Treatment toxicity was as expected for the drug regimen employed and did not differ between study strata. Abacavir hypersensitivity was seen in nine patients, six of 73 (8%, two acute infection, four recent infection) of those in the primary analysis and three of 48 (6%, no acute infection, three recent infection) of the remaining patients. No myocardial infarctions were reported.
During the first 52 weeks after initiating treatment, clinical symptoms associated with drug toxicity of grade 2 or 3 were reported in 71 of the overall 121 enrolled patients, 26 of 50 (52%) in the acute infection stratum and 45 of 71 (63%) in the recent infection stratum. There were no grade 4 signs or symptoms reported during the first 52 weeks and only one grade 4 chest pain in the acute infection stratum in the subsequent weeks. Laboratory toxicities of grade 2 and above were reported in 44 of the 121 enrolled patients in the first 52 weeks (18/50 acute infection, 26/71 recent infection). Lipoatrophy was not systematically defined in this trial but no cases were reported as reason for treatment discontinuation. The safety of treatment interruption was examined after the SMART trial results were presented and there was no evidence detected of accelerated disease progression or clinical events.
The disposition of patients registered into ACTG 371 is shown in Table 3. Study treatment was discontinued before week 52 in 24 patients (11 acute infection, 13 recent infection). In seven (four acute infection, three recent infection), toxicity was the stated cause, eight patients (four acute infection, four recent infection) discontinued treatment for other reasons including intolerance and pill burden, in three (one acute infection, two recent infection) treatment was stopped for virologic failure and six (two acute infection, four recent infection) patients were lost to follow-up.
Twenty-four patients who were on study for at least 52 weeks did not undergo treatment interruption. Of these, eight patients (two acute infection, six recent infection) completed an early study version, three (one acute infection, two recent infection) had toxicities, six (two acute infection, four recent infection) did not interrupt due to patient preference, four (three acute infection, one recent infection) had virologic failure, and three (three acute infection) were lost to follow-up.
The primary efficacy endpoint, plasma HIV RNA concentration less than 5000 copies/ml after 24 weeks of treatment interruption, was achieved in 40% of the 73 patients who underwent treatment interruption and 24% of the 121 patients enrolled overall. Virologic success was achieved in 12 of 28 (43%, 95% CI 24–63%) in the acute infection stratum and in 17 of 45 (38%, 95% CI 24–53%) in the recent infection stratum who underwent treatment interruption. Most (25) primary endpoint successes were achieved in the first treatment interruption. There was no statistically significant difference between the two groups (P = 0.81; 95% CI on the difference between groups −31 to 19%). Considering the first treatment interruption, 34 (47%) patients re-initiated treatment prior to week 24. We also found no differences between the acute infection and recent infection strata in having average plasma HIV RNA concentration less than 5000 or 10 000 copies/ml between weeks 18 and 30 of treatment interruption (acute infection: 13 of 28, 46%, recent infection: 18 of 45, 40% P = 0.63; acute infection: 16 of 28, 57%, recent infection: 21 of 45, 47% P = 0.47, respectively), or plasma HIV RNA concentration less than 10 000 copies/ml at week 24 of treatment interruption (acute infection: 14/28, 50%, recent infection: 22/45, 49% P = 1.0).
Secondary efficacy analysis for the first treatment interruption also revealed no statistically significant difference between the two strata in terms of:
- time to three consecutive plasma HIV RNA concentrations at least 5000 copies/ml or two at least 50 000 copies/ml (median, weeks acute infection: 10, recent infection: 14; P = 0.76);
- peak (maximum) plasma HIV RNA concentration (median, 28 224 copies/ml acute infection, 36 241 copies/ml recent infection; P = 0.67);
- time to peak plasma HIV RNA concentration (median weeks acute infection: 8, recent infection: 8; P = 0.35).
- rate of initial increase in plasma HIV RNA concentration (median, log10/week acute infection: 0.29, recent infection: 0.50; P = 0.46).
