Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic immunization with the ALVAC-HIV vaccine (vCP1452)
Autran, Brigittea,b,c; Murphy, Robert Ld,e,f; Costagliola, Dominiqued,e,g; Tubiana, Rolandd,e,g; Clotet, Bonaventurah; Gatell, Josei; Staszewski, Schlomoj; Wincker, Normak; Assoumou, Lamberte,g; El-Habib, Raphaellel; Calvez, Vincentm,n; Walker, Bruceo; Katlama, Christined,e,g; and the ORVACS Study Group
From the aUPMC Univ Paris 06, UMR_543, France
bAP-HP, Pitié-Salpétrière Hospital, France
cINSERM, UMR_ 543, Cellular Immunology Laboratory, France
dAP-HP, Infectious and Tropical Diseases Department, Pitié-Salpétrière Hospital, France
eUPMC Univ Paris 06, UMR_720, Clinical and Therapeutic Epidémiology of HIV Infection, Paris, France
fNorthwestern University, Chicago, Illinois, USA
gINSERM, UMR_720, Clinical and Therapeutic Epidémiology of HIV Infection, Paris, France
hIrsi Caixa, Foundation, Spain
iInfectious Diseases Department, Hospital y Clinic Provincial, Barcelona, Spain
jJ. W. Goethe-University, Frankfurt, Germany
kORVACS, F-75013, Paris
lSanofi-Pasteur, Marcy l'Etoile, France
mAP-HP, Virology Laboratory, Pitié-Salpétrière Hospital, France
nUPMC Univ Paris 06,Paris, France
oPartners AIDS Research Center, General Hospital and Division of AIDS, Harvard Medical School, Boston, Massachussets, USA.
Received 19 November, 2007
Revised 18 February, 2008
Accepted 19 February, 2008
Correspondence to Professor Brigitte Autran, Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié Salpétrière, 83 Blvd de l'Hôpital, 75013 Paris, France. E-mail: firstname.lastname@example.org
Objective: Evaluate immunogenicity and clinical efficacy of two immunization strategies with the ALVAC-HIV-recombinant canarypox vaccine (vCP1452) in treated HIV-infected patients.
Design: Randomized, double-blind, placebo-controlled, phase II study of vCP1452 immunization in chronically HIV-infected patients on therapy with CD4 T-cell count more than 350 cells/μl, CD4 nadir less than 400 cells/μl and pHIV-RNA less than 400 copies/ml. Patients were equally randomized to four injections at weeks 0, 4, 8, 20; three injections at weeks 4, 8, 20; and placebo. The primary endpoint was vaccine immunogenicity at week 24 measured by enzyme-linked immunospot-interferon-γ against the HIV-gag-reverse transcriptase-nef vaccine sequences. Secondary endpoints included time to treatment resumption and viral quantitation following treatment interruption at week 24. Criteria to resume therapy included CD4 T-cell count decline less than 250 cells/μl or 50% decrease from baseline or pHIV-RNA more than 50 000 copies/ml.
Results: Sixty-five patients enrolled. Changes from baseline in HIV-specific T cells in the four injection arms (+480 spot-forming cells/M-peripheral blood mononuclear cell) were significant compared to placebo (+8; P = 0.014), but not in the three injection arms (+322). The week 36 pHIV-RNA (log10 copies/ml) after treatment interruption was higher in the four (4.71; P = 0.023) and three (4.82; P = 0.009) injection arms compared to placebo (4.40). Percentages of patients reaching treatment resumption criteria by week 48 were 74, 55 and 23% in the three respective arms (P = 0.013). Two independent factors influenced time to therapy resumption: immunization (hazards ratio = 2.7, P = 0.048 for three injections; hazards ratio = 4.1, P = 0.003 for four injections) and CD4 nadir (hazards ratio = 0.4, P = 0.002).
Conclusions: Significant immunogenicity was induced by vCP1452; however, this strategy was independently associated with a shorter time to resume therapy and higher viral rebound.
