The covariates indicating the current duration of time spent with a viral load >10,000 copies/mL while patients were treated with HAART showed a weak association with the risk of CP. A longer time spent with a viral load of 0 to 500 copies/mL (RR = 0.63, 95% CI: 0.51 to 0.77; P = 0.0001; see Fig. 2B) or even with a viral load of 501 to 10,000 copies/mL (RR = 0.60, 95% CI: 0.39 to 0.93; P = 0.02) was associated with a reduced risk of CP.
As to the adjusted RRs associated with viral suppression compared with the set point, there was evidence for an increased risk of progression in patients with a current suppression between >0 and 1.5 log10 copies/mL (RR = 2.34, 95% CI:1.16 to 4.74; P = 0.02) and in those with no suppression or a viral load higher than their set point (RR = 2.39, 95% CI:1.17 to 4.89; P = 0.02; see Fig. 3A) compared with those with suppression >3 log10 copies/mL. Again, we found strong evidence for the existence of a linear trend when we fit the variable as an ordinal (RR = 1.52 per unit higher, 95% CI: 1.20 to 1.92; P = 0.0005). Longer duration on HAART with a viral load suppressed to less than the set point seemed to confer protection against AIDS and HIV-related death (35% reduction in risk per year longer on average; see Fig. 3B).
Other factors associated with the risk of CP in this analysis were the CD4 nadir (RR = 0.81 per 100 cells/μL higher, 95% CI: 0.71 to 0.92; P = 0.002) and CDC stage (RR = 1.64 for stage B vs. stage A, 95% CI: 1.04 to 2.58; P = 0.03 and RR = 2.59 for stage C vs. stage A, 95% CI: 1.58 to 4.25; P = 0.0002).
When we repeated the analysis after having excluded events and person-years of patients for whom the viral load had been measured less than twice per year, the results were similar. The overall rate of CP was slightly lower than the estimate of the main analysis: 88 events during 9125 PYFU (9.6 per 1000 PYFU, 95% CI: 7.7 to 11.9). The results for the comparisons of interest were similar, however: the RR per year spent on HAART with a viral load >100,000 copies/mL was 1.81 (95% CI: 0.95 to 3.46), and it was 0.69 (95% CI: 0.34 to 1.40) for time on a viral load of 10,001 to 100,000 copies/mL, whereas this risk was significantly <1 for the other viral load strata (RR = 0.37, 95% CI: 0.18 to 0.79 for time on a viral load of 501-10,000 copies/mL and RR = 0.51, 95% CI: 0.38 to 0.67 for time on a viral load suppressed to less than 500 copies/mL). Similarly, any time spent with a viral load suppressed lower than the set point seemed to confer clinical benefit (RR = 0.51, 95% CI: 0.34 to 0.76 per year longer with a suppression >3 log copies/mL; RR = 0.56, 95% CI: 0.39 to 0.81 per year longer with a suppression of 1.5-3.0 log copies/mL; and RR = 0.49, 95% CI: 0.28 to 0.85 per year longer with a suppression of 0-1.5 log copies/mL).
Drug Resistance Analysis
Only 2357 PYFU of the total 11,447 PYFU (20.6%) over the period starting from the dates of the first available genotypic test to the date of last clinical follow-up were used in this subanalysis. It should be noted that, as expected, patients with a genotypic test were more likely to be patients who had experienced virologic failure. Patients with a genotypic test were not different from those who did not have a genotypic test with respect to a number of general characteristics, however: female gender (26.3% vs. 29.4%; P = 0.14), age (median: 36 vs. 35 years; P = 0.94), and mode of HIV transmission (injection drug user [IDU]: 31.9% vs. 35.8%, homosexual: 23.9% vs. 19.7%, and heterosexual: 38.0% vs. 37.8%; P = 0.11).
We found that there was no evidence of accumulation of resistance for 1487 PYFU (63.1%) and that there was evidence of accumulation of resistance to 1 drug class for 501 PYFU (21.3%), to 2 drug classes for 315 PYFU (13.4%), and to all 3 drug classes for 53 PYFU (2.3%). These proportions were similar across groups stratified by the current viral load level; however, a significantly higher proportion of PYFU spent with resistance to 3 drug classes was in the stratum of >100,000 copies/mL (10.1% vs. average of 3.2%; P = 0.0001).