- changes in CD4+ T cells between those immediately preceding treatment interruption (median, 893 cells/μl acute infection, 829 cells/μl recent infection) and the average of all measurements between weeks 18 and 30 of continuous treatment interruption were not significantly different (median changes, −165 cells/μl acute infection, −90 cells/μl recent infection; P = 0.25).
Immune activation markers were elevated at baseline, especially in the acute infection stratum. These markers declined with treatment in both strata in the study population overall (Fig. 1) and similarly in the 73 patients analyzed for primary efficacy endpoint (data not shown).
The most important predictor of success in meeting the primary efficacy endpoint was baseline plasma HIV RNA concentration (P = 0.003 for log 10 RNA) as summarized in Table 4. Successful outcomes were more common in the group with baseline plasma HIV RNA concentration less than 100 000 copies/ml (22/46, 48%) than in those with baseline plasma HIV RNA concentrations above 100 000 copies/ml (7/27, 26%). A higher percentage of activated CD4+ T cells at baseline (HLA-DR+/CD38+, overall median: 11%, Q1–Q3: 7–16%) was also associated with primary endpoint success in a model that controlled for baseline plasma HIV RNA concentration and acute infection/recent infection strata [odds ratio (OR) = 3.3 comparing CD4+ activation above versus below the median, 95% CI 1.03–10.7, P = 0.036); without controlling for baseline plasma HIV RNA concentration, baseline activated CD4+ T-cell percentage showed no association (P > 0.2). Baseline percentages of activated CD8+ T cells, naive and memory CD4+ and CD8+ T cells, and absolute CD4+ and CD8+ T-cell counts were not associated with primary endpoint success in models adjusted for baseline plasma HIV RNA concentration.
The trial was an ambitious and complex trial of potent ART in patients with acute and recent HIV infection with up to two cycles of intentional treatment interruption. This trial of 121 patients with acute and recent HIV infection is the largest trial to date to evaluate the frequency of HIV viral load suppression after structured treatment interruption and was based on an earlier study of 14 patients that had suggested this approach would allow a high frequency of prolonged viral control after treatment discontinuation. Additionally, it tested the hypothesis that the benefits of this strategy would be most apparent in those with acute as opposed to recent HIV infection based on the supposition that a more intact immune system at study entry would be more responsive to the antigenic stimulation provided by structured treatment interruptions. Indeed, approximately 40% of patients in the primary endpoint analysis group had plasma HIV RNA concentrations less than 5000 copies/ml after 24 weeks and remained off all ART. Among all those initially enrolled, control of viremia was seen in 12 of 50 (24%) acute infection and in 17 of 71 (24%) recent infection. Contrary to our initial hypothesis, however, there was no evidence of differences in the rate of viral control between individuals treated during acute and recent infection. Baseline tests for genomic predictors of viral suppression were not anticipated in the trial design and therefore not included. Also, the relatively wide confidence intervals of viral suppression rates leave open the possibility of a clinically relevant difference between the treatment groups. The high number of enrolled patients not meeting criteria for primary endpoint analysis and the baseline differences between these groups was concerning and probably reflected the trial's complexity. Whereas the rate of viral suppression was lower overall than in the primary endpoint group, there was still no difference between the acute infection and recent infection strata.
Overall, the study was well tolerated, although the rates of adverse effects and drug discontinuations were almost certainly higher than expected with more current antiretroviral regimes. Whereas the regimen used in this trial is not currently recommended for initial treatment, it resulted in prompt HIV viral load suppression with high rates of medication adherence. Relatively few patients discontinued study treatment for toxicity or virologic failure, and rates of toxicity were similar to those in chronically infected individuals treated with these medications. Lipoatrophy commonly associated with the use of one of the study drugs, stavudine, may not have been a common or severe problem because of the relatively short duration of therapy in this trial, although it was not systematically monitored, a reflection of the limited knowledge of this problem when the study was designed.
