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JAC Advance Access published online on November 11, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn461
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Influence of repeated cycles of structured therapy interruption on the rate of recovery of CD4+ T cells after highly active antiretroviral therapy resumption

Agathe León1,*, Esteban Martinez1, Ana Milinkovic1, Borja Mora1, Josep Mallolas1, Jose L. Blanco1, María Larrousse1, Montserrat Laguno1, Teresa Gallart2, Montserrat Plana3, José M. Gatell1 and Felipe Garcia1

1 Infectious Diseases Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Spain 2 Immunology Department, Hospital Clinic of Barcelona, 08036 Barcelona, Spain 3 Laboratory of Retrovirology and Viral Immunopathology, Hospital Clinic of Barcelona, 08036 Barcelona, Spain

* Corresponding author. Tel: +34-93-2275586; Fax: +34-93-4514438; E-mail: aleon{at}clinic.ub.es

Received 9 June 2008; returned 8 July 2008; revised 30 September 2008; accepted 12 October 2008


   Abstract
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Background: CD4+ T cell recovery dynamics were analysed during the ‘on treatment’ periods in structured therapy interruption (STI) as well as the long-term immune reconstitution with highly active antiretroviral therapy (HAART) after finishing STI.

Methods: One hundred and twenty HIV-1-infected patients on successful HAART were randomized to receive for 2 years continuous HAART (n = 37) or two different strategies of STI (n = 83). After this period, most patients received continuous HAART for 2 years.

Results: During the STI period, the rate of recovery of CD4+ T cells decreased progressively from the first to the last resumption of HAART {median change of increase: +232 [interquartile range (IQR): +126, +318], +116 (IQR: +10, +471), +87 (IQR: –54, +252) and –26 (IQR: –352, +211) cells/mm3 after the first, second, third and fourth resumption, respectively}. After the STI period and 2 years of continuous HAART, the median CD4+ count remained significantly lower than at baseline in STI arms, both in the virological arm [559 (IQR: 383, 727) versus 771 (IQR: 625, 913) cells/mm3, P < 0.0001] and the immunological arm [619 (IQR: 501, 789) versus 787 (IQR: 657, 954) cells/mm3, P < 0.0001], but not in the control arm [886 (IQR: 564, 1122) versus 780 (IQR: 539, 945) cells/mm3, P = 0.68]. In a multivariate analysis, the nadir of CD4+ T cells and the baseline value of CD4+ before the STI period independently predicted the level of CD4+ T cells 2 years after resumption of HAART (in both cases, P < 0.0001).

Conclusion: The drop in CD4+ cell count after a first and a second period of 3 months of interruption of HAART was completely recovered after resuming HAART; conversely, interruptions longer than 6 months were deleterious for the recovery of CD4+. CD4+ cell count did not rebound completely in patients who received 2 years of HAART after 2 years of STIs.

Key Words: STI , HAART , CD4+ T cell recovery


   Introduction
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After the interruption of the SMART study by the data safety monitoring board in January 2006,1 structured therapy interruption (STI) has been almost abandoned as a drug saving strategy. The SMART study included 5472 HIV-infected patients who had a CD4+ cell count >350 cells/mm3, randomly assigned to continuous use of antiretroviral therapy (control group) or episodic use of antiretroviral therapy (STI group). The STI group stopped therapy until the CD4+ count decreased to <250 cells/mm3 and then resumed therapy until the CD4+ count increased to >350 cells/mm3. After an average of 16 months of follow-up, they concluded that an STI, as used in their study, significantly increased the risk of opportunistic disease or death, when compared with continuous antiretroviral therapy and did not reduce the risk of adverse events that had been associated with antiretroviral therapy.

The available data from brief analytic treatment interruptions provide information about the development of clinical events,2,3 emergence of resistance mutations,4 drop of CD4+ cell count5 and the reduction of costs/toxicity of highly active antiretroviral therapy (HAART) after STI periods.3 However, there are few data reported about the dynamics of CD4+ T cell recovery during the periods on treatment during the STI, or the long-term immune reconstitution with HAART after the period of STI has been finished. This information about CD4+ T cell recovery can be useful to improve our knowledge about HIV pathogenesis and the safety of short periods of analytical HAART interruption, for example, to test a potential candidate for a therapeutic vaccine.


