The increasingly widespread use of combination antiretroviral therapy (cART) since 1996 has substantially improved the prognosis of HIV-infected patients who have access to these drugs [1–4]. Despite this improvement in HIV treatment, some patients discontinue their clinical follow-up [5,6]. Several recent studies have analyzed the factors associated with loss to follow-up (LTFU) [7–11], but, to our knowledge, no study has assessed outcomes in patients who are lost to follow-up. The aims of this study were to evaluate the characteristics of patients who returned to care after LTFU and to estimate their risk of death compared with patients who attended clinic regularly.
In a recent study, we estimated the incidence of and risk factors for LTFU in 1007 HIV-infected patients in five clinical centres in the Nord Pas-de-Calais region of France, from January 1997 to December 2006 . Overall, 135 patients (13.4%) were lost to follow-up during the study period  and the incidence of LTFU was 3.5 per 100 person-years. Patients were considered to be lost to follow-up if: they did not show upto their clinic for at least 12 months; they were not known to be under the care of a physician or at any other hospital during this period; and they were not known to have died within 12 months of their last visit .
In the current study, we first determined the proportion of patients who returned to care after LTFU. Next, we assessed the risk of death associated with returning to care after varying durations of LTFU, compared with regular clinic attendance, by determining the time to death since first presentation to care. We assessed this association using the Kaplan–Meier method with the Log rank test. Using a multivariate Cox  proportional hazard model, we adjusted the risk of death by duration of LTFU, CD4 cell count and the presence or absence of AIDS-defining events at enrollment.
Among the 135 patients who were lost to follow-up, 74 (54.8%) returned to care after missing more than 1 year of appointments and 61 (45.2%) permanently interrupted care. At enrollment, the characteristics of patients who returned to care after LTFU vs. patients who attended clinic regularly were: median age, 31 years [interquartile range (IQR) = 27–38] vs. 35 years (IQR = 28–43) (P < 0.01); men, 45 (60.8%) vs. 620 (71.1%) (P = 0.06); heterosexuals, 43 (58.1%) vs. 442 (51.3%) (P = 0.26); intravenous drug users, 9 (12.2%) vs. 22 (2.6%) (P < 0.0001); sub-Saharan African origin, 21 (28.4%) vs. 177 (20.3%) (P = 0.11); AIDS-defining illness at enrollment, 8 (10.8%) vs. 156 (19.9%) (P = 0.01); and median CD4 cell count at enrollment, 369/mm3 (IQR = 236–577) vs. 334/mm3 (IQR = 155–531) (P = 0.048).
Of the 74 patients who returned to care after LTFU, the median duration of LTFU was 19 months (IQR = 15–27). The median CD4 count at the time of LTFU was significantly higher than at the time of return [401/mm3 (IQR = 324–649) vs. 305/mm3 (IQR = 172–536), P < 0.0001]. Similarly, the proportion of patients with AIDS-defining events was significantly lower at the time of LTFU than at the time of return to care [8 (10.8%) vs. 20 (27.0%), P < 0.001].
The five most frequent AIDS-defining events with which patients presented to care after LTFU were: Pneumocystis jiroveci pneumonia (n = 7; 35%), bacterial pneumonia (n = 3; 15%), cytomegalovirus (CMV)-related infection (n = 3; 15%), cerebral toxoplasmosis (n = 2; 10%), and HIV encephalitis (n = 2; 10%). Ten out of 74 patients who returned to care after LTFU (14.3%) were hospitalized within 6 months of their return, for a median duration of 23 days (IQR = 12–52). Six of these patients (8.1%) died, compared with 40 of the 872 (4.6%) patients who attended clinic regularly.
When we adjusted for CD4 cell count and AIDS-defining events at enrollment, patients who returned to care after LTFU were 5.14 times more likely to die than patients who attended clinic regularly (95% confidence interval = 2.11–12.54) (Fig. 1). The causes of death among patients who returned to care after LTFU were: multiple opportunistic infections (pneumocystosis, esophageal candidiasis, CMV infection) in four patients, cerebral toxoplasmosis in one patient and mandibular malignancy in one patient.
The incidence of LTFU in our study was comparable to that reported by Mocroft et al.  in the Eurosida cohort. Few studies have estimated the proportion of HIV-infected patients who return to care after LTFU. In the study by Mocroft et al. , only 27.1% of patients who were LTFU for more than 1 year returned to care (743/2743 patients), compared with 54.8% (74/135) in our study . We should be cautious when comparing these study results. This discrepancy may be explained by the different settings in which these studies were conducted: Eurosida comprised 93 centres across Europe as well as HIV centres in Eastern Europe and Argentina , whereas our was conducted in a single region of France. In addition, the Eurosida cohort contained precART era patients, whereas ours did not. Finally, since 2002, trained technicians contact all patients who are lost to follow-up in the Nord Pas-de-Calais region to persuade them to return to care, but no such system existed for the Eurosida cohort.
As in other studies [8,13], most of the patients who were lost to follow-up were asymptomatic at the time of LTFU: 47 patients (63.5%) had CD4 cell counts more than 350/mm3 and no history of AIDS-defining events. In contrast, upon return to care, 33 patients (44.6%) had CD4 cell counts less than 200/mm3 and/or AIDS-defining illness. Similar to patients who present to care very late, these patients are more likely to have one or more AIDS-defining illnesses, to be hospitalized as a result of an AIDS-defining event, and to die . Patients who returned to care after LTFU in our study were five times more likely to die than patients who attended clinic regularly. In another study on HIV-infected patients in the 2006 French hospital database, the risk of death in patients with delayed accessed to care (CD4 cell count less than 200/mm3 and/or AIDS at enrollment) was 13 times higher 6 months after enrollment, and five times higher 12 months after enrollment . LTFU may also increase the risk of HIV transmission, as patients who interrupt cART cannot benefit from the favorable effect of antiretroviral drugs on infectiousness . Increased efforts are needed to reduce LTFU and to encourage those patients who no longer attend clinic to return to care.
We acknowledge the assistance to all the participants in the five French Clinical centres in Northern France for data collection. We also thank the Stop-SIDA association for their financial support.
Supported in part by: STOP SIDA association.
Conflict of interest: Yazdan Yazdanpanah has received honorariums for presentation at workshops and consultancy honoraria from Bristol-Myers Squibb, Gilead, Glaxo-SmithKline, Merck, Pfizer, Roche and Tibotec.
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