Volume 13, Issue 6 , Pages e360-e364, November 2009
Safe substitution to zidovudine among HIV-infected patients initiated on stavudine-containing highly active antiretroviral therapy from a resource-limited setting
Article Outline
Summary
Objective
To describe the safe substitution with zidovudine (AZT) among South Indian HIV-infected patients who were initiated with stavudine (d4T)-containing highly active antiretroviral therapy (HAART) due to anemia.
Methods
Therapy-naïve patients initiating HAART between January 2006 and December 2007 and who had had d4T substituted for AZT at a tertiary HIV referral center in India were analyzed.
Results
Six hundred and nineteen patients initiated d4T-containing HAART (median CD4 110 cells/μl; median hemoglobin 10.4
g/dl) during the study period. Subsequently half of these patients substituted d4T for AZT (median CD4 350 cells/μl; median hemoglobin 12.8g/dl). After substituting with AZT, three patients (2.7%) who substituted after less than 6 months and one patient (0.6%) who substituted at between 6 and 12 months developed anemia. Patients who substituted after less than 6 months had significantly higher median CD4 cell counts at 1-month and 6-months of follow-up than patients who substituted at between 6 and 12 months (p<0.05). Few patients (1.6%) experienced treatment failure; about a tenth of patients developed d4T-related toxicities.
Conclusion
Few patients developed anemia (1.4%) within 6 months of substitution with AZT. In settings where tenofovir is either expensive or not available and where patients are anemic, initiating d4T followed by prompt substitution with AZT can be a safe and tolerable treatment option.
Keywords: India, Resource-limited settings, HAART, Anemia, AZT, d4T, HIV
Introduction
Current United States Department of Health and Human Services (DHHS) and World Health Organization (WHO) treatment guidelines for initiating highly active antiretroviral therapy (HAART) for HIV-infected patients recommend tenofovir (TDF)- or zidovudine (AZT)-containing regimens as preferred first-line treatment options as compared to stavudine (d4T)-containing regimens.1, 2 In resource-limited settings where TDF is currently either not affordable or unavailable and where many patients are anemic and therefore cannot be initiated on AZT, d4T-containing regimens have been employed as a first-line treatment option in diverse settings.3, 4
Though d4T-containing regimens have routinely been prescribed as first-line therapy due to low cost and ready fixed-dose availability, d4T can be associated with long-term toxicities, including lipodystrophy, peripheral neuropathy, and lactic acidosis.3, 5 AZT has been associated with increased hematological toxicities; prior studies have shown that patients develop anemia within the first few months of initiating AZT-containing HAART.4, 6 The current study was conducted to assess the safety and tolerability of substitution with AZT from d4T-containing HAART regimens among HIV-infected South Indians.
Methods
Setting
This was a retrospective study conducted at YRG Center for AIDS Research and Education (YRG CARE), Chennai, which is a large HIV tertiary care center in South India. Since 1996, it has provided a continuum of care for over 10000 HIV-infected individuals.7 All patients are treated according to the WHO treatment guidelines. Co-trimoxazole prophylaxis is initiated for all patients as per WHO guidelines.8 Patients are advised to initiate antiretroviral therapy (ART) when CD4 counts are <200 cells/μl or when CD4 counts range between 200 and 350 cells/μl with an AIDS-defining illness (ADI). Nevirapine (NVP)-based regimens, which are the least expensive and most widely available, are generally used as first-line therapies. Patients are seen every 3 months or as clinically indicated. CD4 monitoring is done every 3 to 6 months.