The efficacy of combination antiretroviral therapy (cART) against the human immunodeficiency virus (HIV) remains unquestioned; however, uninterrupted lifelong therapy, with its associated adverse effects and expense, is required . Although effective in restoring immune protection against opportunistic pathogens, cART is not associated with the restoration of an effective HIV immune response  most likely because of the physiological contraction in HIV-specific effector T cells that follows a successful pathogen control.
Various strategies have been proposed to help restimulate HIV-specific immunity and help limit time on cART such as treatment interruption [3–5]; however, this latter approach has not been shown to be beneficial and may actually be unsafe [6,7]. An alternative strategy consists of boosting the immune defenses with anti-HIV vaccines while patients are receiving cART in order to better control viral replication and disease progression when cART is discontinued . A consensus exists recommending the use of vaccines that are capable of eliciting T-cell-mediated immunity to HIV . Indeed, the best correlates of protection against established HIV infection appear to be the frequency, polyfunctionality and breadth of both CD8 and CD4 T cells specific for HIV [10–12]. Various candidates have shown modest efficacy as therapeutic vaccines in experimental animal models [13–15] and patients [16–20]. The most thoroughly investigated vaccine candidate to date is the HIV-recombinant canarypox vaccine that expresses the HIV-1 env, gag and protease genes and part of the nef and RT genes and has been shown to elicit CD4 Th1 and CD8 cell responses to HIV in healthy human volunteers [21–23]. Both types of responses were significantly enhanced after immunization with the HIV-recombinant canarypox vaccine ALVAC-HIV (vCP1452) alone or when combined with other vaccines in patients treated at the time of primary HIV infection [24–26]. No clear clinical benefit has been observed in this setting, however, as no viral control or prolongation of the time off cART following such intervention has been reported [25–27]. In contrast, a modest effect was reported on the duration of time off cART and the level of viremia during postvaccination treatment interruption in chronically infected patients with the same vaccine used alone or in combination with other immune-based therapies [28–31].
The optimal vaccine candidate and immunization schedule remains to be determined yet. Peak immune responses have been observed after two or three vCP1452 injections, whereas subsequent vaccine injections were followed either by a plateau in HIV-specific responses in acutely infected patients or by a decrease in chronically infected patients, suggesting multiple vaccine injections might actually exhaust HIV-specific T cells .
The aim of this study was to evaluate and compare the immunogenicity and efficacy of two different immunization strategies with the vCP1452 vaccine in chronically HIV-infected patients receiving cART. We tested whether immunogenicity was influenced by the number of vaccine injections and whether immunogenicity could be enhanced by providing a 3-month ‘rest’ before the last vaccine injection. A treatment interruption was scheduled a month following the last vaccine injection; patients were followed for an additional year with strict criteria for resuming cART in the event viral replication or CD4 cell counts were not controlled.
Population and methods
This was a multicenter, randomized, placebo-controlled study that included two phases: an immunization phase on suppressive cART, followed by a phase of treatment interruption (Fig. 1). Patients were randomized 1: 1: 1 into three treatment groups: four vaccine injections; three vaccine injections; and placebo. At week 24, cART was interrupted and patients followed through week 96. The protocol was approved by the independent Ethics Committees of the participating sites. All patients provided written informed consents.
Inclusion criteria were age more than 18 and less than 65 years, documented HIV-1 infection, suppressive cART for at least 6 months with the same regimen for at least 2 months, CD4 T-cell count at least 350 cells/μl for at least 1 year and a plasma HIV-RNA (pHIV-RNA) less than 400 copies/ml for at least 6 months. Patients were excluded if cART was administered at the time of primary HIV infection, cART was started when CD4 T-cell count was more than 400 cells/μl, any acute infection occurred within 30 days prior to enrollment, there was a past history of any AIDS-defining event, chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, there was any prior HIV vaccine or immunomodulatory trial participation, systemic corticotherapy was used in the past 6 months or any non-HIV immunization was administered within 1 month prior to study entry.
