At 5 years and for the entire study population, the range in the risk of clinical progression from the lowest to the highest category of risk (Table 3) was wider in model 4 than in other models, again indicating that model 4 better discriminates the data than other models. The risk of clinical progression ranged from 7% in patients whose CD4 count at 6 months was ≥350 cells/μL and whose HIV-1 RNA level was <3 log10 to 63% in patients whose CD4 count at 6 months was <100 cells/μL and whose HIV-1 RNA level was ≥5 log10 (model 4), whereas the risk ranged roughly from 10% to 30% in other models.
In the present study, we aimed to determine the importance of the initial immunologic and virologic responses to HAART as a determinant of clinical progression over 5 years in a large cohort of patients with HIV-1 infection who started protease inhibitor-based HAART. Because existing definitions of immunologic and virologic responses vary, we compared different prognostic models that were based on these definitions. We found that the initial response was prognostic of the further clinical outcome at 5 years and that the initial response, defined as CD4 cell count and viral load attained after 6 months of HAART, was most strongly associated with subsequent clinical progression. When considering naive and treatment-experienced patients together according to viral load and CD4 cell count at 6 months, the probability of clinical progression at 5 years ranged from 7% in patients in the lowest risk stratum to 63% in patients in the group at highest risk. Finally, in patients who had previously received antiretroviral therapy but not in treatment-naive patients, the viral load at the time of starting therapy was also of prognostic importance.
We and others in the Antiretroviral Therapy Cohort Collaboration have recently described clinical progression according to initial virologic and immunologic responses in a large sample of treatment-naive patients from different cohort studies.21 We found that baseline CD4 count and viral load were no longer of prognostic relevance once the 6-month values had been taken into account. The present study confirms these results with a longer follow-up in naive patients and demonstrates that prognosis is also affected by plasma HIV-1 RNA at baseline in treatment-experienced patients. This may reflect the impact of mutations conferring resistance to nucleoside reverse transcriptase inhibitors in patients who previously received only an NRTI regimen and not HAART. The prognostic impact of pretreatment viral load in patients pretreated with HAART may be somewhat different, because the number of potentially active antiretroviral drugs left may be lower in patients having received drugs from 2 or 3 of the main antiretroviral classes available. One may assume, however, that the situation of patients pretreated by NRTI dual therapy would be closer to the situation of patients initiating second-line HAART, particularly for patients who had failed a first-line regimen combining 2 NRTIs and 1 NNRTI, who also harbor resistance to NNRTIs. This needs to be verified by further studies.
Our results have important implications for the management of antiretroviral treatment-experienced patients who start HAART. Prognosis depends on the CD4 cell count at 6 months rather than on the number of CD4 cells gained. Baseline and 6-month plasma HIV-1 RNA levels are of prognostic importance. The prognosis of a patient with a viral load of less than 1000 copies/mL at 6 months and a viral load at baseline equal to or greater than 10,000 copies/mL is worse, on average, compared with that of a patient who also reached a viral load of less than 1000 copies/mL but whose baseline viral load was less than 10,000 copies/mL. These results suggest that individuals on monotherapy or dual therapy or patients with a history of such therapy should start HAART before HIV-1 RNA concentrations reach 10,000 copies/mL.
Interestingly, there was no significant difference in clinical outcome between patients whose viral load at 6 months was less than 1000 copies/mL and patients with a viral load greater than 1000 copies/mL but less than 10,000 copies/mL. Clearly, over 5 years of follow-up, even a partial virologic response is beneficial. Findings from the Antiproteases Cohorte (APROCO) cohort suggest that only when viral replication rebounds to more than 10,000 copies/mL does a decrease in the CD4 cell count follow.23 A partial virologic response to HAART could thus be defined as a viral load at 6 months of between 1000 and 10,000 copies/mL.24 In protease inhibitor-treated patients, who have only a few treatment options left because of drug intolerance or resistance, delaying changes to other regimens until the viral load increases to greater than 10,000 copies/mL may thus be reasonable, although there is clearly a risk of selecting mutant resistant viruses.25-27 Some preliminary results28 have shown that in patients with persistent low viremia (<10,000 copies/mL), protease inhibitor mutations were found in less than one third of the patients. It would be of particular interest to compare the rate of viral mutations according to levels of persistent viral replication (<1000 copies/mL vs. 1000-10,000 copies/mL) and the subsequent virologic response if the treatment regimen is modified.
