Longitudinal evolution of HIV-RNA: viral load ‘set point’
Figure 3a and b shows cross-sectional medians of HIV-RNA levels (on log10 scale) for ‘early’ and ‘deferred’ treatment groups. After initiation of cART, a rapid decrease in viral load is observed followed by a rapid increase following cART cessation. Viral load levels of ‘early treated’ individuals while off cART appear to be comparable to the corresponding levels of untreated individuals in the ‘deferred treatment’ group.
Viral load ‘set point’ levels were estimated by taking the average of all HIV-RNA measurements per individual, provided that individuals in the ‘deferred treatment’ group were still ART naïve, and individuals in the ‘early treated’ group had stopped cART for at least 6 months. All measurements taken within the first year after seroconversion were excluded. The estimated mean [95% confidence interval (CI)] ‘set point’ levels were similar at 4.30 (4.14, 4.46) for those who deferred treatment, and at 4.37 (4.01, 4.73), 4.09 (3.68, 4.50) and 4.18 (3.87, 4.48) log10 copies/ml for individuals in the ‘early’ group, respectively, treated for up to 6 months, 6–12 months or more than 12 months and individuals (P = 0.57).
Combination antiretroviral therapy (re)initiation
Of 147 individuals who interrupted cART, 90 patients (61%) reinitiated therapy. Of the 675 individuals in the ‘deferred treatment’ group, 226 (34%) initiated a cART regimen during the available follow-up. The 25th (95% CI) percentiles of time to cART (re)initiation were 3.5 (2.8–4.3) and 2.3 (2.0–2.6) years after seroconversion for the ‘early’ and ‘deferred’ treatment groups, respectively, corresponding to a hazard ratio (95% CI) of 0.65 (0.51, 0.83), suggesting a lower rate of cART (re)initiation among the ‘early’ treatment group. However, taking into account the time interval that the ‘early treated’ individuals spent on cART initially, and using the appropriate ‘late entry’ adjustment the hazard ratio (95% CI) became 2.63 (2.05, 3.37) indicating a significantly higher rate of cART reinitiation in the ‘early treatment’ group compared with the ‘deferred treatment’ group. Investigating the issue of cART (re)initiation further, we excluded from analysis individuals in the ‘early treatment’ group who did not interrupt their first cART during follow-up and using a modified Kaplan–Meier technique , we estimated the median (95% CI) CD4 cell count at cART (re)initiation to be 351 (303, 421) and 278 (261, 292) cells/μl (P < 0.001) for ‘early’ and ‘deferred’ treatment groups. Thus, ‘early treated’ individuals tend to reinitiate cART at approximately 80 cells/μl higher CD4 cell levels compared with individuals in the ‘deferred treatment’ group. Differences remained practically unchanged even after adjustment for presence of seroconversion illness.
There were no deaths during either the cART-free period, for the ‘deferred treatment’ group, or following reinitiation, for the ‘early treatment’ group. Of the 348 ‘early treated’ individuals and 664 in the ‘deferred’ group, six (1.7%) and 11 (1.6%) developed clinical AIDS, respectively (P = 0.776). Four of the six AIDS events in the ‘early’ treatment group were observed during treatment interruption. Considering the whole available follow-up time, the numbers of AIDS events were also similar at 13 (3.7%) and 20 (3%) in the ‘early’ and ‘deferred’ treatment groups, respectively (P = 0.95). Two (0.6%) and 12 (1.8%) individuals in the ‘early’ and ‘deferred’ treatment groups, respectively, died during the whole follow-up period. This difference was marginally statistically significant (P = 0.05), but it should be noted that the majority of deaths (nine out of 12) in the ‘deferred treatment’ group were not AIDS defining, three of which may have been HIV related (one bacterial infection, one respiratory disease, one malignancy, two drug overdoses, one suicide and three cases with unknown cause of death). The corresponding proportion of non-AIDS deaths among ‘early treated’ individuals was 1/2 (drug overdose).