Patients who completed the immunization phase interrupted cART if their CD4 T-cell count were at least 350 cells/μl and pHIV-RNA less than 400 copies/ml. Patients were evaluated monthly and cART was resumed if either of the following criteria was met: from week 24 to 40, immunologic deterioration, defined as CD4 T-cell count decrease to less than 250 cells/μl or more than 50% loss from baseline; and/or from week 40 to 48, significant virologic rebound, defined as having pHIV-RNA levels at least 50 000 copies/ml on two consecutive measurements at least 2 weeks apart.
vCP1452 is a recombinant canarypox virus vaccine (Sanofi Pasteur, Marcy L'Etoile, France) expressing the gene products of the HIV-1 MN strain gp120 and the LAI strain including the anchoring region of gp41, p55 gag polyprotein, the protease, and reverse transcriptase and Nef (cytotoxic T lymphocyte) CTL epitopes [21–25]. Additionally, vaccinia virus E3L and K3L coding sequences had been inserted into the ALVAC genome to increase virus-specific gene expression by downregulating PKR activity, which in addition decreases apoptosis. Each 1 ml dose contained 107.08 CCID50 (cell culture infective dose) vCP1452. The placebo was a mixture of 10 nmol/l Tris-HCl buffer pH 9.0, virus stabilizer and freeze-drying medium and reconstituted with sterile saline 0.4% NaCl solution. Vaccine and placebo were injected intramuscularly.
The primary endpoint was immunogenicity as measured by the change in frequency of HIV-specific peripheral blood mononuclear cell (PBMC) producing IFN-γ between baseline and 4 weeks after the last injection (week 24) in the immunized arms as compared to placebo.
Secondary endpoints included proportions of ‘High Responders’ to the HIV vaccine sequences, as defined by an increase in the numbers of HIV-specific PBMC more than 0.7 log, the lymphoproliferative responses to HIV, the numbers of IFN-γ producing PBMC specific for the canarypox vector, the safety and tolerability of vCP1452, changes in CD4 cell counts and pHIV-RNA, the cell-associated HIV-DNA content and time to cART treatment resumption following treatment interruption. For treatment resumption criteria following treatment interruption, we chose a viral load rebound level of 50 000 copies/ml, an amount high enough to be a treatment resumption criteria unlikely to be deleterious for the patients and/or a CD4 T-cell count decrease of 50% of baseline or to less than 250 cells/μl.
Standard laboratory measurements including CD4 cell count, pHIV-RNA, complete blood count, aspartate transferase (AST), alamine transferase (ALT) and creatinine were performed locally.
Immunogenicity measurements were performed at each time point between baseline and week 24 (weeks 0, 12, 20 and 24). Blood samples were processed within 24 h either locally or after shipping. PBMCs were isolated by ficoll centrifugation and stored in liquid nitrogen. A cryopreservation quality control was carried out between the five participating laboratories.
ELISPOT assays were performed in the two core immunology laboratories (Paris, Boston) to measure the numbers of IFN-γ producing PBMC directed against vaccine HIV sequences using a single standard operating procedure (SOP). Briefly, assays were performed as described using pools of 15-mer synthetic HIV peptides covering the whole HIV-1 LAI-gag, reverse transcriptase and nef vaccine sequences (Sigma, Gillingham, Dorset, UK) and grouped by pools of 10 or 11 peptides . Env-specific responses were not monitored because of the expected large interpatient variability. Cells were tested in parallel against the recombinant HIV-p24 and gp120 proteins (Protein Science, Meriden, Connecticut, USA). Negative controls were obtained with unstimulated cells. Positive controls included phytohemaglutimin A (PHA) (Abbott, Rungis, France) and two pools of 10 9-mer EBV peptides (Neosystem, Strasbourg, France). All patients' timepoints were tested in a single assay. Read-out was centralized on a single ELISPOT reader (Zeiss, Le Pecq, France). Results were expressed as the number of spot-forming cells (SFC) per million of PBMC after subtracting the background. The positivity threshold for each peptide pool and antigen was defined at 50 SFC/million PBMC. High Responders were arbitrarily defined by net gain of at least 0.7 log SFC/million PBMCs from baseline. An ELISPOT quality control was carried out between the two core laboratories on two HIV-negative and nine HIV-positive samples and showed no significantly different results.