In our analysis, 9.9% of the total person-years of therapy with HAART (1130 of 8778 PYFU) were spent with moderate viremia (between 501 and 10,000 copies/mL). We found no evidence that a longer duration of time with such moderate viremia was associated with a higher risk of subsequent CP, however.
Current guidelines recommend a switch of therapy as soon as virologic failure is confirmed, and complete viral suppression remains the ultimate goal of therapy, especially in antiretroviral-naive people.1 If it is possible to construct a new regimen that is potent virologically (eg, contains ≥3 active drugs) and is expected to be easily accepted by the patient, this is certainly the recommended strategy. This is not always possible, however; some patients have limited options because they carry a multiresistant virus or are intolerant to specific drugs.
Our study and several other reports4-7 offer different arguments in favor of keeping patients on failing regimens and delaying the switch to when more active drugs are available. First of all, CD4 cells may remain stable or even increase in some patients taking HAART despite the persistence of low but detectable viremia4,5,14,15 as long as the viral load is suppressed to less than the natural set point6 or despite a rebound after an initial virologic response.16,17 A viral load rise in patients with a sustained virologic failure between 1000 and 10,000 copies/mL and continuing the same failing HAART was estimated to be only 0.024 log10 copies/mL per month, with little impact on the slope of the CD4 count.6 The maintenance of a stable CD4 count is important, because in patients without complete virologic suppression when taking HAART, the risk of CP is strongly correlated to this marker.14 In a recently published article, Deeks et al8 observed a complex, curvilinear, bell-shaped association between the steady-state viral load and the frequency of virus-specific CD4+ T cells (as assessed by measurement of levels of Gag-specific CD4+ T-cell responses); only at high levels of viremia (>3.3 log10 copies of RNA per milliliter) was an increase in the level of viral replication associated with a decrease in the HIV-specific CD4+ T-cell response.
The preservation of a stable CD4 count or of a low risk of CP despite persistent HIV viremia may be attributable to different mechanisms, including diminished fitness of mutant viruses potentially associated with a decreased cytopathic effect,8,18 inability of mutant strains of HIV to replicate in the human thymus,19 decreased T-cell apoptosis,20 and stimulation of HIV-specific CD8 T cells by exposure to HIV antigens.21
Even though the relation between viral replication and immune reconstitution is probably linked in a complicated and nonlinear manner, it may be possible to hypothesize that if a patient's viral load is kept below a certain threshold, there would potentially only be the risk of drug resistance accumulation without an immediate increase in CP. In a study by Deeks at al,4 there was no decline in CD4 count in people who failed to maintain undetectable HIV viremia; rather, it remained less than 30,000 copies/mL. Le Moing et al17 identified an HIV viremia threshold of 5000 to 10,000 copies/mL, below which the risk of immunologic failure is not significantly increased. In a large intercohort analysis in people who had experienced 3-class virologic failure and continue to take HAART,7 viremia less than 10,000 copies/mL or suppression at least 1.5 log copies/mL less than the pretherapy value was not associated with a decline in CD4 cell count.
Our study focused not only on the association between the current viral load (or viral load suppression relative to the set point) and CP but on that between the duration of time spent in these viral load categories and progression. A longer time spent with a viral load between 501 and 100,000 copies/mL does not seem to be detrimental to the future clinical prognosis of our patients. Only a longer time spent with a viral load >100,000 copies/mL seemed to be associated with an increase in the risk of future CP, although the risk was not statistically significant (22% increase in risk per year longer, P = 0.25). When we looked at the current viral suppression relative to patient's natural set point to identify a threshold that could be useful for patients who have a viral load measured before ART initiation or while off therapy, however, we found that those who currently had viral suppression less than 1.5 log10 relative to the set point tended to have an increased risk of CP compared with those with viral suppression >1.5 log10 (see Fig. 3A). This result is in agreement with the result of another study,7 and it suggests that the 1.5-log suppression may be a crucial threshold. Interestingly, however, as long as suppression below the set point was achieved, a longer time spent with such suppression (whatever the level) was associated with a clinical benefit.