Results from analyses using stricter definitions of ‘early’ treatment were consistent with those reported in the main analysis (data not shown). Results from individuals without symptoms of seroconversion illnesses were similar to those reported in the main analysis. However, as expected, individuals who had symptoms of seroconversion illnesses and deferred treatment had, in general, lower CD4 cell counts than those without symptoms making differences between the ‘early’ and ‘deferred’ groups slightly more pronounced compared with the main analysis (data not shown).
Our findings suggest that any early immunologic gain from initiating cART within the 6 months following HIV seroconversion is unlikely to be sustained, with the possible exception of cART administered for longer than 1 year. Although there is some evidence that the initial CD4 cell gain, in those treated for longer than 1 year during early HIV-1 infection, may persist for at least some years after interruption, available follow-up data in the present study limit any firm conclusions. The question still remains, therefore, as to whether it is beneficial to initiate cART in primary infection and, more crucially, for how long. Although we are not able to address these questions through this study, given the dangers of inferring treatment efficacy from observational data [31,32], our study, nonetheless, is the largest to date to report on CD4 cell, HIV-RNA and clinical events of persons treated during primary HIV infection.
We found no evidence for a difference in the average estimated slope beyond the first 6 months following treatment cessation between the ‘early’ and ‘deferred’ treatment groups. Furthermore, HIV-RNA levels of ‘early treated’ individuals while off cART appear to be comparable to the corresponding levels of untreated individuals in the ‘deferred’ group. This is confirmed by a number of other studies [16,17] but refuted by others [7–10] though the length of follow-up reported in most studies is typically limited.
A number of factors are likely to influence findings and make between-study comparisons difficult. First, the time interval between seroconversion and cART initiation maybe an important determinant in the enduring effect of transient cART. Following HIV seroconversion, massive unchecked viral replication and permanent damage of CD4 cell-mediated immune functions  typically occur within a period of weeks, rather than months, and initiation of cART at 6 months may fall short of preventing permanent distortion of immune function. A small study  setup to investigate the effects of timing of cART initiation during PHI showed a greater benefit when cART was initiated within 2 weeks of seroconversion compared with between 2 weeks and 6 months. However, in our sensitivity analyses, we did not observe any trend for slower long-term CD4 cell count declines when we used stricter definitions of ‘early’ treated.
Second, duration of transient cART may also play a part though cART appears to be given for a few months, rather than years, in most of these studies. To our knowledge, however, this is the only published study to consider the effect of different durations of cART on these outcomes. We found that individuals receiving ‘early’ cART for less than 1 year appear to reach comparable CD4 cell levels within approximately 6 months of stopping treatment as those still untreated. Our findings indicate that prolonged cART for more than 1 year may lead to a CD4 cell count benefit compared with a strategy of deferred cART. However, whether this initial benefit persists over several years remains to be seen as longer follow-up time is needed.
Third, the large number of different drug combinations used in this population makes comparison difficult. A total of 64 treatment combinations were used by the 147 individuals who initiated treatment early and subsequently stopped therapy. The most common combinations were zidovudine, lamivudine and boosted lopinavir (25, 10.6%) and zidovudine, lamivudine and nevirarpine (20, 8.5%). Of note, for 73 individuals (49.7%), the first regimen contained a nonboosted protease inhibitor. This explains in part the seeming discrepancy with our earlier finding of significantly improved CD4 cell slope for individuals treated for 12 weeks at one clinical center where no patient received a nonboosted protease inhibitor . In general, when interpreting the results of our study, one should take into account that it partly includes individuals who started therapy during the early years of cART and that therapies which became available in later years, particularly after 1999, are better at maximizing patient outcomes and reducing therapeutic failures. When we reanalyzed CD4 cell count data, restricting the study population to those who seroconverted on or after 1999, we observed a slightly better discrimination between treatment groups (data not shown), which is probably an indication that we may have underestimated any beneficial effects of transient therapy less than 12-month duration.