A lymphoproliferation assay was performed on fresh PBMCs in a subgroup of 36 patients from two clinical sites (Paris, Frankfurt). Assays were performed in a single core immunology laboratory (Paris) against the same recombinant HIV p24 and gp120, as described . Results were expressed as stimulation indices and were considered as positive if antigen-stimulated values were above 3000 cpm with a stimulation index above 3.
The numbers of IFN-γ producing PBMCs specific for the canarypox vector were measured in parallel in the same ELISPOT assay as above against the empty canarypox vector provided by Sanofi Pasteur.
Cell-associated HIV-DNA was measured at baseline and at all study time points during the immunization phase. DNA was extracted from PBMCs and quantified according to published techniques .
The expected difference in the change from baseline of cumulative frequencies of HIV-specific PBMCs was set at 0.7 log10; the standard deviation in the primary endpoint was derived from the Agence Nationale de Recherches sur le SIDA (ANRS) 094 trial at 0.5 log10 . Using a Bonferoni correction for multiple tests, two main comparisons were planned: the four and the three injection arms compared to placebo. Using a type I error of 0.05, a power of 90% and two-sided nonparametric tests, 20 patients were needed in each arm taking into account 10% for nonassessable patients.
All statistical tests were two-sided and nonparametric (Mann–Whitney). The analyses were performed following the intention-to-treat principles on available data.
The percentages of patients reaching predefined cART resumption criteria in each arm were determined using Kaplan–Meier estimates and compared by the log-rank test. Factors associated with the risk of reaching treatment resumption criteria were analyzed using univariate and multivariate Cox proportional hazards models. The role of the following variables was assessed: sex, age, transmission group, duration of ARV treatment, nadir and baseline CD4 cell counts, pre-cART pHIV-RNA, baseline and week 24 cell-associated HIV-DNA, week 24 change from baseline in the numbers of PBMCs against HIV peptide pools and against HIV p24 and treatment arm. For continuous variables, we assessed if they were better modeled as continuous variables or as terciles using the Akaike criteria. Variables with univariate P values lower than 0.15 were then entered in a multivariate backward Cox model.
Characteristics of patients
A total of 66 patients were randomized and 65 completed the immunization phase; 21, 22 and 22 patients were enrolled in the four injection, three injection and placebo arms, respectively (Fig. 1). At week 24, 54 patients interrupted cART as per the protocol design; 11 patients did not for personal reasons. Patient characteristics were well balanced between the treatment groups except for the pre-cART pHIV-RNA for which the values, when available, were higher in the immunization arms with 5.1, 4.8 and 4.6 log10 copies/ml, respectively (Table 1). The median CD4 nadir was 240 cells/μl.
The primary endpoint was evaluable in 56 out of the 65 patients and unevaluable in seven because of lack of cell viability after shipping and in two because of high background ELISPOT activity.
At baseline, the mean frequencies of PBMCs producing IFN-γ against tested HIV peptides did not significantly differ between the groups [1203 ± 1252, 1 009 ± 1379 and 1095 ± 1566 SFC/million PBMCs in the four injection (n = 18), three injection (n = 20) and placebo arms (n = 18), respectively]. At week 24, a mean net gain of 480 ± 652, 322 ± 1124 and 8 ± 460 HIV-specific SFC/million PBMCs was observed, respectively (Fig. 2a). The increase from baseline compared to placebo was significant in the four injection (P = 0.014), but not in the three injection arm (P = 0.169). No booster effect was observed after the last vaccine administration at week 24 in either vaccine group. In addition, neither vaccine group showed a significant increase in the number of High Responders at any time point during immunization compared to baseline. In the subgroup of 36 patients who had measured HIV-specific lymphoproliferative responses, no significant differences were observed between the immunization and placebo groups (four injection group, P = 0.770; three injection group, P = 0.100) (Fig. 2b). Finally, there were no detectable T-cell responses against the canarypox vector at baseline in the three arms (data not shown); however, a modest but significant increase from baseline was observed at week 24 for the vector-specific immunity in both vaccine groups with a mean net gain of +66 and +46 SFC/million PBMCs in the four and three injection arms (Fig. 2c).