The present study has several limitations. First, the median of follow-up was only 3.8 years. It is possible that a higher rate of CP associated with the duration of time spent with a viral load ranging between 501 and 100,000 copies/mL may become apparent with longer follow-up.
Second, only limited data on the accumulation of drug resistance mutations over time were available. Thus, based on this study, it is difficult to assess how much damage in terms of the rate of accumulated resistance has been created by keeping patients on failing therapy. Under the pressure of a failing regimen, the probability of accumulating drug resistance mutations is high,22-24 especially at low but detectable viremia,15,25 even though this may partially be in the patient's favor if the accumulated mutational pattern is associated with a reduction in HIV replicative capacity. For example, the selection of 184V seems to resensitize HIV partially to thymidine analogues.26 In a large cohort study on the survival of HIV-infected people, the prevalence of multidrug resistance was relatively low, indicating that the exhaustion of treatment options because of drug resistance was not a significant contributor to mortality.27
Conversely, it has been shown that the replicative capacity of PI-resistant variants may be restored over time by the acquisition of compensatory mutations.28 Moreover, the stable number of CD4 cells observed in people with low but detectable viremia may provide a larger pool of susceptible cells reinforcing a detectable burst of viral replication (“predator/prey” phenomenon).29 Then, it would be interesting to know from future studies whether specific patterns of mutations that confer reduced replicative capacity are associated with slower increase of viral load.
Third, we cannot exclude the possibility that our data could be influenced by a large variability in adherence to HIV therapy guidelines and by an awareness of the consequences of moderate viremia by clinicians managing patients at the different sites. Furthermore, there may be specific reasons why clinicians and/or patients decide to delay a therapy switch that are not entirely captured by our analysis. The reasons for deferring a therapy switch in different settings should be further investigated, possibly in a separate study.
Virologic suppression to less than 50 copies/mL is not always achieved in patients treated with HAART. Even if we did not find, in the short term, an excess of risk of CP in patients who retained a viral load between 501 and 100,000 copies/mL for a longer period or with viral suppression not greater than 1.5 log10 compared with the viral set point, on the basis of this finding alone, we cannot recommend a deferred therapy switch in people with virologic failure.
In case of virologic failure, when at least 3 active antiretroviral drugs are still available, switching therapy should be considered the main strategy.
Only prospective clinical trials that randomize multidrug-experienced patients with virologic failure and few remaining options to an immediate or delayed therapy switch may help to determine the feasibility of this “drug conservation” strategy. In patients who have exhausted all treatment options, continuing a virologically failing therapy rather than waiting for the availability of new therapeutic options seems to be a better strategy than interrupting. Indeed, it has been shown that therapy interruption is associated with a high immediate risk of CP,30 whereas continued therapy, especially with a PI, seems to be associated with protection against opportunistic infections over and above that conferred by the increase in CD4 count and decrease in viral load alone.9 Moreover, Deeks et al31 have shown that in patients with detectable viremia, an immunologic deterioration may occur but only after a prolonged period (3 years).
In conclusion, virologic failure to antiretroviral drugs is common even in patients starting HAART when they are antiretroviral naive. Current treatment guidelines, mainly because of the risk of drug resistance accumulation in patients receiving virologically failing regimens, recommend that treatment should be modified shortly after virologic failure. This seems to be the best available strategy in patients who are likely to achieve viral suppression. Nevertheless, our data suggest that in patients who are kept on nonfully suppressive regimens, the risk of subsequent CP may remain low despite a low but detectable level of HIV viremia. These data need to be re-evaluated at a later stage when a longer follow-up interval is available to confirm whether a longer duration of time with a viral load ranging between 501 and 100,000 copies/mL is still not associated with a remarkable increase in the risk of CP. Further studies, possibly with a longer follow-up interval than ours and a larger number of events, are warranted.