Most studies of ART treatment interruption in chronic HIV-1 infection have found no virologic benefit [16–19] with one exception in which a modest benefit from two interruptions was reported , nor did the addition of hydroxyurea add benefit . The strategy of antiretroviral treatment interruption has fallen into disfavor based upon recent findings in chronically HIV-1-infected individuals that interruption of ART is associated with increased morbidity and mortality . The patients in the present study were distinct from those in the SMART study in that they were recently infected and most would not have met standard guidelines for initiation of ART. When findings of the SMART study were released, a systematic review of ACTG 371 occurred and it was concluded that there was no evidence of harm from treatment interruption in these patients and the study was allowed to complete enrollment. Importantly, however, patients in ACTG 371 were more frequently monitored during treatment interruptions than those in the SMART study, and therefore the interruption strategies were not truly comparable.
As expected, acute infection cases had higher baseline plasma HIV RNA concentrations than those with recent infection; however, when adjusted for baseline viremia titer, suppression was seen equally commonly in the two study strata. Baseline plasma HIV RNA concentration was also the most significant negative predictor of ability to control viremia in patients who underwent treatment interruption. Thus, patients with high baseline plasma HIV RNA concentrations were least likely to meet the endpoint success definition in this interruption trial.
Results from cohort studies of untreated primary HIV infection suggest a higher plasma HIV RNA concentration at set point than in the current trial [5–7,23], but selection differences make such comparisons hazardous. Thus, it is not possible to firmly conclude from the present study that early treatment enhances virologic suppression. The results of the present study are nonetheless important in that they establish the expected outcomes for potent ART in acute and recent infection, and response rates following one or two cycles of intentional treatment interruption. As such, this trial should serve as an important point of reference for future interventions in this vitally important patient population so much now a focus on questions of the kinetics of viral replication and dissemination after infection and of the rate and specific nature of early immune damage.
We had hypothesized that the earlier ART would limit immune damage thereby enhancing acutely infected individuals' ability to control virus replication compared to recently infected individuals. The failure to observe this, however, does not necessarily disprove the hypothesis that early intervention confers greater benefit, as it is unclear whether the acutely and recently infected individuals were comparable. Previous studies have demonstrated that highly symptomatic seroconverters who are identified during acute HIV-1 infection have a worse prognosis than other HIV-1-infected individuals [1–4,7]. Thus, the finding that acutely infected and recently infected individuals had similar rates of virologic control could mask the true immune benefit of treatment in acute infection. It is possible, as well, that immune benefits may take longer than 24 weeks of treatment interruption to be appreciated. Hecht et al. in a nonrandomized study compared plasma HIV RNA concentrations among acute and recent HIV-1 seroconverters who received a minimum of 12 weeks of ART and subsequently interrupted therapy for at least 6 months with concentrations in untreated seroconverters, after controlling for baseline viral load and CD4+ T-cell counts. They concluded that both acute and recent seroconverters who received treatment during acute infection had significantly lower viral loads and higher CD4+ T-cell counts at 24 weeks, but the effects seemed to wane in the recent group after longer follow-up . In contrast, longer-term follow-up of the same cohort of patients who initially prompted the ACTG 371 study design at 3 years and comparison of their outcomes with those of historical controls within the MACS suggested a loss of apparent immune benefit from early treatment and structured treatment interruptions . Clearly, the lack of randomized, controlled trials has impaired the ability to achieve conclusive results on this issue. Nevertheless, collectively, these data suggest that early ART followed by treatment interruption does not produce the profound alterations in disease course that were initially suggested by uncontrolled studies.