At week 24, 54 patients entered the treatment interruption phase: 19, 20 and 15 in the four injection, three injection and placebo arms, respectively. The patients entering the treatment interruption phase were not significantly different from the group not undergoing treatment interruption. A month after treatment interruption (week 28), pHIV-RNA became detectable in all patients except one in the placebo arm. At week 36, median pHIV-RNA was significantly higher in the four injection (P = 0.023) and three injection (P = 0.009) arms compared to placebo: 4.76, 4.82 and 4.40 log10 copies/ml, respectively (Fig. 3a). The average area-under-the-curve for pHIV-RNA was also significantly higher during treatment interruption in the four injection arm compared to placebo but not in the three injection arm (median values: 4.88, 4.63 and 4.36 log10 copies/ml; P = 0.017 and 0.096, respectively). The median CD4 cell counts declined to 454, 501 and 459 cells/μl at week 36 in each of the study arms, reaching a median loss of −296, −176 and −176 at week 36 in the respective arms (P = ns). Two patients in the four injection arm, two in the three injection arm and none in the placebo arm had CD4 cell counts decrease to less than 250 cells/μl (Fig. 3b).
By week 48, the number of patients who reached virologic or immunologic criteria to resume ART was 14 out of 19 in the four injection arm (eight virologic/six immunologic), 10 out of 20 in the three injection arm (seven virologic/three immunologic) and three out of 15 in the placebo arm (three immunologic). Kaplan–Meier estimates for reaching criteria to resume cART were 74, 55 and 23% at week 48 and 90, 71 and 59% at week 96 (Fig. 4). Overall, eight out of 54 (14.8%) remained off cART through week 96 (P = 0.013).
Factors influencing time to resuming therapy
In the univariate analysis, several factors were associated with a shorter time to reach criteria for resuming cART (Table 2) including receiving four vaccine injections (hazards ratio = 3.2, P = 0.033); low CD4 cell count nadir (hazards ratio = 0.5, P = 0.011); baseline cell-associated HIV-DNA content more than 2 log10/106 PBMCs (hazards ratio = 1.8, P = 0.004); and change from baseline more than 0.312 HIV-specific SFC/106 PBMCs (hazards ratio = 2.9, P = 0.041). In addition, the week 24 changes from baseline in the numbers of PBMCs recognizing HIV peptide pools tend to correlate with a shorter delay to reach treatment resumption criteria (hazards ratio = 2.3, P = 0.081). All other tested variables, including vector-specific immunity, were not significant.
In the final backward multivariate analysis, two independent predictors of a shorter time to reach treatment resumption criteria were identified: receipt of an immunization (P = 0.013) with receipt of four vaccine injections having a hazards ratio of 4.1 (P = 0.003) and receipt of three injections having a hazards ratio of 2.7 (P = 0.048); and the CD4 cell count nadir (hazards ratio = 0.4, P = 0.002) (Table 2).
Overall, the vaccine was safe and well tolerated. During the immunization phase, there were 12, eight and three mild-to-moderate local reactions in the four injection, three injection and placebo arms, respectively. There was one severe local reaction in the three injection arm and two in the placebo arm. The four injection arm had significantly more local reactions compared to placebo (P = 0.01). There were no significant differences in systemic events between the groups. No significant changes were observed in CD4 counts, pHIV-RNA or in any standard biological parameter.
