The incidence of first new WHO stage 4 events or death was increased more than twofold in the STI arm: from nine (2.4/100 person-years) in CT to 24 (6.4/100 person-years) in STI (HR, 2.73; 95% CI, 1.27–5.88; P = 0.007; Table 2 and Fig. 2a). Oesophageal candidiasis was the most frequent first new WHO stage 4 event (STI, 13; CT, 3) followed by extrapulmonary tuberculosis (STI, 4; CT, 1); other new WHO stage 4 events were Pneumocystis jiroveci pneumonia (CT), cryptococcosis (STI) and chronic mucocutaneous herpes simplex (STI). Nine patients died without a confirmed new WHO stage 4 event (STI, 5; CT, 4). There was a trend towards an increased rate of WHO stage 4 events other than oesophageal candidiasis or death (HR, 2.05; 95% CI, 0.77–5.47; P = 0.14).
Similar results were obtained if recurrences of previous events were included in the endpoint (Table 2). Including new and recurrent WHO stage 3 events increased the difference between randomized arms, driven predominantly by differences in oral candidiasis.
In exploratory analyses by subgroups (centre; sex; year, CD4 cell count or age at ART initiation; LCM/CMO; weeks of continuous ART; CD4 cell count or age at STI/CT randomization), there was no evidence of significant heterogeneity in the relative difference between STI and CT, although power was low. There was no evidence of a subgroup favouring the STI arm. There was an excess of new WHO stage 4 events or death in the STI arm in each 12 week period following randomization (heterogeneity P = 0.94), although absolute event rates were higher in the first 12 weeks after randomization [12.0 for STI versus 4.4 for CT; HR, 2.81 (95% CI, 0.89–8.82)] than subsequently [4.6 versus 1.7; HR, 2.64 (95% CI, 0.94–7.40)], possibly reflecting early events in STI participants most at risk.
Hospitalization was required for 46 (11%) STI participants after STI/CT randomization compared with 30 (7%) in the CT arm [exact P = 0.07; median duration 6 days (IQR, 3–14) and 4 days (IQR, 3–6), respectively; rank sum P = 0.16]. On self-reported questionnaire, 172 (43%) in the STI arm and 117 (29%) in the CT arm reported being too sick to work at one or more visits (P < 0.001), and 251 (62%) and 186 (46%), respectively, had visited a healthcare centre (P < 0.001). Although participants made similar numbers of visits to DART clinics in the two arms [STI, median 13 (IQR, 9–16); CT, median 12 (IQR, 9–16); rank-sum P = 0.30), more STI participants saw the doctor (median, 9 doctor visits; IQR, 6–14) than did CT participants (median, 6 (IQR, 4–9) (P < 0.0001; referral reasons not recorded).
CD4 cell count changes
Interrupting ART resulted in rapid and significant declines in CD4 cell count: the mean decrease compared with baseline (STI/CT randomization) was 194, 174 and 165 cells/μl 8 weeks after stopping ART for the first, second and third STI, respectively (Fig. 2b). Eight weeks after restarting ART following the first, second and third STI, there was still a net decrease in CD4 cell count in the STI arm compared with baseline (mean decrease of 70, 81 and 63 cells/μl, respectively). In contrast, after an initial small decline, CD4 cell count increased slightly in the CT arm, likely owing to regression to the mean as eligibility was based on a threshold of ≥ 300 cells/μl (mean increase, 25 cells/μl at 56 weeks after randomization) (global P < 0.001). Around half the STI participants had CD4 cell counts < 200 cells/μl during treatment interruption and approximately 10% had < 100 cells/μl.
There was no difference between the STI and CT arms in time to first serious adverse event (P = 0.78), first new grade 4 adverse event (P = 0.47) or first new grade 3/4 adverse event (P = 0.90; Table 2). The most common grade 3/4 adverse event was neutropenia (Table 3) but only 21 occurrences were grade 4 (STI, 12; CT, 9). However, more ART changes for toxicity occurred in the CT than the STI arm (P = 0.02).
Statistically significant differences between STI and CT arms were observed for changes in haemoglobin, platelets, aspartate aminotransferase and weight after randomization (all global P < 0.0001; Table 4), although mean changes were small and most values remained in the normal range. Haemoglobin was lower in the STI arm during the 12 weeks back on ART (90% participants received Combivir-containing regimens: the rest stavudine/lamivudine). In contrast, platelets and aspartate aminotransferase declined substantially off ART in the STI arm, similarly to CD4 cell counts. There was a mean weight loss of 1.5 kg at the end of the first STI (week 12) compared with gain of 0.1 kg in CT arm (t-test, P < 0.0001): but from the end of the second period back on ART for the STI group (week 48) the difference between the groups had attenuated, with a small mean weight loss in both groups (Table 4). There were smaller differences between groups in neutrophils (global P = 0.03), and no difference in alanine aminotransferase (P = 0.98), creatinine (P = 0.49) or estimated glomerular filtration rate (P = 0.85).