The fact that the CD4 cell response is strongly associated with clinical outcome in treatment-naive and treatment-experienced patients has important implications for clinical trials. The recommendations of the European and American licensing authorities on efficacy endpoints are exclusively based on virologic outcomes at 6 months.7,8 The results from this and other studies21 indicate that immunologic and virologic responses are important when assessing the efficacy of antiretroviral drugs and that both should be considered as independent efficacy endpoints.
Despite the fact that our analyses were based on the intent-to-continue-treatment principle, which ignores modifications or interruptions of HAART during follow-up, the initial response was strongly associated with clinical outcome up to 5 years after initiation of HAART. Maintenance of a durable response is certainly a primary goal of therapy in patients treated with HAART. The association between the 6-month response and the long-term outcome could possibly be driven by the fact that patients who have stronger initial immunologic and virologic responses also have more durable responses.29 Nevertheless, our results indicate that the time at which therapy is started and the nature of the initial regimen should be carefully considered and that the motivation of patients and caregivers should be maximized to ensure the best adherence to therapy possible,30 because the long-term prognosis seems to be highly related to the early success of the first regimen.
The plasma HIV-1 RNA level and CD4 cell count at 6 months should be taken into account independently when assessing the early response of patients to antiretroviral therapy. The persistent impact of an early response on clinical progression at 5 years emphasizes the major importance of success of first-line HAART.
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Clinical Epidemiology Group of the French Hospital Database on HIV
Scientific Committee: E. Billaud, F. Boué, D. Costagliola, X. Duval, C. Duvivier, P. Enel, S. Fournier, J. Gasnault, C. Gaud, J. Gilquin, S. Grabar, M. A. Khuong, J. M. Lang, M. Mary-Krause, S. Matheron, M. C. Meyohas, G. Pialoux, I. Poizot-Martin, C. Pradier, E. Rouveix, D. Salmon-Ceron, A. Sobel, P. Tattevin, H. Tissot-Dupont, and Y. Yasdanpanah
DMI2 coordinating center: French Ministry of Health (E. Aronica, V. Tirard-Fleury, and I. Tortay)
Statistical analysis center: INSERM U720 (S. Abgrall, D. Costagliola, S. Grabar, M. Guiguet, E. Lanoy, H. Leneman, L. Lièvre, M. Mary-Krause, V. Potard, and S. Saidi)
Centres d'Information et de Soiur de l'immunodéficience humaine (CISIH), Paris area: CISIH de Bichat-Claude Bernard (Hôpital Bichat-Claude Bernard: S. Matheron, J. L. Vildé, C. Leport, P. Yeni, E. Bouvet, C. Gaudebout, B. Crickx, C. Picard-Dahan), CISIH de Paris-Center Ouest (Hôpital Européen Georges Pompidou: L. Weiss, D. and Tisne-Dessus; G. H. Tarnier-Cochin: D. Sicard and D. Salmon; Hôpital Saint-Joseph: J. Gilquin and I. Auperin; Hôpital Necker adultes: J. P. Viard and