During treatment interruption, there were no significant differences in events between the groups. Overall there were six severe clinical events: two in the four injection group (pulmonary embolism and vesicular tumor), four in the three injection arm (radicular neuritis, postappendectomy peritonitis, testicular cancer and gastric ulcer) and none in the placebo group.
Following treatment resumption, all patients had pHIV-RNA less than 400 copies/ml by week 12 except two (431 and 960 copies/ml). Median CD4 cell counts increased in all patients by week 12 after resuming therapy without any differences noted between groups.
This randomized, placebo-controlled study demonstrated that the vCP1452 vaccine administered to chronically infected cART-treated patients induced significant T-cell immunogenicity. This vaccine-induced immunity, however, was associated with less control of viral replication. We found that two factors were independently associated with a shortened time to reach criteria to resume therapy following treatment interruption: the vaccine immunization and the CD4 cell count nadir.
In designing this study, we had hypothesized that a three injection vaccine schedule could be more immunogenic than four injections and therefore more effective in controlling viral replication following treatment interruption. A decrease in immune parameters had indeed previously been observed following multiple injections, suggesting that an exhaustion in immune responses may occur with excessive boosting [28,33]. We had therefore hypothesized that providing a 3-month ‘resting period’ before the last vaccine inoculation would allow the latter to boost the generated immune response. This study demonstrates that the vCP1452-induced immunogenicity is actually enhanced by the fourth injection that, however, did not boost the vaccine-generated immune responses. As the three vaccine injection strategy did not induce higher immunogenicity than the four injection strategy, our results also suggest that the weak, though significant, immunity observed against the vector itself was not a limiting factor. Overall, the vCP1452-induced immunogenicity remained weak, however, far below the levels usually observed in ‘Long Term Nonprogressors’ . The magnitude of the HIV-specific T-cell response is, nevertheless, comparable to the one observed in other canarypox vaccine studies [24–29], even in those performed in acutely infected patients  suggesting this relatively weak immunogenicity does not reflect chronic alterations of the immune system.
The most striking result from our study is the poor after treatment interruption viral control and the shorter time to a predefined resumption of cART in patients who were vaccinated. These results differ from prior studies in chronically infected patients that had shown some benefit during treatment interruption after immunization with a canarypox HIV vaccine used either alone [28,31] or in combination with other immunostimulants [29,30]. Indeed, the HIV-specific responses at week 24 negatively influenced the time to resume cART in the univariate analysis, however the week 36 viral load did not correlate with HIV-specific or vector-specific T-cell responses (data not shown).
These results raise a number of questions. First, the vaccine-associated negative effects might reflect particularities of the study population. There was a half log imbalance in pre-cART pHIV-RNA with higher levels noted in the two immunized groups compared to those receiving placebo. Pre-cART pHIV-RNA was not an inclusion criteria and could only be retrospectively collected in two-thirds of the patients because many had initiated cART prior to routine pHIV-RNA testing or results were simply unavailable. Such an imbalance might be partially explained by another factor observed between the HLA (human leukocyte antigen ) class I genes that also did not figure into the inclusion criteria and were only retrospectively analyzed. It turned out that three patients receiving placebo but none of those immunized had either the HLA-B27 or B57 allele, two HLA alleles that have been associated with a lower risk of disease progression [34,35]. In contrast, five and three patients from the three and four injection groups, but none in the placebo group, had the HLA-B35 allele that has been associated with a poorer prognosis [34,35]. Altogether these points suggest both pretherapeutic pHIV-RNA and HLA typing should be part of the inclusion criteria in future therapeutic immunization studies. In contrast, the CD4 nadirs observed in our study were equally balanced among the three immunization arms ranging between eight and 393 CD4 cells/μl [IQR (interquartile range) 171–390], similar to those reported in other therapeutic vaccine trials [28–31]. We also found that the CD4 nadir was a strong predictive factor that increased the risk two-fold for resuming cART after treatment interruption, in accordance with various studies in which treatment interruption was not preceded by an immune-based therapy [3,5,6,36,37]. At the time this protocol was designed, we elected to focus on the likely patient in our clinic; someone who typically initiated cART prior to having clinical AIDS with CD4 T-cell count nadir less than 350 cells/μl and currently with CD4 T-cell count more than 400 cells/μl and a viral load less than 400 copies/ml.
