17th Report from: 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, Friday Feb 4th

Conference Late Breakers:

Following are two therapy interruption studies presented last in the final session of the conference. One study incorporates a vaccine. And, a third safety and test of concept study giving 8 individuals a vaccine while on therapy. The results reported from both studies are preliminary but positive and encouraging. There are a few key points. In the first study, patients had very well suppressed HIV and started treatment relatively early in disease progression. After a 2^nd interruption 4 of 9 patients experienced a spontaneous drop in plasma VL off therapy accompanied by a strong immune response described below.

In the second study Jin and colleagues reported on a study where 4 patients who were treated with HAART within 60 days of HIV-infection discontinued therapy. After approx. 2.5 years of therapy, subjects were vaccinated with a course of ALVAC 1452 and recombinant gp160. In 2 of 4 patients rebound of viral load did not occur until 68 and 85 days after therapy discontinuation. The other 2 patients had VL rebound 13 and 23 days after discontinuation. The "delayed rebounders" appeared to display good immune responses (increased CTLs to more than 1 viral antigen) and better responses than the 2 "early rebounders". Currently, the 2 delayed rebounders are off therapy 4 and 8 months, respectively and their viral loads are 3.75 log and 2.52 log. The 2 "rapid rebounders" have viral loads of 3.55 log and >4.70 log after 4 months off therapy. Although encouraging this is a small study with limitations in its interpretation. Since the study was small and had no control group the benefits seen for the delayed rebounders could have occurred without having received the vaccine. Although 2 individuals experienced a delayed rebound that may be associated with the vaccine, there have been reports from studies of structured therapy interruptions without vaccinations where viral load has remained low for a period of time. A number of larger studies similar in nature are ongoing using the same vaccine and also exploring Remune, a therapeutic vaccine. These studies will explore therapy interruption.

In a third study, Jin and colleagues from the Aaron Diamond AIDS Research Institute, Rockefeller Univ., Pastuer Merieux Connaught, and Virogenetics reported on a small study in which individuals interrupted HAART. The purpose of the study was to explore whether boosting of the immune response can result in control of the residual HIV-1 after prolonged HAART, and to test safety. Patients were treated with HAART within 90 days of HIV-infection and their HIV was completely suppressed for >2 years. While continuing HAART patients received several intramuscular vaccinations using vCP1452, a recombinant canarypox virus vaccine carrying sequences from 4 HIV-1 genes (gag, pol, env and nef), together with recombinant gp160. Immune responses were observed and are described below. And no significant adverse events were seen.

At the Conference, Merck reported on early studies of their DNA-based vaccine. They said they saw some encouraging responses from animal studies, although not all the animals responded as hoped. But the results are encouraging enough so that they are planning to proceed ahead with human studies first in healthy volunteers and if warranted then in HIV-infected individuals.

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Garcia and colleagues presented an update on a study that had previously been reported. The purpose of this study is to analyze the dynamics of viral load rebound and the HIV-1 specific immune responses after three consecutive cycles of STI. The VL set-point reached after the 3rd and definitive interruption of therapy and the safety of this approach were also assessed.

Ten chronic HIV-1 infected patients treated with d4T, 3TC and ritonavir or indinavir for 52 weeks and VL <20 copies/ml for >32 weeks performed three cycles of STI separated by 6 months of the same triple HAART. Plasma VL, genotyping resistance, immunophenotyping, HIV-1 specific CTL and CD4+ T lymphocytes proliferative responses were assessed.

Immediately before discontinuing HAART at week 0, 28 and 56 (1st, 2nd, and 3rd stop, respectively), plasma VL was <20 copies/ml in all cases and <5 copies/ml in 7 of 10 cases (1st stop), and in 7 of 9 cases (2nd, 3rd stop) (1 patient was lost for follow-up). A rebound in plasma viral load was detected in all cases with a mean [SE] doubling time of 2.23 [0.32], 3.38 [1] and 3.25 [0.38] days (1st, 2nd, and 3rd stop, respectively) (p=0.05, for the comparison between DT 1st vs. 3rd stop). At 2nd stop, in 4 of the 9 patients, viral load rebounded to similar levels of baseline (week -52) and dropped spontaneously thereafter (0.8, 0.8, 1.3, and 2.09 log_{10}, respectively). These 4 patients developed strong and broad HIV=1 specific CTL responses and a strong CD4+ lymphocyte proliferative response to HIV-1 antigens. After the 1st, 2nd stop, and 3rd stop, known mutations associated with resistance to reverse transcriptase or protease inhibitors were not detected. After 3rd stop, spontaneous drop in VL and recover of specific CD4+ lymphocyte proliferative response was detected in first 3 out of 3 and 3 out of 5 evaluable patients, respectively.

Structured antiretroviral therapy interruption may induce effective specific cytotoxic and CD4+ lymphocyte proliferative immune responses against HIV-1 antigens associated with a spontaneous drop in plasma viral load in chronic HIV-1 infection.

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Safety and Immunogenicity Study on vCP1452/gp160 Vaccine in Patients Treated with HAART for Over Two Years.

The purpose of this study was to explore whether boosting of the immune response can result in control of the residual HIV-1 after prolonged HAART, we conducted a safety and immunogenicity study using vCP1452, a recombinant canarypox virus vaccine carrying sequences from 4 HIV-1 genes (gag, pol, env and nef), together with recombinant gp160. Eight individuals treated within 90 days of primary infection and whose plasma viremia had been completely suppressed by HAART for ≥2 years were enrolled. Since one patient has been lost to follow up and one patient is pending a fourth vaccination, the results of the first 6 cases are presented. While continuing antiretroviral therapy, each subject received four intramuscular doses (days 0, 30, 90 and 180) of vCP1452 as well as recombinant gp160. No significant adverse effects were observed except for mild transient tenderness at injection sites. All subjects have 2- to 3-log increases in anti-gp120 antibody titers post vaccination, and 2 had marked elevations in anti-p24 antibody titers. T helper cell activity, as assessed by lymphocyte proliferation to gp160 and p24, increased markedly in 3 subjects (20-90 S.I.). Longitudinal changes in CTL responses to HIV-1 were measured after each vaccination, using intracellular cytokine staining for gamma-interferon after in vitro exposure to viral antigens. Two had no discernible change in CTL activity, two had a detectable rise in CTL recognizing Gag, and two had an increase in CTL against more than one viral antigen (Gag, Pol and/or Nef) (+ 0.25-0.45% of CD8+ T cells). The heightened CTL responses to Gag and Pol were confirmed using tetramers of MHC class I/peptide in two patients with the appropriate HLA haplotype. In summary, vaccination with vCP1452 and recombinant gp160 is safe and immunogenic in this cohort of HIV-1 infected patients on effective antiretroviral therapy. The functional consequences of the enhanced immunity are being assessed by follow-up studies.