   Patients and methods
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Patients included in this study came from a prospective, open and randomized (computer generated randomization list) trial started in 2002 in the Hospital Clinic of Barcelona (Spain). Different physicians performed allocation sequence and enrolment of patients. Recruitment and follow-up of patients finished in 2003 and 2005, respectively. The major outcome of this trial was to evaluate the change in body fat in patients undergoing STI. The secondary outcome was to assess immunological and virological safety and efficacy of STIs. Inclusion criteria were: (i) HIV-1 infection confirmed; (ii) age ≥18 years; (iii) clinically stable for the last 3 months; (iv) documented HIV-1 RNA <200 copies/mL for the last 3 months; (v) documented pre-study CD4+ cell count >450 cells/mm3 for the last 3 months; (vi) documented nadir CD4+ cell count >200 cells/mm3; and (vii) signed written informed consent. Subjects were excluded if they had a history of a US Centers for Disease Control and Prevention (CDC)-defined clinical category C, they were pregnant or breast-feeding or they had a history of drug abuse or psychiatric disorder. Patients included were randomized 1:1 to receive for 2 years continuous HAART [control arm (CA)] or two different strategies of STI: interruption of HAART until viral load (VL) increased >30 000 copies/mL in the virological arm (VA) or CD4+ drop to <350 cells/mm3 in the immunological arm (IA). When these virological or immunological criteria were achieved, a resumption of HAART was performed until VL or CD4+ changed again to VL < 20 copies/mL or CD4+ > 450 cells/mm3, and then antiretroviral therapy was stopped and a new STI cycle according to the same VA or IA interruption was performed.

Sample size was not pre-defined at the design stage, because of lack of information related to STIs at that time. Treatment failure was considered whenever a virological failure (VL > 200 copies/mL on HAART), immunologic failure (CD4+ < 200 cells/mm3 on HAART) or clinic failure (development of a CDC class C event) was detected. The patients were removed from the trial in cases of treatment failure, loss to follow-up or death.

After conclusion of the STI trial, a subset of the patients (those who accepted it) were enrolled in a substudy with an additional 2 years of follow-up (until 2007), during which they received continuous HAART. The purpose of this substudy was to assess the CD4+ T cell recovery dynamics during the periods on treatment in the context of STIs and the long-term immune reconstitution with HAART after finishing the periods of STI. The institutional ethical review board approved the study and patients gave written informed consent.

Quantitative characteristics were described with median and interquartile range (IQR) and qualitative characteristics with frequencies and percentages. Comparisons of laboratory parameters were performed using a Wilcoxon signed-rank test.

Univariate and multivariate analyses were performed to identify factors predictive of the rate of recovery of CD4+ cell count after resuming HAART. The following variables were included: CD4+ at baseline, baseline VL, nadir of CD4+ cell count (above or under the median of CD4+ nadir), lowest CD4+ during the STI, time off HAART and highest VL during STI.


   Results
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From the 150 patients recruited in the STI trial, 120 were included in the present substudy. Forty-five patients in the VA arm, 38 in the IA arm and 37 in the CA arm. Baseline characteristics (Table 1) including CD4+ T cell counts were well-balanced between arms. Sixty-eight percent of patients were men with a median age of 39 years (IQR: 36, 47). Sexual contact was the most frequently reported risk factor for acquiring HIV-1 (91%). Co-infection with hepatitis B or C viruses was 3.3% and 13.3%, respectively. At baseline, HIV-1-infected patients had been on HAART for a median of 53 months (IQR: 38, 65) and 34.2% were receiving a protease inhibitor-containing regimen.


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  		Table 1. Baseline characteristics of the patients

 
The median absolute CD4+ T cell count at baseline was 756 cells/mm3 (IQR: 607, 930) and the median percentage of CD4+ T cells was 32% (IQR: 25, 37). The median nadir CD4+ T cell count was 291 cells/mm3 (IQR: 225, 385).

Of the 120 patients, 114 (44 in VA, 36 in IA and 34 in CA) included in the study (95%) completed the 2 year study (of the remaining six patients, three were lost to follow-up, one had a stroke, one had breast cancer and one died from lung cancer) (Figure 1). The number of cycles of STI [median (IQR)] was 3 (1; 4) in the VA arm and 1 (1; 2) in the IA arm. Median duration of STI cycles was 6 (3.4, 24) months in the VA arm and 24 (10.5, 24) months in the IA arm. Fifteen patients (3 in VA and 12 in IA) performed one cycle of STI. Seventeen patients performed two cycles (14 in VA and 3 in IA). Seven patients performed three cycles and four completed four cycles (in the VA arm).


