Figure 2 shows the Kaplan-Meier estimate of the probability of being anemia free at 1 year after starting the ZDV-based regimen to be about 0.75.
Factors Associated With Incident Anemia
In univariate analysis, age, sex, and duration on d4T-based regimen before switch were not associated with the risk of grades 3-4 anemia. The odds of developing severe anemia within 1 year after the switch were higher in patients with CD4 count less than 200/mm3 at the time of ZDV initiation, in malnourished patients, and in patients on co-trimoxazole prophylaxis at the time of ZDV initiation (Table 4). There was a significant trend of the odds of anemia with decreasing BMI.
All variables used in the univariable analysis were included in a multiple regression model, except for co-trimoxazole prophylaxis. As the program protocol recommended the administration of co-trimoxazole prophylaxis based on CD4 count, we checked for multicollinearity between these 2 variables. The correlation coefficient between co-trimoxazole prophylaxis and CD4 category was found to be 0.75, and it was, therefore, removed from the analysis.
In the multivariable analysis, the odds of severe anemia for patients with less than 200 CD4 cells/mm3 when starting ZDV-based regimen were 2.40 (95% CI 1.19 to 4.87) greater than for those with more than 200 CD4 cells/mm3. Malnutrition, as defined by BMI less than or equal to 18.0 kg/m2, was found to be significantly associated with occurrence of severe anemia (odds ratio = 2.72 CI 1.29 to 5.72) (Table 4).
In an attempt to distinguish anemia induced by ZDV from that related to concomitant diseases, we looked at the clinical events reported within 1 month of the lowest Hb level. Of the 40 patients with grades 3-4 anemia, 4 had an opportunistic infection: 3 pulmonary tuberculoses and 1 severe bacterial pneumonia.
ZDV Discontinuation and Mortality
Within 1 year after the switch, ZDV was stopped in 51 patients (9.8%) of the study population. The overall rate of ZDV discontinuation was 54/461.61 person-years or 11.70/100 person-years (95% CI 8.96 to 15.27). Forty-three patients discontinued ZDV because of intolerance: 38 cases of intolerance were due to anemia, 2 had lactic acidosis, 2 developed myopathy, and 1 developed neutropenia with anemia. Only mild and self-limited cases of gastrointestinal intolerance (nausea and vomiting) were observed. No cases of ZDV-associated gastrointestinal intolerance requiring treatment discontinuation were recorded in our program.
One patient with grade 3 anemia died 91 days after ZDV initiation and 33 days after developing anemia. Mortality rate was therefore 1/40 for patients who developed at least one episode of grade 3 or 4 anemia.
The introduction of the systematic switch resulted in a number of changes in the clinic including: (1) adjustments in drug forecasting and procurement to ensure constant supply of antiretrovirals and reagents for blood tests and blood for transfusions, (2) simplification and rationalization of the flow of patients to absorb the increased patient load coming for the extra consultations, (3) organization of additional, specific counseling sessions for patients undergoing the regimen change, (4) elaboration of patient health educational tools on the d4T- and ZDV-associated adverse events.
For patients previously on HAART for many months and followed up on a 3-monthly basis, the treatment switch represented an increase in scheduled appointments, which disturbed their daily routine. These extra appointments led to increased absenteeism from work and increased transportation costs although the latter costs were mostly covered by nongovernmental organizations. The majority of patients understood the rationale for the treatment change and agreed upon the additional follow-up visits for clinical and laboratory monitoring. However, 207 patients did not accept the switch mainly because of the problems associated with the additional follow-up visits or their physician/counselor concluded that they did not fully understand the rationale of this protocol change.
To our knowledge, this is the first study describing the results of a systematic switch from d4T to ZDV in a large cohort of patients after having received an initial HAART regimen containing d4T for a relatively long time (median time 18 months). The overall survival and the immunological response in this cohort of patients are comparable to other studies in resource-poor settings,2-6 and severe side effects, besides anemia, were relatively uncommon. However, clinically significant anemia and severe anemia requiring a treatment change from ZDV occurred fairly frequently. Although patients generally understood the rationale for switching and agreed to the extra visits to monitor side effects, the perceived burden of extra visits and the consequent work absenteeism were not acceptable for many others.
Regarding anemia, the median time found for development of grades 3-4 anemia was similar to that reported in a comparable setting in Cambodia.12 The low prevalence of diagnosed concomitant infections, at the time of the lowest Hb level, suggests that most cases of anemia detected were related to drug toxicity.
Risk factors for human immunodeficiency virus (HIV)-related anemia reported in the literature include advanced HIV disease, female sex, African origin, low BMI, and older age.17-22 Despite the fact that our study population was relatively young (median age 35), with a median Hb at the time of the switch of 12.8 g/dL, 75% of them had CD4 counts above 200, 81% presented with normal BMI, and only one third of them were on co-trimoxazole prophylaxis at the time of the switch, still an important proportion of them developed anemia. In a prospective study in West Africa on a cohort of 498 HIV-infected patients, an incidence rate of 9.6/100 person-years grades 3-4 anemia was reported.18 Despite the similar rate observed here, their study population was different with respect to co-trimoxazole intake23 (80% had received at baseline versus 33% in our study population) and prior history of HAART treatment.
In our cohort, we observed that the risk of developing severe anemia was related to malnutrition as measured by BMI less than 18 kg/m2 and low CD4 count less than 200/mm3. Although the management of severe anemia requiring blood transfusion can be difficult in finding a blood donor, the mortality rate was very low in our program setting with 1 death.
