer-term follow-up is important. Some doctors and researchers have expressed concern about the longer term potential implications of re-seeding tissue such as lymph nodes after they had been reduced significanyly due to HAART. As well, they have expressed concerns about uncertainty of future complications. For example, after the introduction of protease inhibitors 3 years ago eradication was thought possible. The longer term side effects and toxicities now seen such as elevated lipids & glucose, fat redistribution, etc. were not anticipated. So, unanticipated developments can occur).