Figure 1
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  		Figure 1. Patient disposition.

 
The median drop of CD4+ T cells after the first (3 months), second (6 months), third (9 months) and fourth (12 months) STI cycle, was –222 (IQR: –309, –87), –114 (IQR: –246, 1), –110 (IQR: –193, –15) and –157 (IQR: –352, –11) cells/mm3, respectively. During the STI period, the rate of recovery of CD4+ T cells decreased progressively from the first to the last resumption of HAART. There was a complete recovery of the CD4+ T cell count after the first and second resumption of HAART, with a median change of CD4+ T cell increase of +232 (IQR: +126, +318) and +116 (IQR: +10, +471) cells/mm3, respectively. However, after the third and fourth resumption, the recovery was incomplete, with a median change of CD4+ T cell increase of +87 (IQR: –54, +252) and –26 (IQR: –352, +211) cells/mm3, respectively.

After the end of the STI period, a follow-up of an additional 2 years was performed, in which 99 out of 114 patients from all arms (86.8%; 38 patients in VA; 33 in IA and 28 in CA) received continuous HAART (Figure 1). To evaluate the dynamics of CD4+ T cell recovery after resuming HAART after the STI period, we compared CD4+ after these 2 years on continuous HAART with baseline values before the STI period. Median CD4+ T cell counts at 2 years after STI remained significantly lower than at baseline in both STI strategies [VA 559 (IQR: 383, 727) versus 771 (IQR: 625, 913) cells/mm3, respectively, P < 0.0001) and IA 619 (IQR: 501, 789) versus 787 (IQR: 657, 954) cells/mm3, respectively, P < 0.0001)], but not in the CA [886 (IQR: 564, 1122) versus 780 (IQR: 539, 945) cells/mm3, P = 0.68] (Figure 2).


Figure 2
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  		Figure 2. Evolution of the median CD4+ T cells counts in the three study arms from baseline (Year 0) to the end of the STI period (Year 2) and after 2 years of resumption of HAART (Year 4).

 
In the univariate analysis, the level of CD4+ T cells after this follow-up of 4 years (2 years of STI and 2 years of continuous HAART) was associated with the CD4+ T cell nadir (r = 0.614, P < 0.0001), CD4+ T cells at baseline before STI (r = 0.596, P < 0.0001), the lowest value of CD4+ T cells during STI (r = 0.45, P < 0.0001), the peak value of VL during STI (r = –0.265, P = 0.028) and the time off HAART during the STI period (r =– 0.316, P = 0.003). In the multivariate analysis, the nadir of CD4+ T cells and the baseline value of CD4+ before the STI period independently predicted the level of CD4+ T cells 2 years after resumption of HAART (in both cases, P < 0.0001).


   Discussion
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We have found during the STI period that after a first and a second cycle of 3 months off HAART (overall 6 months), the drop in CD4+ T cells completely recovered after a similar period of resumption of HAART. However, repeated interruptions of HAART of more than two cycles (more than 6 months) were progressively deleterious for the recovery of CD4+ T cells, even though an equivalent period on HAART was performed [median drop in CD4+ T cells after the third and the fourth cycle of STI was –110 (IQR: –193, –15) and –157 (IQR: –352, –11) cells/mm3, respectively; median change of increase after resuming HAART after the third and the fourth STI cycle was +87 (IQR: –54, +252) and –26 (IQR: –352, +211) cells/mm3, respectively].

It has been reported that the recovery of CD4+ T cells after the first 3 months of HAART is explained by redistribution from lymph nodes to peripheral blood.6 Therefore, our data suggest that periods off HAART longer than 6 months or repeated interruptions of therapy would be associated with changes in lymph nodes that would preclude a rapid and complete response to HAART.7

There is scant information related to this issue and because of that we believe these data could be useful to decide how long an analytical treatment interruption should last. As noted, the risk of HIV progression or death in STI patients in the SMART trial began to exceed that in the non-STI group at around 4 months, which could suggest that a ‘safe’ interruption would be of shorter duration in a similar population.8 Our data support this finding, since periods of interruption of HAART longer than 6 months were associated with poorer CD4+ T cell recovery after a similar period on HAART.