The findings that higher percentages of activated CD4+ T cells at baseline were associated with greater likelihood of virologic success upon treatment interruption, after adjusting for baseline viral load, and that baseline CD8+ T-cell activation was unrelated to virologic success were unexpected. Previous studies have found a negative association between T-cell immune activation and the ability to suppress virus replication during antiretroviral treatment [24–26] and we had anticipated that similar patterns would be observed during treatment interruption. To our knowledge, this is the first study to report a direct relationship between CD4+ T-cell activation prior to treatment and ability to control viremia following treatment interruption. It is conceivable that high levels of CD4+ T-cell immune activation in early disease signify a more competent immediate host immune response. Further studies are needed to confirm whether higher levels of CD4+ T-cell immune activation in early HIV-1 disease after adjusting for plasma HIV RNA concentrations indeed signal a better prognosis.
The results of this trial do not prove that immediate treatment is superior to deferred treatment or that there is a benefit to the strategy of treatment interruption, a popular concept when this trial was designed. The lack of difference in the acute versus recent infection cases is worth further reflection. It seems highly unlikely that any trial will enroll patients any closer to the actual moment of infection than in ACTG 371. Most of the acute infection stratum had plasma viremia with no antibody response and were almost certainly within the first 4 weeks of infection at study screening. Treatment strategies or trials relying on finding even earlier cases do not address the reality of primary infection as seen in the clinical setting. Even with the very early infection entered in the acute infection stratum of ACTG 371, we now know that immune damage had already occurred. Whereas much more is known in this regard than when ACTG 371 was designed it remains as difficult now to study these issues in human patients. Recent data from simian infection in particular suggest that initial infection dramatically affects T-lymphocyte populations, particularly the CD4+ CCR5+ memory cells in the gut lymphoid tissue, within one to several weeks of exposure .
Further insight into the appropriate care of acute or recent infection could be provided by a comparison to a concurrent untreated control group, especially if randomization between strategies was possible. Whereas not feasible when ACTG 371 was launched, these data should help provide the equipoise needed to conduct controlled trials and, in fact, several prospective trials with a randomized control are now in progress. Treatment interruption may not be needed in future trials, especially given evidence of adverse outcomes of a similar strategy in chronic infection. An obvious question is whether ART, if initiated in primary infection, should ever be discontinued. Whereas ACTG 371 does not directly answer this question, it does provide evidence of the safety of treatment discontinuation followed in 40% of cases by prolonged viral control.
These data were presented in part at the Conference on Retroviruses and Opportunistic Infections February 2008, Boston MA, USA.
The clinical trial is registered in the national clinical trials database, # NCT00000940. ‘Five-Drug Anti-HIV Treatment Followed by Treatment Interruption in Patients Who Have Recently Been Infected With HIV’.
The work was supported by the AIDS Clinical Trials Group, under the National Institute of Allergy and infectious Diseases grant AI-68636, AI-38858, AI 69450, AI-38855, AI-69432 and AI-68634.
1. Dorrucci M, Rezza G, Vlahov D, Pezzotti P, Sinicco A, Nicolosi A, et al
. Clinical characteristics and prognostic value of acute retroviral syndrome among injecting drug users. Italian Seroconversion Study. AIDS 1995; 9:597–604.
2. Pedersen C, Lindhardt BO, Jensen BL, Lauritzen E, Gerstoft J, Dickmeiss E, et al
. Clinical course of primary HIV infection
: consequences for subsequent course of infection. BMJ 1989; 299:154–157.
3. Schacker TW, Hughes JP, Shea T, Coombs RW, Corey L. Biological and virologic characteristics of primary HIV infection
. Ann Intern Med 1998; 128:613–620.
4. Kelley CF, Barbour JD, Hecht FM. The relation between symptoms, viral load, and viral load set point in primary HIV infection
. J Acquir Immune Defic Syndr 2007; 45:445–448.
5. Lyles RH, Munoz A, Yamashita TE, Bazmi H, Detels R, Rinaldo CR, et al
. Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J Infect Dis 2000; 181:872–880.
6. Hubert JB, Burgard M, Dussaix E, Tamalet C, Deveau C, Le Chenadec J, et al
. Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. The SEROCO Study Group. AIDS 2000; 14:123–131.
