The interest in transient antiretroviral therapy (ART) at the time of primary HIV-1 infection (PHI) remains controversial [1–3]. We report on a cohort of patients with long-term immunovirological control following discontinuation of ART initiated at PHI and try to identify factors associated with this unusual pattern.
The present study is the retrospective observational cohort study of HIV-1-infected patients followed since PHI in the setting of the ‘HIV Reservoirs’ Working Group at the Agence Nationale de Recherche sur le SIDA (ANRS), including three French clinical centres. PHI was defined as a negative/incomplete HIV-1 western blot and a p24 Ag positive test, and/or a current positive HIV antibody test with a negative one within the previous 3 months. Patients who experienced PHI between 1996 and early 2007 were included and then followed prospectively. We extracted cases of patients treated early (i.e. ART started within 3 months after PHI, for at least 3 months), successfully (i.e. HIV-RNA level undetectable within 6 months, with no subsequent failure on therapy) and who subsequently interrupted ART with at least 24 months of follow-up off treatment. We collected demographic, clinical, therapeutic and immunovirological data. Cell-associated HIV-DNA levels in peripheral blood mononuclear cells (PBMCs) were measured as previously described . All patients had biological investigations according to standard of care (three to four times per year). We categorized patients according to the duration of viral control after ART discontinuation. Two consecutive HIV-RNA loads above 50 copies/ml defined virological failure. Data were censored when ART was resumed.
Comparisons of categorical data were performed with Fisher's exact test or a χ2 test. Continuous variables were compared with Kruskal–Wallis or Mann–Whitney U-tests. Linear correlations were analysed using Spearman's test.
Among 72 patients followed since PHI, 32 matched our definition of successful treatment, with subsequent interruption. They were monitored for a median duration of 46 months [interquartile range (IQR): 23–71], until last follow-up or visit at which treatment was resumed. Main characteristics are summarized in Table 1.
Interestingly, five out of 32 patients presented virological control during follow-up (median duration: 75 months; IQR: 71–82), with only one blip being observed among the 99 HIV-RNA measurements. These patients, qualified as ‘post-treatment controllers’ (PTCs), had stable CD4+ T-cell counts over time. None experienced B or C events, according to Centers for Disease Control classification. Of note, all PTC patients exhibited low levels of cell-associated HIV-DNA (median: 2 log10 copies/106 PBMC) determined at a distance from ART discontinuation, and these levels were stable over the past 4 years. None of them had HLA class I B*27 or B*57 alleles or homozygous Delta 32 deletion for the CCR-5-encoding gene, although one was heterozygous.
Of the remaining 27 patients, 21 presented with a rapid virological failure after ART discontinuation (i.e. viral rebound within 6 months), whereas six patients had a transient HIV-RNA control (i.e. rebound after more than 6 months). We qualified these patients as ‘noncontrollers’ and ‘transient controllers’, respectively. In the transient controller group, the median duration of viral control was 10 months (IQR: 9–21 months).
These groups showed no demographic, clinical, immunologic or HIV-RNA level differences at the time of PHI and received similar ART regimens (Table 1). At ART interruption, they had similar CD4+ and CD8+ T-cell counts. Time elapsed from PHI to ART initiation and duration of treatment were not significantly different between groups. In contrast, the ratio between ART duration and time to treatment initiation (delay from PHI to ART) was significantly higher in the PTC group vs. the transient controller and noncontroller groups (P = 0.006 and 0.04, respectively).
After ART interruption, the PTC group had a significantly slower decline in CD4+ T-cell counts than the transient controller and noncontroller groups (Table 1). Consequently, none of the PTC patients had to resume ART, compared to 50% in the transient controller group and 66% in the noncontroller group (P = 0.01 between PTC and noncontroller). Moreover, HIV-DNA at the last visit was significantly lower in the PTC group than in the noncontroller group (P < 0.0001) and slightly lower in the PTC group than in the transient controller group (P = 0.07). Finally, within the whole cohort of 32 patients, HIV-DNA levels were strongly correlated with HIV-RNA levels (r = 0.78, P < 0.0001) at the last visit.
Our so-called ‘PTC patients’ controlled viral infection over years, with no other apparent explanation than having received both very early and prolonged treatment.
Without predetermined criteria to start and stop ART in our study, we cannot exclude some biases. However, despite the small cohort size, PTC frequency (15.6%) was so much higher than expected (<0.5% of patients had spontaneous control in other cohorts), such that it is very unlikely that PTCs were elite controllers [5,6]. Moreover, PTCs did not exhibit the same clinical history and fundamental ‘protective’ HLA B*27 and B*57 alleles as elite controllers and long-term nonprogressors (LTNPs) [5,7]. Like elite controllers and LTNPs, PTCs showed very low and stable cell-associated HIV-DNA after ART interruption, with this marker being an independent prognostic factor of the risk of progression strongly correlated with the body reservoir and dynamics of viral infection [5,7–10]. Interestingly, three PTC patients gave their consent for a rectal biopsy, wherein we also found very low cell-associated HIV-DNA levels, within the same range as in LTNPs . It has been previously shown that only patients treated at the time of PHI for at least 2 years were likely to have a steep decline in the viral reservoir, reaching the range of values found in elite controllers and LTNPs [5,11–13]. Additionally, early treatment might help in maintaining the capacity to develop potent specific anti-HIV responses, decrease T-cell activation and protect innate immunity, allowing viral control, even after treatment interruption [1–3,14]. Altogether, these data suggest that, in some patients in whom potent ART has been given early during PHI and for an extended period, control of viral replication is associated with a low viral reservoir that may not be replenished after ART interruption.
