Among the 181 subjects whose CD4 cell counts were higher when HAART was discontinued than when it was initiated, 73 experienced a drop in CD4 cells to pre-HAART levels. The cumulative incidence (95% CI) of CD4 drop to pre-HAART level was 37.0% (30.1%-45.6%) at 12 months after a TI.
The mean (95% CI) rate of HIV-RNA change during the first 3 months of TI was 0.49 (0.42-0.56) log10 copies/(mL·mo), resulting in a mean (95% CI) increase of 1.47 (1.26, 1.68) log10 copies/mL in the first 3 months. The subsequent mean (95% CI) rate of HIV-RNA levels change after the first 3 months was −0.0027 (−0.0115, 0.0062) log10 copies/(mL·mo), confirming descriptive results for relatively stable levels after the initial fast increase during the first 3 months of TI.
From the 125 subjects with undetectable viral load at start of TI, 102 (81.6%) experienced a virological rebound during TI, whereas 19 (15.2%) reinitiated treatment without a virological rebound. Over half (57.6%) of the 236 subjects had an increase of at least 1 log10 in their HIV-RNA levels during the TI, whereas 80 (33.9%) reinitiated ART before the occurrence of such an increase in their viral load levels.
Higher viremia at HAART initiation is associated with increased hazard of having a log10 increase in viral load during TI. However, subjects with relatively high HIV-RNA levels at TI initiation (thus with relative small reductions during HAART) had reduced probabilities to further increase their HIV-RNA levels compared with the rest of the subjects (data not shown). Of the 190 subjects with HIV-RNA levels at TI initiation below those at HAART initiation, 98 (51.6%) increased their viral load to pre-HAART levels in a median time of 14.9 months.
During first stable HAART, patients had been followed-up for 3115 person/y. During this time, 49 patients developed clinical AIDS, and 9 died before developing AIDS, whereas 15 of the 230 with AIDS at HAART initiation experienced a new AIDS event. The 299 persons who interrupted first HAART had been followed-up for 472.8 days during HAART and 242.8 person/y during TI. Eight patients developed clinical AIDS during HAART and 7 during TI, whereas 1 of the 48 patients with AIDS at HAART initiation experienced a new AIDS event during HAART and 2 during TI. The overall incidence rate (95% CI) of any AIDS event was 0.019 (0.010-0.037) during HAART and 0.037 (0.019-0.071) cases per person per year during TI, the difference being nonsignificant (P = 0.158).
In this study, we have found that by 2 years after HAART initiation, 15.9% of the study population had stopped all ART drugs, whereas another 16.3% initiated a new HAART regimen. Similar rates were reported by Monforte et al.18 The relative higher rates of TI found in other studies19,20,29 can be explained by different design such as the inclusion only of women19 or ignoring competing risks because of switching HAART regimen, which is known to lead to overestimated rates for TI as the first event after initiating HAART.26
We found that women had higher probabilities of TI than men among both IDUs and MSW, with the gender difference being similar within both risk groups. A similar finding was reported by Monforte et al.18,30 The reason for this gender difference is unclear. Providing that medical care is adequate, women do respond equally well or even better than men to ART.31,32 However, recent studies reported lower ART adherence rates in women compared with men,33 with this difference being explained mainly by social and behavioral factors. Alternatively, sex differences in drug-related adverse events (reported to be higher in women34) can explain this observed difference in rates of TI. Unfortunately, reasons for TI or adherence rates were not available in our study. The higher rates of TI for IDUs (evident in both men and women) can be explained by poor adherence and/or higher rates of treatment failure.35 Our finding of higher viremia at HAART initiation and poor immunologic response to HAART being associated with increased probabilities of TI are in line with results from other studies.19,20,29 Interestingly, history before HAART initiation (ie, time elapsed since seroconversion or rate of CD4 decline) does not seem to be associated with TI.
Age at HAART initiation, pre-HAART nadir, and CD4 cell count at TI initiation were associated with the relative rate of CD4 loss during TI in this study. Subjects aged above 40 years at HAART initiation, with nadir CD4 cell counts below 200 cells/μL and with CD4 cell count at TI initiation below 350 cells/μL had the steepest CD4 declines. Age has also been identified as a significant determinant in other studies.16,36 It has been reported that CD4 cell count decline is more pronounced among subjects who interrupt HAART because of toxicity or side effects,19 but this finding could not be tested in our study.