L. Roudière), CISIH de Paris-Sud (Hôpital Antoine Béclère: F. Boué and R. Fior; Hôpital de Bicêtre: J. F. Delfraissy and C. Goujard; Hôpital Henri Mondor: Ph. Lesprit and C. Jung; Hôpital Paul Brousse), CISIH de Paris-Est (Hôpital Saint-Antoine: M. C. Meyohas, J. L. Meynard, O. Picard, and N. Desplanque; Hôpital Tenon: J. Cadranel, C. Mayaud, G. Pialoux, and W. Rozenbaum), CISIH de Pitié-Salpétrière (GH Pitié-Salpétrière: F. Bricaire, C. Katlama, S. Herson, and A. Simon), CISIH de Saint-Louis (Hôpital Saint-Louis: J. M. Decazes, J. M. Molina, J. P. Clauvel, and L. Gerard; GH Lariboisière-Fernand Widal: P. Sellier and M. Diemer), CISIH 92 (Hôpital Ambroise Paré: C. Dupont, H. Berthé, and P. Saïag; Hôpital Louis Mourier: E. Mortier and C. Chandemerle; Hôpital Raymond Poincaré: P. de Truchis), and CISIH 93 (Hôpital Avicenne: M. Bentata and P. Honoré; Hôpital Jean Verdier: S. Tassi and V. Jeantils; Hôpital Delafontaine: D. Mechali and B. Taverne)
CISIH, area outside Paris: CISIH Auvergne-Loire (CHU de Clermont-Ferrand: H. Laurichesse and F. Gourdon; CHRU de Saint-Etienne: F. Lucht and A. Fresard); CISIH de Bourgogne-Franche Comté (CHRU de Besançon; CHRU de Dijon; CH de Belfort: J. P. Faller and P. Eglinger; CHRU de Reims); CISIH de Caen (CHRU de Caen: C. Bazin and R. Verdon), CISIH de Grenoble (CHU de Grenoble), CISIH de Lyon (Hôpital de la Croix-Rousse: D. Peyramond and A. Boibieux; Hôpital Edouard Herriot: J. L. Touraine and J. M. Livrozet; Hôtel-Dieu: C. Trepo and L. Cotte), CISIH de Marseille (Hôpital de la Conception: I. Ravaux and H. Tissot-Dupont; Hôpital Houphouët-Boigny: J. P. Delmont and J. Moreau; Institut Paoli Calmettes: J. A. Gastaut; Hôpital Sainte-Marguerite: I. Poizot-Martin, J. Soubeyrand and F. Retornaz; CHG d'Aix-En-Provence: P. A. Blanc and T. Allegre; Center pénitentiaire des Baumettes: A. Galinier and J. M. Ruiz; CH d'Arles; CH d'Avignon: G. Lepeu; CH de Digne Les Bains: P. Granet-Brunello; CH de Gap: L. Pelissier and J. P. Esterni; CH de Martigues: M. Nezri and R. Cohen-Valensi; CHI de Toulon: A. Laffeuillade and S. Chadapaud), CISIH de Montpellier (CHU de Montpellier: J. Reynes; CHG de Nîmes), CISIH de Nancy (Hôpital de Brabois: T. May, C. Rabaud), CISIH de Nantes (CHRU de Nantes: F. Raffi and E. Billaud), CISIH de Nice (Hôpital Archet 1: C. Pradier and P. Pugliese; CHG Antibes Juan les Pins), CISIH de Rennes (CHU de Rennes: C. Michelet and C. Arvieux), CISIH de Rouen (CHRU de Rouen: F. Caron and F. Borsa-Lebas), CISIH de Strasbourg (CHRU de Strasbourg: J. M. Lang, D. Rey, and P. Fraisse; CH de Mulhouse), CISIH de Toulouse (CHU Purpan: P. Massip, L. Cuzin, E. Arlet-Suau, and M. F. Thiercelin Legrand; Hôpital la Grave; CHU Rangueil), CISIH de Tourcoing-Lille (CH Gustave Dron; CH de Tourcoing: Y. Yasdanpanah), and CISIH de Tours (CHRU de Tours; CHU Trousseau)
CISIH overseas: CISIH de Guadeloupe (CHRU de Pointe-à-Pitre), CISIH de Guyane (CHG de Cayenne: M. Sobesky and R. Pradinaud), CISIH de Martinique (CHRU de Fort-de-France), and CISIH de La Réunion (CHD Félix Guyon: C. Gaud and M. Contant)