The rationale for investigating ART interruptions during chronic HIV infection is similar in resource-rich and resource-limited settings: if safe, such a strategy could reduce long-term toxicity, costs and treatment fatigue. However, the population of patients treated, disease manifestations and healthcare infrastructure vary greatly between these settings, so approaches evaluated in resource-rich settings cannot necessarily be generalized to all settings. Given the limited access to CD4 cell count monitoring, an STI approach guided by CD4 cell counts will not be feasible in many resource-limited settings. DART, therefore, investigated fixed-duration STI and is the only STI trial to be undertaken in patients also randomized to CMO versus LCM. Review of unblinded data by the Data Safety and Monitoring Committee as well as additional frequent observation of CD4 cell count data in the STI arm by two members of the Trial Steering Committee were instituted as safety measures.
DART is also the largest fixed-period STI trial to be undertaken to date. Other fixed-period STI trials have all had slightly different designs. Two with short cycles off/on ART (7–28 days) were terminated early because of increased resistance [14,15]. The WINDOW trial  randomized 403 patients with HIV-1 RNA < 50 copies/μl and CD4 cell count > 450 cells/μl between CT and a strategy of cycles of 2 months on or off therapy, and found no difference in the proportion with CD4 cell count < 300 cell/μl at 96 weeks. The fixed period STI TRIVACAN trial is the only other study in a resource-limited setting: although the CD4 cell count-driven STI arm was terminated early , the fixed-period STI and CT arms are continuing. Results are awaited with interest, as, compared with DART, participants had higher pre-ART CD4 cell counts and spent less time off therapy in the STI arm (2 months off; 4 months on ART). A number of studies from resource-rich countries have suggested that CD4 cell count-guided interruptions are shorter in those with lower CD4 cell count nadir [17,18], and, therefore, shorter fixed-duration interruptions may be more feasible in patients with low pre-ART CD4 cell count, as in our study (approximately 130 cells/μl), provided that CD4 cell count gains on ART are substantial.
As observed by others [4–7,19], CD4 cell counts in the STI arm fell sharply after stopping ART, although there was some attenuation during later interruptions, possibly because of selection bias if those patients with largest CD4 cell count falls did not interrupt therapy repeatedly. CD4 cell counts rose substantially following ART reinitiation, although we cannot estimate maximum CD4 cell count loss and regain as measurements were taken 8 weeks into each 12 week off/on ART cycle. While our results clearly indicate increased risk of the STI strategy compared with CT in terms of disease progression, it should be noted that over 90% of patients in the STI arm had no WHO stage 3/4 clinical events despite low CD4 cell counts during the interruptions; further, nearly 80% had two or more STI cycles and over 40% had three or four cycles. Although approximately 10% had CD4 cell count < 100 cells/μl during the interruptions, relatively few of these developed WHO stage 3/4 events, and most with clinical events did not experience CD4 cell count decreases to these levels. Whether these patients would have eventually developed clinical events, or whether substantial but very transient CD4 cell count decreases could have been maintained over the longer-term without clinical deterioration remains unknown. In addition, although initial weight loss occurred in the STI arm, differences from the CT arm attenuated over time, a pattern also seen with other laboratory parameters, suggesting that some patients in the STI group were able to tolerate repeated STI cycles. The WHO stage 4 events in the STI arm were mainly oesophageal candidiasis and extrapulmonary tuberculosis; mortality was very similar in both arms. The same WHO stage 4 events, as well as bacterial infections, were the commonest events in the CD4 cell count-guided STI arm of the West African TRIVACAN trial .
Compliance with the randomized strategy was high so that ART exposure was almost 100% in the CT arm compared with 49% in the STI arm, implying significant drug cost savings if such a strategy were successful. Further, there were significantly fewer toxicity-related ART changes in the STI arm. However, these need to be balanced against the increased resource utilization for visits to healthcare personnel and hospital admissions that were reported in the STI arm. Despite staggered stop over 7 days for the NRTI in those receiving nevirapine, the potential for emergence of resistance cannot be excluded, particularly over repeated STI cycles: viral load and genotypes have not been assayed in real-time, although retrospective testing of stored samples would be possible. Increased viral load during treatment interruptions also carries a potential risk for increased HIV transmission, not evaluated in our study.
The largest STI trial to date, the CD4 cell count-driven SMART trial, was stopped early because of a highly statistically significant 2.6-fold relative increase in HIV disease progression in the STI arm , although absolute differences in event rates were small (3.3 versus 1.3 per 100 person-years). As in DART, subgroup analysis could not identify any group that might benefit from this strategy. However, an unexpected finding in SMART was the significant increase in renal, hepatic and cardiac events in the STI arm, postulated to be related to immune activation following viral load rebound. Although we did not observe an excess in such events in DART, these were not specifically sought and other clinical events may have predominated given the lower average CD4 cell counts.