Finally, levels of adherence may differ among study populations, though this is generally not reported.
When we accounted for the total time spent on cART, individuals in the ‘early’ group compared with the ‘deferred’ group were twice as likely to reinitiate cART and tended to reinitiate it at higher median CD4 cell count. The reason for this is not clear, in particular, when we consider that the rates of clinical events and CD4 cell loss during the cART-free period were similar in both groups. It maybe that, for clinicians and patients, once the decision is made to begin treatment in primary infection, an aggressive approach is taken to subsequent management.
As with all observational studies, there are a number of limitations to consider. First, we do not have information on the reasons for initiation of therapy during PHI or for stopping it. Patients with seroconversion illness are overrepresented in the ‘early’ group and, given that they will have, in general, worse prognosis compared to those without it, this imbalance could have resulted in diluting the potential beneficial effect of early treatment. However, results from separate analysis for participants without symptoms of seroconversion illnesses were consistent with those reported in the main analysis; thus, do not support this hypothesis. On the contrary, results from the analysis of individuals with symptoms of seroconversion illnesses showed that, while those who deferred treatment had a similar rate of CD4 cell decline to those who received ‘early’ transient cART, they had constantly lower CD4 cell count levels. This finding is consistent with the current treatment guidelines that suggest that early therapy should be considered in cases with symptoms of acute retroviral syndrome .
Second, interlaboratory variability in HIV-RNA and CD4 T-cell quantification and the lower frequency of those two measurements among the ‘deferred treatment’ group may have diluted differences between the early treated and deferred groups.
Finally, our negative findings regarding differences in HIV-RNA set point and long-term CD4 cell count evolution between those treated for less than 12 months and those who deferred treatment should be judged considering also the higher non-AIDS death rates among the deferred group and the higher AIDS rates observed following treatment cessation compared with rates during the transient cART period among ‘early treated’ groups.
In conclusion, in the absence of randomized evidence, and awaiting the results from the Short Pulse HIV Anti Retroviral Treatment at Sero Conversion (SPARTAC) trial (http://www.ctu.mrc.ac.uk/studies/spartac.asp), uncertainty in relation to the long-term clinical benefit of early treatment of early HIV infection persists. Evidence from our data suggests that higher CD4 cell gains may result when early treatment is maintained for at least 12 months. Continued careful monitoring of such individuals, however, will be crucial while on treatment and once it is stopped.
CASCADE has been funded through grants from the European Union BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708 and LSHP-CT-2006-018949.
There are no conflicts of interest.
Author contributions: N.P. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Statistical expertise: N.P. and G.T., supervised by G.T., N.P., G.T., P.V., J.G., H.C.B., K.P. were responsible for study concept and design. Analysis and interpretation of data undertaken by N.P., G.T., K.P., who also drafted manuscript with critical revision for important intellectual content undertaken by P.V., J.G., H.C.B.
CASCADE Collaboration consists of the following members:
Steering Committee: Julia Del Amo (Chair), Laurence Meyer (Vice Chair), Heiner C. Bucher, Geneviève Chêne, Deenan Pillay, Maria Prins, Magda Rosinska, Caroline Sabin, Giota Touloumi. Coordinating Centre: Kholoud Porter (Project Leader), Sara Lodi, Sarah Walker, Abdel Babiker, Janet Darbyshire. Clinical Advisory Board: Heiner Bucher, Andrea de Luca, Martin Fisher, Roberto Muga.