Understanding the mechanisms of immunovirological control in such patients could provide new arguments favouring early antiretroviral administration. Although treatment interruptions are no longer recommended in HIV infection , we think that this strategy should be re-assessed for patients treated since PHI.
The authors gratefully acknowledge the patients of the cohort.
L.H. wrote the manuscript. L.H., T.P., V.A.F., J.P.V. and C.R. participated in conception and design of study. Data were acquired by L.H., A.L., B.C. and J.P.V. L.H. analysed and interpreted the data, with review by T.P., V.A.F., A.L., J.P.V. and C.R. C.R. supervised the project. All authors reviewed, revised for content and approved the final version of this paper.
All authors declare having no conflict of interest.
This work has been presented in part at the 15th Conference on Retroviruses and Opportunistic Infections [abstract #695]; 3–6 February 2008; Boston, Massachusetts, USA.
1. Hicks CB, Gay C, Ferrari G. Acute HIV infection: the impact of antiretroviral treatment on cellular immune responses. Clin Exp Immunol 2007; 149:211–216.
2. Cellerai C, Little SJ, Kinloch-de Loes S. Treatment of acute HIV infection: are we getting there? Curr Opin HIV AIDS 2008; 3:67–74.
3. Rowland-Jones S, de Silva T. Resisting immune exhaustion in HIV-1 infection. PLoS Med 2008; 5:e103.
4. Avettand-Fènoël V, Chaix ML, Blanche S, Burgard M, Floch C, Toure K, et al
. French Pediatric Cohort Study ANRS-CO 01 Group. LTR real-time PCR for HIV-1 DNA quantitation in blood cells for early diagnosis in infants born to seropositive mothers treated in HAART area (ANRS CO 01). J Med Virol 2009; 81:217–223.
5. Lambotte O, Boufassa F, Madec Y, Nguyen A, Goujard C, Meyer L, et al
. SEROCO-HEMOCO Study Group. HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 2005; 41:1053–1056.
6. Goujard C, Chaix ML, Lambotte O, Deveau C, Sinet M, Guergnon J, et al
. Agence Nationale de Recherche sur le Sida PRIMO Study Group. Spontaneous control of viral replication during primary HIV infection: when is ‘HIV controller’ status established? Clin Infect Dis 2009; 49:982–986.
7. Sáez-Cirión A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, et al
. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A 2007; 104:6776–6781.
8. Yerly S, Günthard HF, Fagard C, Joos B, Perneger TV, Hirschel B, et al
, Swiss HIV Cohort Study. Proviral HIV-DNA predicts viral rebound and viral setpoint after structured treatment interruptions. AIDS 2004; 18:1951–1953.
9. Rouzioux C, Hubert JB, Burgard M, Deveau C, Goujard C, Bary M, et al
. Early levels of HIV-1 DNA in peripheral blood mononuclear cells as a predictor of disease progression independently of HIV-1 RNA levels and CD4+ T cell counts. J Infect Dis 2005; 192:46–55.
10. Avettand-Fenoel V, Prazuck T, Hocqueloux L, Melard A, Michau C, Kerdraon R, et al
. HIV-DNA in rectal cells is well correlated with HIV-DNA in blood in different groups of patients, including long-term nonprogressors. AIDS 2008; 22:1880–1882.
11. Viard JP, Burgard M, Hubert JB, Aaron L, Rabian C, Pertuiset N, et al
. Impact of 5 years of maximally successful HAART on CD4 cell count and HIV-1 DNA level. AIDS 2004; 18:45–49.
12. Martinez V, Costagliola D, Bonduelle O, N'go N, Schnuriger A, Théodorou I, et al
. Asymptomatiques à Long Terme Study Group. Combination of HIV-1-specific CD4 Th1 cell responses and IgG2 antibodies is the best predictor for persistence of long-term nonprogression. J Infect Dis 2005; 191:2053–2063.
13. Hocqueloux L, Avettand-Fènoël V, Jacquot S, Prazuck T, Mélard A, Viard JP, et al.ANRS Reservoir Study Group. Better HIV-1 DNA depletion and CD4 restoration with HAART initiated at the time of primary HIV infection than with HAART started during chronic HIV infection
[abstract #515]. 16th Conference on Retroviruses and Opportunistic Infections
. Montreal, Canada; 2009.
14. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol 2010; 10:11–23.
15. Strategies for Management of Antiretroviral Therapy (SMART) Study Group; El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al.CD4+ count-guided interruption of antiretroviral treatment
. N Engl J Med