In addition, after 24 months on continuous HAART during the post-STI period of follow-up, the CD4+ counts did not return to baseline in patients who had performed cycles of STI. These results suggest that the immunological damage after 2 years of repeated cycles of STI is not repaired after an equivalent period on continuous HAART. How long is needed to recover CD4+ T cell counts completely after 2 years of STI needs to be evaluated with longer follow-up. Data recently reported from the SMART study9 showed results similar to ours. After a median period of antiretroviral interruption of 16.8 months (IQR: 5.7, 42.3), and a median period of 18 months of resumption of continuous HAART, they found an incomplete recovery of CD4+ T cell counts in the ART interruption group. CD4+ T cells declined from a median of 620 at baseline to 450 cells/mm3 at the end of the STI period and recovered partially after 18 months on HAART after STI (507 cells/mm3).

Finally, it should also be noted that those patients with lower nadirs of CD4+ T cells or lower baseline values of CD4+ count before the STI period showed a worse recovery of CD4+ T cells after 2 years of HAART. Previous reports have shown that the nadir of CD4+ cell count is an independent predictor of CD4+ cell decline during STI,5,10 and we show here the same relation but with the CD4+ T cell recovery after resuming HAART post-STI.

All these data suggest that analytical therapy interruption should last <6 months to avoid an increased risk for disease progression or death1 and delays in CD4+ T cell recovery. Patients with a low nadir of CD4+ T cell count or low baseline values of CD4+ count should not be considered for an analytical STI.


   Funding
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 Funding
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This study was supported in part by grants: IRSICAIXA- HIVACAT (Center for Research and Development of HIV Vaccines in Catalonia), ISCIII-RETIC RD06/006 [Red Temática Cooperativa de Grupos de Investigación en Sida del Fondo de Investigación Sanitaria (Fondo de Investigación Sanitaria de la Seguridad Social)], FIPSE (a non-profit Foundation including: Spanish Ministry of Health, Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme, and Roche) 36536/05, SAF 05/05566, FIS 04/0503 and PI050058, and FIT 090100-2005-9. A. L. and M. P. were supported by contracts CM06/00170 and FIS 03/00072, respectively, from the Institut de Investigacions biomèdiques August Pi I Sunyer and Fundació Clínic in collaboration with the Spanish Health Department.


   Transparency declarations
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E. M., F. G. and J. L. B. have received research grants from Abbott, Bristol-Myers Squibb and Gilead Sciences. J. M. has received research grants from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences and Roche. J. M. G. has received honoraria or research grants from Bristol-Myers Squibb, MSD, GlaxoSmithKline, Gilead Sciences, Tibotec, Roche, Boehringer-Ingelheim, Abbott and Pfizer. The remaining authors have no conflicts of interest to declare.


   Acknowledgements
 
We are indebted to the participants in the study. This study was presented in part at the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2008. Abstract no. H-106.


   References
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 Patients and methods
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 References
 
1 . El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med (2006) 355:2283–96.[Abstract/Free Full Text]

2 . Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet (2006) 368:459–65.[CrossRef][Web of Science][Medline]

3 . Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet (2006) 367:1981–9.[CrossRef][Web of Science][Medline]

4 . Arnedo-Valero M, Garcia F, Gil C, et al. Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection. Clin Infect Dis (2005) 41:883–90.[CrossRef][Web of Science][Medline]

5 . Fagard C, Bandelier CY, Ananworanich J, et al. Biphasic decline of CD4 cell count during scheduled treatment interruptions. AIDS (2005) 19:439–41.[Web of Science][Medline]

6 . Pakker NG, Notermans DW, de Boer RJ, et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med (1998) 4:208–14.[CrossRef][Web of Science][Medline]

7 . Alos L, Navarrete P, Morente V, et al. Immunoarchitecture of lymphoid tissue in HIV-infection during antiretroviral therapy correlates with viral persistence. Mod Pathol (2005) 18:127–36.[CrossRef][Web of Science][Medline]

8 . El-Sadr WM. Re-initiation of ART in the CD4-guided ART interruption group in the SMART study lowers risk of opportunistic disease or death. In: Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2008. Abstract H-106. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.

9 . Emery S, Neuhaus J, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis (2008) 197:1133–44.[CrossRef][Web of Science][Medline]

10 . Maggiolo F, Ripamonti D, Gregis G, et al. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. AIDS (2004) 18:439–46.[CrossRef][Web of Science][Medline]


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