Nadir CD4 cell count has been recognized as one of the most important predictors of both rate of CD4 loss and time on TI in several studies.17,21,36,37 An inverse correlation between CD4 gain during therapy and loss during TI has been reported by many researchers.17,22,34,38 This finding has been interpreted as suggesting that CD4 cells gained during HAART are lost much more rapidly than the pretreatment CD4 cells. This is in accordance with pre-HAART nadir CD4 cell count being a significant predictor of CD4 loss during TI. We found that subjects with CD4 cell counts higher than 350 cells/μL at TI initiation had lower relative rates of CD4 decline. Although this finding seems to contradict previous findings,17,22,36,38 it should be emphasized that we report proportional rates of drop, whereas the other studies reported absolute rates of drop. Similar proportional rates of drop are translated to larger absolute drops in subjects with higher initial values.
Although many of our results have been reported in previous studies, the strengths of this analysis are its rigorous adjustment for potential confounding factors, notably, a switch in HAART regimen as a potential "competing risk" for patients currently on their first HAART regimen and patients resuming treatment during a TI. Furthermore, by virtue of its size, we were also able to have reasonable power to look jointly at CD4 at TI, HAART initiation, and nadir, and assess the combined effects of these different parameters, whereas the known infection dates enabled us to asses the pre-HAART history effect.
Treatment interruption was not associated with significantly increased risk for clinical progression in our study. Results from other studies are mixed.10,30,38 Treatment discontinuation though may have other potential negative consequences such as development of drug-resistant mutations. However, it has been found that this problem seems to be rare and mainly in subjects who were on suboptimal therapy before the initiation of HAART39,40 and those on regimens that include drugs with long half-lives such as nevirapine and efavirenz (nonnucleoside reverse transcriptase inhibitors).41
In conclusion, in this large observational study, a substantial and increasing number of subjects interrupt HAART. Discontinuing treatment seems to be safe for subjects with a well-retained immune system. However, subjects above 40 years old, with a pre-HAART CD4 below 200 cells/μL or with limited immune reconstitution during HAART (CD4 at TI below 350 cells/μL), had the greatest proportionate decrease in CD4 cell counts during TI. For such subjects, if TI is considered, caution and close monitoring are essential to ensure that risks are minimal.
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Steering Committee: Valerie Beral, Roel Coutinho, Janet Darbyshire (project leader), Julia Del Amo, Noël Gill (chairman), Christine Lee, Laurence Meyer, Giovanni Rezza.
Coordinating Center: Kholoud Porter (scientific coordinator), Abdel Babiker, Sarah A. Walker, Janet Darbyshire, Krishnan Bhaskaran.
Collaborators: Aquitaine cohort, France: Francois Dabis, Rodolphe Thiébaut, Geneviève Chêne, and Sylvie Lawson-Ayayi; Seropositive cohort, France: Laurence Meyer and Faroudy Boufassa; German cohort, Germany: Osamah Hamouda and Gabriele Poggensee; Italian Seroconversion Study, Italy: Benedetta Longo, Maria Dorrucci, and Giovanni Rezza; Greek Haemophilia cohort, Greece: Giota Touloumi, Angelos Hatzakis, Anastasia Karafoulidou, and Olga Katsarou; Edinburgh Hospital cohort, United Kingdom: Ray Brettle; Madrid cohort, Spain: Julia Del Amo and Jorge del Romero; Amsterdam Cohort Studies among homosexual men and drug users, the Netherlands: Liselotte van Asten, Akke van der Bij, Ronald Geskus, Maria Prins, and Roel Coutinho; Copenhagen cohort, Denmark: Court Pedersen; Valencia IDU cohort, Spain: Ildefonso Hernández Aguado, Santiago Pérez-Hoyos, and Josefina Belda; Oslo and Ulleval Hospital cohorts, Norway: Anne Eskild, Johan N Bruun, and Mette Sannes; Royal Free haemophilia cohort, United Kingdom: Caroline Sabin and Christine Lee; UK Register of HIV Seroconverters, United Kingdom: Anne M. Johnson, Andrew N. Phillips, Abdel Babiker, Janet H Darbyshire, Noël Gill, and Kholoud Porter; Swiss HIV cohort, Switzerland: Patrick Francioli, Philippe Vanhems, Heiner Bucher, and Martin Rickenbach; Sydney AIDS Prospective Study, Australia: David Cooper, John Kaldor; Sydney Primary HIV Infection cohort, Australia: David Cooper, John Kaldor, Tim Ramacciotti, and Don Smith; Badalona IDU hospital cohort, Spain: Roberto Muga and Jordi Tor; Lyon Primary Infection cohort, France: Philippe Vanhems; South Alberta clinic, Canada: John Gill; Barcelona IDU cohort, Spain: Joan Cayla and Patricia Garcia de Olalla; MRC Biostatistics Unit, Cambridge, United Kingdom: Nicholas E Day and Daniela De Angelis.