Given increasing evidence of d4T-associated long-term toxicity, clinicians, program managers, and policy makers want to address this issue, and the switch strategy was developed as a possible solution. There are valid arguments for adopting it. Prescribing a generally well-tolerated d4T-based regimen for a few months before switching to ZDV allows for easier stabilization of the patients. This is particularly important in contexts where many patients have advanced HIV disease before starting HAART. These patients would be at higher risk of developing anemia, and it would be difficult for clinicians to differentiate symptoms of anemia due to ZDV toxicity from those due to HIV-related illnesses.
Although a recent publication suggested that prior HAART experience was protective for development of ZDV-induced anemia,12 the incidence of anemia in our study was comparable to that occurring among populations who were initiated on ZDV,24-26 and the duration on d4T-based regimen before switch was not associated with the occurrence of anemia.
There are several program management concerns regarding a switch strategy. Patient adherence could potentially be challenged. As a change in treatment regimen might result in confusion over pill intake, carefully planned counseling sessions are required and toxicities of drugs have to be discussed with the patient in detail. In addition, as most patients are on d4T-based regimens that called for 3-monthly visits, over many months or years, the intensified follow-up required for clinical and laboratory monitoring became a burden for them. In fact, 207 patients declined the switch, claiming that the foreseen increased absenteeism of work was challenging. Despite this, among patients who accepted the treatment change, we did not experience an increase in missed or delayed appointments. This was probably the result of the additional support given to these patients, including financial support for transportation. Both the additional counseling and increased laboratory monitoring required more clinic appointments, all adding significantly to the workload. This issue has to be considered as a cost of making the switch.
Huffam et al12 showed a relatively high proportion (38%) of patients experiencing a drop in CD4 on at least one occasion after switching from d4T to ZDV, highlighting a possible negative impact from a change in HAART regimen. In our study, 156 (29.8%) patients experienced a drop in CD4 from the time of switch to the end of the observation period. Even though only few patients were diagnosed with virological failure, we cannot exclude that the ZDV switch might have led to a suboptimal CD4 increase and to treatment failures that we could not detect. The limited access to VL testing in our program setting did not allow for systematic VL measurement in patients switched to ZDV and thus did not allow for accurate evaluation of treatment effectiveness. It is one more example of the need for readily available, affordable VL technologies in resource-constrained settings.
Finally, of major concern is the fact that for patients who developed severe anemia and had to be switched to TDF after having received d4T and ZDV, the sequence of future HAART regimens in the event of treatment failure will be difficult.
On the other hand, TDF is a potent and safer alternative to both d4T- and ZDV-based standardized first-line regimens.9 Its use as a core drug in first-line regimen could avoid the problems commonly encountered with other NRTIs. Although laboratory monitoring is required with TDF, associated toxicities are less frequent than those related to d4T and ZDV.27,28 This points to the need to develop low-cost, fixed-dose combinations containing TDF for the future.
The timing of a switch is still in question. In the previous study, patients were switched at 6 months whereas our median switch timing was at 18 months.12 Choosing the optimum timing requires balancing the d4T toxicity avoided by the switch against the increased rate of ZDV-induced anemia and the extra burdens for patients and the programs.
There are some limitations to the study including the fact that it was based on program data and did not allow for measurement of the benefits of avoiding d4T toxicity. Information on concomitant OIs could be incomplete, and a greater proportion of the anemia observed could then be attributed to opportunistic infections than ZDV toxicity. The relatively high number of patients who declined the switch might have influenced the results. We compared selected characteristics between this group and the study population, at different time points (6, 12, and 18 months after HAART initiation) (data not shown). Statistically significant differences found were as follows: a higher CD4 count at month 18, a higher proportion of women, and a lower proportion of patients on efavirenz-based regimen at 6 and 12 months, among patients who accepted the switch. It is likely that the difference in CD4 counts between these 2 groups had no clinical significance as it was observed at only one time point, and all CD4 count means were above 300 cells/μL. Efavirenz in our setting was mostly prescribed concomitantly with antituberculosis treatment. This suggests that there were more patients with tuberculosis in the group that declined the switch, which could have led to an underestimation of anemia in the study population, as tuberculosis is associated with a greater risk of anemia. On the other hand, the higher proportion of women in our study population may have led to an overestimation of anemia, as female sex is a known factor for anemia. However, in the univariable and multivariable analyses, female sex was not found to be associated with severe anemia in our setting.
The study design did not allow to assess the best time of switch, and we had to rely upon expert advice. Although program implications for patient follow-up were reported, patient satisfaction was not assessed. Randomized controlled trials could produce stronger evidence on the best switch strategy in terms of safety and efficacy, especially regarding long-term treatment success.
Our study showed that after 18 months of d4T-based HAART, a systematic switch to ZDV in a large cohort of patients resulted in a relatively high incidence of anemia and an unexplained drop in CD4 counts in a significant number of patients. Programmatic challenges observed included an increased laboratory monitoring and adherence counseling, a heavier workload for staff, and a burden for patients. Nevertheless, satisfactory overall clinical and immunological outcomes were recorded in this cohort of patients. Programs in rural areas in resource-limited settings may neither have the laboratory capacity for frequent Hb and VL measurements nor the organizational capacity for an effective implementation of the switch. If a strategy for substituting ZDV for d4T-based HAART is to be applied in resource-limited settings, then ZDV-associated adverse events and context-specific programmatic challenges need to be weighed against the expected benefit of decreased long-term d4T toxicity.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
zidovudine; stavudine; substitution; highly active antiretroviral treatment (HAART); resource-limited settings