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8. Deeks SG, Martin JN, Sinclair E, et al. Strong cell-mediated immune responses are associated with the maintenance of low-level viremia in antiretroviral-treated individuals with drug-resistant human immunodeficiency virus type 1. J Infect Dis
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11. d'Arminio Monforte A, Cozzi Lepri A, Rezza G, et al. Insight into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve patients. AIDS
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Members of the ICONA Study Group
Ancona: M. Montroni, G. Scalise, M. C. Braschi, and M. S. Del Prete; Aviano (PN): U. Tirelli and R. Cinelli; Bari: G. Pastore, N. Ladisa, and G. Minafra; Bergamo: F. Suter and C. Arici; Bologna: F. Chiodo, V. Colangeli, C. Fiorini, and O. Coronado; Brescia: G. Carosi, G. P. Cadeo, C. Torti, C. Minardi, and D. Bertelli; Busto Arsizio: G. Rizzardini and G, Migliorino; Cagliari: P. E. Manconi and P. Piano; Catanzaro: T. Ferraro and A. Scerbo; Chieti: E. Pizzigallo and M. D'Alessandro; Como: D. Santoro and L. Pusterla; Cremona: G. Carnevale and D. Galloni; Cuggiono: P. Viganò and M. Mena; Ferrara: F. Ghinelli and L. Sighinolfi; Firenze: F. Leoncini, F. Mazzotta, M. Pozzi, and S. Lo Caputo; Foggia: G. Angarano, B. Grisorio, A. Saracino, and S. Ferrara; Galatina (LE): P. Grima and P. Tundo; Genova: G. Pagano, G. Cassola, A. Alessandrini, and R. Piscopo; Grosseto: M. Toti and S. Chigiotti; Latina: F. Soscia and L. Tacconi. Lecco: A. Orani and P. Perini; Lucca: A. Scasso and A. Vincenti; Macerata: F. Chiodera and P. Castelli; Mantova: A. Scalzini and G. Fibbia; Milano: M. Moroni, A. Lazzarin, A. Cargnel, G. M. Vigevani, L. Caggese, A. d'Arminio Monforte, D. Repetto, R. Novati, A. Galli, S. Merli, C. Pastecchia, and M. C. Moioli; Modena: R. Esposito and C. Mussini; Napoli: N. Abrescia, A. Chirianni, C. M. Izzo, M. Piazza, M. De Marco, R. Viglietti, E. Manzillo, and M. Graf; Palermo: A. Colomba, V. Abbadessa, T. Prestileo, and S. Mancuso; Parma: C. Ferrari and P. Pizzaferri; Pavia: G. Filice, L. Minoli, R. Bruno, and S. Novati; Perugia: F. Baldelli and M. Tinca; Pesaro: E. Petrelli and A. Cioppi; Piacenza: F. Alberici and A. Ruggieri; Pisa: F. Menichetti and C. Martinelli; Potenza: C. De Stefano and A. La Gala; Ravenna: G. Ballardini and E. Briganti; Reggio Emilia: G. Magnani and M. A. Ursitti; Rimini: M. Arlotti and P. Ortolani; Roma: R. Cauda, F. Dianzani, G. Ippolito, A. Antinori, G. Antonucci, S. D'Elia, P. Narciso, N. Petrosillo, V. Vullo, A. De Luca, S. Di Giambenedetti, M. Zaccarelli, R. Acinapura, P. De Longis, M. Ciardi, G. D'Offizi, M. P. Trotta, P. Noto, M. Lichtner, M. R. Capobianchi, E. Girardi, P. Pezzotti, and G. Rezza; Sassari: M. S. Mura and M. Mannazzu; Taranto: F. Resta and K. Loso; Torino: P. Caramello, A. Sinicco, M. L. Soranzo, G. Orofino, M. Sciandra, and M. Bonasso; Varese: P. A. Grossi and C. Basilico; Verbania: A. Poggio and G. Bottari; Venezia: E. Raise and S. Pasquinucci; and Vicenza: F. De Lalla and G. Tositti
London: A. Cozzi Lepri
Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
detectable viremia; virologic failure; highly active antiretroviral therapy; clinical progression; viral load set point