Patients
Patients who were older than 18 years of age, attending the YRG CARE clinic between January 2006 and December 2007, and who had been substituted with AZT from d4T-containing ART were included in this retrospective analysis. Since 2006, in order to balance the short-term risks posed by AZT therapy with the long-term toxicities associated with d4T, patients with hemoglobin <11g/dl have been initiated on d4T-containing HAART for a minimum of 3–6 months and then substituted to AZT-containing HAART. Patients were substituted with AZT after elevation of hemoglobin to >11g/dl and underwent evaluation of hemoglobin and hematocrit on follow-up at 1 month after substitution and then subsequently every 3 months. Data were collected with the approval of YRG CARE's freestanding institutional review board (IRB). Analyses used the YRG CARE HIV Natural History Study Observational Database. This database is updated daily by research nurses who are trained to use a validated prospective data collection instrument, which includes demographics, clinical assessments, current treatment regimens and adverse events (AEs), as well as laboratory data, including hemoglobin, liver and renal function tests, CD4 cell counts, plasma viral load (PVL), and genotypic testing, if available.
The most recent National Institutes of Health (NIH) definitions of AIDS-associated AEs were employed for diagnosis.9 Treatment failure was used to refer to those patients who modified therapy because of clinical, immunological, or virological treatment failure. The clinical criterion for failure was the development of an AIDS-defining illness after at least 3 months on HAART. According to WHO treatment guidelines, immunologic failure was defined as a decrease in CD4 to baseline (or below) after 6 months of therapy, a persistent CD4 below 100 cells/μl after 6 months of therapy, or a 50% decline from the on-treatment peak CD4 value.1 Virologic failure was defined as a viral load >400 copies/ml at 6 months after initiating ART.
Statistical analysis
Descriptive statistics were calculated with means and standard deviations for variables that were normally distributed; the median and interquartile range (IQR) were calculated for variables influenced by extreme values. To compare proportions, Chi-square statistics were used, and the Mann–Whitney U-test was used to compare median durations. All statistical analyses were performed using SPSS software (version 14.0; SPSS, Chicago, IL, USA). A p-value of less than 0.05 was considered statistically significant.
Results
Between January 2006 and December 2007, 619 patients initiated d4T-containing HAART. Almost half of the patients (49.8%) initiating d4T subsequently substituted with AZT. Among these 619 patients, 292 substituted with AZT within 12 months of initiating d4T-containing HAART and had 12 months of follow-up on HAART. Over a third of these patients (38.4%) substituted within 6 months and 180 patients (61.6%) substituted at 6–12 months. The following analyses were undertaken only among these 292 patients who substituted within 12 months and who also had 12 months of follow-up on HAART (Table 1; Figure 1).
Table 1. Characteristics of patients who substituted with AZT from d4T-containing HAART prior to treatment substitution (N=292)
| Median (IQR), mean (%) | |
|---|---|
| Median CD4 (cells/μl) | 110 (57–187) |
| Median hemoglobin (g/dl) | 10.4 (9.0–12.1) |
| Patients who experienced immunological failure | 10 (1.6%) |
| Median time to treatment failure | 12 months (0.8–26) |
| Patients who developed d4T-related toxicity | 44 (7.1%) |
| Among patients who substituted with AZT <6 months | 17 (2.7%) |
| Among patients who substituted with AZT 6–12 months | 27 (4.4%) |
| Median time to development of d4T-related toxicity | 7 months (5.8–11.3) |
| Median time to substitution with AZT | 4 months |
Figure 1.
Flow chart of study participants.
Close to a third of patients (27.3%) were female and the median age was 35 years. The median body mass index (BMI) was 18.9. The two first-line HAART regimens were lamivudine (3TC) plus d4T plus NVP (31%) and 3TC plus d4T plus efavirenz (EFV) (69%). At the time of initiating HAART, the median CD4 cell count was 110 cells/μl (IQR 57–187) and the median hemoglobin was 10.4g/dl (IQR 9.0–12.1). Few patients (1.6%) experienced treatment failure and the median time to treatment failure was 12 months (IQR 0.8–26). Close to a tenth of patients (9.1%) developed peripheral neuropathy and 4.9% of patients developed lipoatrophy after initiating d4T-containing HAART. The median time to development of d4T-related toxicities was 7 months (IQR 5.8–11.3).
At the time of substitution, the median CD4 cell count was 350 cells/μl (IQR 219–438) and the median hemoglobin was 12.8g/dl (IQR 12.5–14.6). The median time to substitution was 4 months. After substituting with AZT, three patients (2.7%) who substituted at <6 months on d4T developed anemia and one patient (0.6%) who substituted after 6–12 months on d4T developed anemia.