7. Henrard DR, Phillips JF, Muenz LR, Blattner WA, Wiesner D, Eyster ME, Goedert JJ. Natural history of HIV-1 cell-free viremia. JAMA 1995; 274:554–558.
8. Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, et al
. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy
. J Infect Dis 2008; 197:714–720.
9. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, McNeil A, Dandekar S. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy
. J Virol 2003; 77:11708–11717.
10. Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996; 272:1167–1170.
11. Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. N Engl J Med 2001; 344:720–725.
12. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, Narvaez AB, et al
. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 2004; 104:942–947.
13. Sodora DL, Silvestri G. Immune activation and AIDS pathogenesis. AIDS 2008; 22:439–446.
14. Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, et al
. Immune control of HIV-1 after early treatment of acute infection. Nature 2000; 407:523–526.
15. Kaufmann DE, Lichterfeld M, Altfeld M, Addo MM, Johnston MN, Lee PK, et al
. Limited durability of viral control following treated acute HIV infection
. PLoS Med 2004; 1:e36.
16. Fagard C, Oxenius A, Gunthard H, Garcia F, Le Braz M, Mestre G, et al
. A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Arch Intern Med 2003; 163:1220–1226.
17. Papasavvas E, Kostman JR, Mounzer K, Grant RM, Gross R, Gallo C, et al
. Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. PLoS Med 2004; 1:e64.
18. Lewin SR, Murray JM, Solomon A, Wightman F, Cameron PU, Purcell DJ, et al
. Virologic determinants of success after structured treatment interruptions of antiretrovirals in acute HIV-1 infection. J Acquir Immune Defic Syndr 2008; 47:140–147.
19. Smith DE, Kaufmann GR, Kahn JO, Hecht FM, Grey PA, Zaunders JJ, et al
. Greater reversal of CD4+ cell abnormalities and viral load reduction after initiation of antiretroviral therapy
with zidovudine, lamivudine, and nelfinavir before complete HIV type 1 seroconversion. AIDS Res Hum Retroviruses 2003; 19:189–199.
20. Jacobson JM, Pat Bucy R, Spritzler J, Saag MS, Eron JJ Jr, Coombs RW, et al
. Evidence that intermittent structured treatment interruption
, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068. J Infect Dis 2006; 194:623–632.
21. Bloch MT, Smith DE, Quan D, Kaldor JM, Zaunders JJ, Petoumenos K, et al
. The role of hydroxyurea in enhancing the virologic control achieved through structured treatment interruption
in primary HIV infection
: final results from a randomized clinical trial (Pulse). J Acquir Immune Defic Syndr 2006; 42:192–202.
22. 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 2006; 355:2283–2296.
23. Hecht FM, Wang L, Collier A, Little S, Markowitz M, Margolick J, et al
. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy
during acute HIV infection
. J Infect Dis 2006; 194:725–733.
24. Hoen B, Cooper DA, Lampe FC, Perrin L, Clumeck N, Phillips AN, et al
. Predictors of virological outcome and safety in primary HIV type 1-infected patients initiating quadruple antiretroviral therapy
: QUEST GW PROB3005. Clin Infect Dis 2007; 45:381–390.
25. Resino S, Bellon JM, Gurbindo MD, Munoz-Fernandez MA. CD38 expression in CD8+ T cells predicts virological failure in HIV type 1-infected children receiving antiretroviral therapy
. Clin Infect Dis 2004; 38:412–417.
26. Shepard BD, Loutfy MR, Raboud J, Mandy F, Kovacs CM, Diong C, et al
. Early changes in T-cell activation predict antiretroviral success in salvage therapy of HIV infection. J Acquir Immune Defic Syndr 2008; 48:149–155.
27. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005; 434:1093–1097.
Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
acute HIV infection; antiretroviral therapy; primary HIV infection; recent HIV infection; treatment interruption