In conclusion, a fixed 12 week off/12 week on ART STI strategy for symptomatic HIV-infected adults initiating ART with low CD4 cell counts in a resource-limited setting, as undertaken in DART, resulted in a greater than twofold risk of disease progression compared with CT and cannot be recommended in this population. Additional data on adherence and patient-reported acceptability, and predictors of response to STI in DART, along with information from completed and ongoing trials in different populations of HIV-infected adults and children may determine whether there are particular populations who could potentially benefit from periods of time off-treatment . In the meantime, all patients in the STI arm in DART have moved to CT and follow-up of the main DART trial, evaluating whether ART can be given safely and successfully in resource-limited settings in the absence of CD4 cell count monitoring and laboratory monitoring for toxicity (unless prompted for clinical reasons), is continuing.
We thank all the participants and staff from all the centres participating in the DART trial.
We particularly acknowledge the contribution of Professor Anne McLaren (Chair of Data Safety Monitoring Committee) who died in July 2007.
Sponsorship: DART is funded by the UK Medical Research Council, the UK Department for International Development (DFID), and the Rockefeller Foundation. GlaxoSmithKline, Gilead and Boehringer-Ingelheim donated first-line drugs for DART.
Analysis and Writing Committee: J. Hakim, D.M. Gibb, A.S. Walker, P. Munderi, C. Kityo, A. Reid, A. Babiker, F. Ssali, A. Kambugu, D. Bray, E. Katabira, P. Muygenyi, H. Grosskurth, C. Gilks, J.H. Darbyshire.
DART Trial Team: A. Latif, J. Hakim, V. Robertson, A. Reid, R. Bulaya-Tembo, C. Chimbetete, A. Jamu, S. Makota, T. Mupudzi, G. Musoro, N. Ngorima, M.J. Pascoe, F. Taziwa, C. Warambwa, E. Chidziva, E. Chigwedere, M. Phiri, L. Chakonza, G. Tinago, H. Chirairo, S. Chitsungo, F. Mapinge, A. Mawora, C. Muvirimi, R. Shoniwa, G.E. Zengeza, J. Chimanzi, J. Machingura, C. Maweni, S. Mutsai, R. Warara, M. Matongo, T. Bafana, N. Mdege, S. Mudzingwa, M. Jangano, I. Machingura, K. Moyo, C. Tsiga, L. Vere, S. Chitsungo, S. Chitongo, K. Manyevere, E. Chivige (University of Zimbabwe, Harare, Zimbabwe); P. Mugyenyi, C. Kityo, D. Tumukunde, F. Ssali, D. Atwine, G. Mulindwa, G. Kabuye, R. Byaruhanga, T. Bakeimyaga-Grace, H. Katabira, E. Nimwesiga, G. Barungi, S. Atwiine, F. Ahimbisibwe, S. Tugume, T. Otim, J. Takubwa, M. Mulindwa, S. Murungi, J. Tukamushaba, D. Muebesa, H. Kyomugisha, J. Kagina, L. Namale (Joint Clinical Research Centre, Kampala, Uganda); H. Grosskurth, P. Munderi, K. Wangati, G. Kabuye, A. Ruberantwari, B. Amuron, D. Nsibambi; R. Kasirye, E. Zalwango, M. Nakazibwe, B. Kikaire, G. Nassuna, R. Massa, M. Aber, M. Namyalo, A. Zalwango, L. Generous, P. Khauka, N. Rutikarayo, W. Nakahima, A. Mugisha, W. Omwony, J. Nakiyingi, S. Muyingo, P. Hughes (MRC Research Unit on AIDS/Uganda Virus Research Institute, Entebbe, Uganda); E. Katabira, J. Oyugi, A. Ronald, A. Kambungu, J. Martin, R. Nalumenya, R. Nairubi, E. Bulume, M. Teopista, C. Twijukye, F. Sematala, H. Byakwaga (Academic Alliance, Mulago Hospital, Uganda); A. Coutinho, B. Etukoit [AIDS Support Organization (TASO), Uganda]; C. Gilks, K. Boocock, C. Puddephatt, D. Winogron (Imperial College); J. Darbyshire, D.M. Gibb, A. Burke, D. Bray, A. Babiker, A.S. Walker, H. Wilkes, M. Rauchenberger, S. Sheehan, L. Peto, K. Taylor (MRC Clinical Trials Unit).
Trial Steering Committee: I. Weller (chair), A. Babiker (trial statistician), S. Bahendeka, M. Bassett, A. Chogo Wapakhabulo, J. Darbyshire, B. Gazzard, C. Gilks, H. Grosskurth, J. Hakim, A. Latif, O. Mugurungi, P. Mugyenyi: Observers S. Jones, E. Loeliger, P. Naidoo, M. Palmer, J. Rooney, J.-M. Steens.
Data and Safety Monitoring Committee: A. McLaren (chair), C. Hill, J. Matenga, A. Pozniak, D. Serwadda
Endpoint Review Committee: T. Peto (chair), A. Palfreeman, M. Borok, E. Katabira, F. Ssali, P. Munderi, A. Reid, D.M. Gibb, H. Bwakaga, D. Winogron.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
Africa; antiretroviral therapy; HIV; randomized controlled trial; treatment interruption