Collaborators: Australia, Sydney: AIDS Prospective Study and Sydney Primary HIV Infection cohort (John Kaldor, Tony Kelleher, Tim Ramacciotti, Linda Gelgor, David Cooper, Don Smith); Canada, South Alberta clinic (John Gill); Denmark, Copenhagen: HIV Seroconverter Cohort (Louise Bruun Jørgensen, Claus Nielsen, Court Pedersen); Estonia, Tartu Ülikool (Irja Lutsar); France, Aquitaine cohort (Geneviève Chêne, Francois Dabis, Rodolphe Thiebaut, Bernard Masquelier), French Hospital Database (Dominique Costagliola, Marguerite Guiguet), Lyon Primary Infection cohort (Philippe Vanhems), SEROCO cohort (Laurence Meyer, Faroudy Boufassa); Germany, German cohort (Osamah Hamouda, Claudia Kucherer); Greece, Greek Haemophilia cohort (Giota Touloumi, Nikos Pantazis, Angelos Hatzakis, Dimitrios Paraskevis, Anastasia Karafoulidou); Italy, Italian Seroconversion Study (Giovanni Rezza, Maria Dorrucci, Benedetta Longo, Claudia Balotta); Netherlands, Amsterdam: Cohort Studies among homosexual men and drug users (Maria Prins, Liselotte van Asten, Akke van der Bij, Ronald Geskus, Roel Coutinho); Norway, Oslo and Ulleval Hospital cohorts (Mette Sannes, Oddbjorn Brubakk, Anne Eskild, Johan N Bruun); Poland, National Institute of Hygiene (Magdalena Rosinska); Portugal, Universidade Nova de Lisboa (Ricardo Camacho); Russia, Pasteur Institute (Tatyana Smolskaya); Spain, Badalona IDU hospital cohort (Roberto Muga), Barcelona IDU Cohort (Patricia Garcia de Olalla), Madrid cohort (Julia Del Amo, Jorge del Romero), Valencia IDU cohort (Santiago Pérez-Hoyos, Ildefonso Hernandez Aguado); Switzerland, Swiss HIV Cohort Study (Heiner C. Bucher, Martin Rickenbach, Patrick Francioli); Ukraine, Perinatal Prevention of AIDS Initiative (Ruslan Malyuta); United Kingdom, Edinburgh Hospital cohort (Ray Brettle), Health Protection Agency (Valerie Delpech, Sam Lattimore, Gary Murphy, John Parry, Noel Gill), Royal Free haemophilia cohort (Caroline Sabin, Christine Lee), UK Register of HIV Seroconverters (Kholoud Porter, Anne Johnson, Andrew Phillips, Abdel Babiker, Janet Darbyshire, Valerie Delpech), University College London (Deenan Pillay), University of Oxford (Harold Jaffe).
1. Markowitz M, Vesanen M, Tenner-Racz K. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis 1999; 179:527–537.
2. Carcelain G, Blanc C, Leibowitch J, Mariot P, Mathez D, Schneider V, et al
. T cell changes after combined nucleoside analogue therapy in HIV primary infection. AIDS 1999; 13:1077–1081.
3. Yerly S, Kaiser L, Perneger TV, Cone RW, Opravil M, Chave JP, et al
. Time of initiation of antiretroviral therapy: impact on HIV-1 viraemia. AIDS 2000; 14:243–249.
4. Smith DM, Berrey MM, Robertson M, Mehrotra D, Markowitz M, Perrin L, et al
. Virological and immunological effects of combination antiretroviral therapy with zidovudine, lamivudine, and indinavir during primary human immunodeficiency virus type 1 infection. J Infect Dis 2000; 182:950–954.
5. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al
. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337:734–739.
6. Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, et al
. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 1998; 351:543–549.
7. Oxenius A, Price DA, Easterbrook PJ, O'Callaghan CA, Kelleher AD, Whelan JA, et al
. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8(+) and CD4(+) T lymphocytes. Proc Natl Acad Sci U S A 2000; 97:3382–3387.
8. Altfeld M, Rosenberg ES, Shankarappa R, Mukherjee JS, Hecht FM, Eldridge RL, et al
. Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med 2001; 193:169–180.