Second, the immunization procedure might have facilitated HIV replication during treatment interruption as the Cox model demonstrated that the four vaccine injection strategy decreased by three to four-fold the time to resume treatment. The failure of this candidate vaccine at controlling virus after stopping therapy is reminiscent of the recent study of the failure of another T-cell-based vaccine at controlling virus contamination and replication in healthy seronegative volunteers (Merck/HIV Vaccine Trials Network News Release, 21 Sept 2007). In our study, immunization might have induced a predator–prey phenomenon by generating activated vaccine-specific CD4 cells directed either against the HIV vaccine sequences or against the vector, which then acted as appropriate targets for the virus. Preliminary results from current complementary analyses suggest that the vaccine-generated primarily CD4 T cells directed against the virus but only a few HIV-specific CD8 T cells (L. Papagno, personal communication).
In addition, the interruption of cART a month after the last immunization might have coincided with a peak of vaccine-induced immune activation, a point currently under investigation. Noteworthy, two other studies that reported a significant benefit during treatment interruption in chronically infected patients had stopped therapy at least 3 months after the last vCP1452 immunization [29–31]. We purposefully set the bar high by before agreeing upon a strategy to restart cART if we did not demonstrate significant viral control following the treatment interruption. We chose 50 000 copies/ml measured 4–6 weeks after the treatment interruption as the maximum amount we could clinically tolerate prior to restarting cART, realizing this could affect the time to treatment resumption, one of our secondary endpoints. Criteria for restarting cART following treatment interruption in the reported studies have been inconsistent making any comparisons difficult to interpret [36–40].
Fortunately, these immunization strategies were safe as there were no significant treatment-related adverse effects, no major losses in CD4 cell counts, nor were there a higher frequency of AIDS-related or unrelated symptoms during treatment interruption. Once reinstituted, cART was effective with rapid control of the virus and increases in CD4 cell counts. Our treatment interruption was brief, which we believe enhanced the safety aspects of this trial. Future studies involving treatment interruptions should minimize time off therapy if plasma HIV-RNA rebounds significantly. We believe that treatment interruptions should not even be considered in future trials unless immunogenicity is significantly improved.
In conclusion, this placebo-controlled study conducted in chronically infected patients suggests that the immunogenicity conferred by the vCP1452 candidate vaccine alone is associated with higher virus production following treatment interruption, independent of the CD4 nadir. Further studies are required to better define the appropriate balance between the levels of generated immune responses by T-cell-based vaccines and its effect on controlling viral replication in the absence of antiretroviral therapy.
The study was supported by ORVACS, a not-for-profit organization supported by Fondation Bettencourt-Schueller (Paris). We are particularly indebted to Mrs Liliane Bettencourt without whom this ORVACS study would not have been possible. C. Quillent-Grégoire contributed significantly to the initiation and monitoring of the project, S. Hilpert developed the SOPs and V. Supervié analyzed the inter-laboratory quality controls. We thank all patients who participated in the study.
Members of the ORVACS Study Group. Clinical: Dr A.H. Mohand and M. Pauchard (Paris, France); B. Berzins (Chicago, USA); L. Ruiz (Badalona, Spain); J. Joseph (Barcelona, Spain); Dr A. Vogt (Frankfurt, Germany). Immunology: S. Hilpert and C. Gameiro (Paris, France); G. Alter and M. Altfeld (Boston, USA); Andrew McMichael and Lucy Dorrell (Oxford, UK); M. Plana (Barcelona, Spain); L. Ruiz (Badalona, Spain). Virology: Cathia Soulié (Paris, France). Statistics: V. Supervié (Paris, France).
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canarypox; HIV; therapeutic vaccine
© 2008 Lippincott Williams & Wilkins, Inc.
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