9. Berrey MM, Schacker T, Collier AC, Shea T, Brodie SJ, Mayers D, et al
. Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS. J Infect Dis 2001; 183:1466–1475.
10. Hoen B, Dumon B, Harzic M, Venet A, Dubeaux B, Lascoux C, et al
. Highly active antiretroviral treatment initiated early in the course of symptomatic primary HIV-1 infection: results of the ANRS 053 trial. J Infect Dis 1999; 180:1342–1346.
11. 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.
12. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, et al
. Vigorous HIV-1-specific CD4(+) T cell responses associated with control of viremia. Science 1997; 278:1447–1450.
13. Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995; 333:450–451.
15. Clumeck N, EACS Euroguidelines Grp. European guidelines for the clinical management and treatment of HIV-infected adults in Europe. AIDS 2003; 17(Suppl 2):3–26.
16. Desquilbet L, Goujard C, Rouzioux C, Sinet M, Deveau C, Chaix ML, et al
. Does transient HAART during primary HIV-1 infection lower the virological set-point? AIDS 2004; 18:2361–2369.
17. Markowitz M, Jin X, Hurley A, Simon V, Ramratnam B, Louie M, et al
. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis 2002; 186:634–643.
18. Bassetti S, Battegay M, Furrer H, Rickenbach M, Flepp M, Kaiser L, et al
. Why is highly active antiretroviral therapy (HAART) not prescribed or discontinued? J Acquir Immune Defic Syndr 1999; 21:114–119.
19. Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al
. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12:F51–F58.
20. Saint-Marc T, Partisani M, Poizot-Martin I, Rouviere O, Bruno F, Avellaneda R, et al
. Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 2000; 14:37–49.
21. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy – a 5-year cohort study. Arch Intern Med 2000; 160:2050–2056.
22. Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al
. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133:21–30.
23. Smith DE, Walker BD, Cooper DA, Rosenberg ES, Kaldor JA. Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence? AIDS 2004; 18:709–718.
24. Fidler S, Oxenius A, Brady M, Clarke J, Cropley I, Babiker A, et al
. Virological and immunological effects of short-course antiretroviral therapy in primary HIV infection. AIDS 2002; 16:2049–2054.
25. Bhaduri S, Miller AR. Response to ‘Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence’ by Smith et al
. AIDS 2004; 18:2448.
26. CASCADE Collaboration. Changes in the uptake of antiretroviral therapy and survival in people with known duration of HIV infection in Europe: results from CASCADE.HIV Med
27. Diggle PJ, Liang KY, Zeger SL. Analysis of longitudinal data. Oxford: Oxford University Press; 1994.
28. Vittinghoff E, Malani HM, Jewell NP. Estimating patterns of CD4 lymphocyte decline using data from a prevalent cohort of HIV-1 infected individuals. Stat Med 1994; 13:1101–1118.
29. 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.
30. Phillips AN, Lee CA, Elford J, Janossy G, Kernoff PB. The cumulative risk of AIDS as the CD4 lymphocyte count declines. J Acquir Immune Defic Syndr 1992; 5:148–152.
31. Miettinen OS. The need for randomization in the study of intended effects. Stat Med 1983; 2:267–271.
32. Clements M, Law M, Pedersen C, Kaldor J, CASCADE Collaboration. Estimating the effect of antiretroviral treatment during HIV seroconversion: impact of confounding in observational data. HIV Med 2003; 4:332–337.
33. Touloumi G, Hatzakis A. Natural history of HIV-1 infection. Clin Dermatol 2000; 18:389–399.
34. 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.
35. Fidler S, Fox J, Touloumi G, Pantazis N, Porter K, Babiker A, et al
. Slower CD4 cell decline following cessation of a 3 month course of HAART in primary HIV infection: findings from an observational cohort. AIDS 2007; 21:1283–1291.
Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
CD4 cell loss; primary HIV infection; short-course ART; viral set point