At 1 month following initiation of AZT, patients who substituted after <6 months on d4T had significantly higher CD4 cell counts than patients who substituted after 6–12 months on d4T (CD4 cell count 391 cells/μl vs. 346 cells/μl; p=0.024) (Figure 2). At 3 months following initiation of AZT, patients who substituted after <6 months on d4T had significantly lower hemoglobin levels than patients who substituted after 6–12 months on d4T (hemoglobin 12.6g/dl vs. 13.5g/dl; p < 0.001). At 6 months following initiation of AZT, patients who substituted after <6 months on d4T had significantly higher CD4 cell counts and lower hemoglobin levels than patients who substituted after 6–12 months on d4T (CD4 cell count 453 cells/μl vs. 445 cells/μl; hemoglobin 13.0g/dl vs. 13.5g/dl; p < 0.001). No differences were found in outcomes between EFV- vs. NVP-containing regimens; additionally no differences were found in hemoglobin levels between men and women.
Figure 2.
CD4 count and hemoglobin comparison between patients who substituted with AZT at <6 months after initiating d4T vs. patients who substituted at 6–12 months. *Signifies a statistically significant difference (p
<0.05).
Discussion
In resource-limited settings, the selection of HAART regimens has been determined not only by treatment efficacy, but also by considerations of availability and affordability. The current study demonstrated the safe substitution with AZT from d4T-containing HAART, and only a few cases of anemia (1.4%) were reported after substitution. The findings of the current study suggest that in settings where TDF is either expensive or not available and where many patients have low hemoglobin levels at the time of initiating therapy, starting d4T followed by prompt substitution with AZT can be a safe and tolerable treatment option.
In the current study, patients developed d4T-related toxicity generally after 6 months of initiating d4T. Due to the long-term toxicities posed by prolonged d4T therapy, it is advisable that patients be substituted as soon as hemoglobin levels have stabilized. Patients and healthcare providers should be adequately trained to recognize the signs and symptoms of possible d4T toxicity, including lipoatrophy, lactic acidosis, and peripheral neuropathy, so that early recognition can lead to prompt treatment substitution.
Rates of anemia have dramatically decreased since the introduction of HAART, but anemia has been identified as an independent risk factor for mortality for patients living with AIDS.10, 11, 12 Hence treatment strategies that minimize the risk of developing anemia are important for effective patient management. In resource-limited settings, such as India, HIV-infected patients often present to clinical care with co-existing nutritional deficiencies, opportunistic infections, and other chronic diseases that may precipitate low hemoglobin levels, which can subsequently be exacerbated by the use of AZT.3, 13, 14 An earlier study at our center documented that patient gender was not associated with anemia.15
Data on anemia from industrialized nations have used cutoffs ranging from <8g/dl to <14g/dl and have documented prevalence ranging from 1.3% to 95% in HIV-infected populations.16 In an earlier study at YRG CARE, 6% of patients experienced anemia after initiating generic HAART.5 However, a fifth of the cohort had received AZT, and more than half of the patients who developed anemia within 1 year of initiating HAART were on an AZT-containing therapy. In the present study, which aimed to minimize the risk of developing anemia through treatment substitution after hemoglobin stabilization, only 1.4% of patients developed anemia. Other studies have similarly noted that prior ART experience can protect against AZT-related anemia.4
The purpose of this study was to focus on this specific treatment strategy of initiating patients with low hemoglobin on d4T and then substituting this for AZT once hemoglobin levels improve. A prior study at our center documented immunological and clinical outcomes of patients who remained on d4T and of patients who initiated AZT as well as rates of anemia among patients on these treatment regimens.5
Due to the present limitation of available first-line regimens in resource-limited settings, innovative treatment strategies that can maximize the current formulary and minimize the risk of drug toxicities for HIV-infected patients are imperative. The findings of the present study suggest that once patients are substituted with AZT, regular hemoglobin monitoring is crucial to detect the short-term risk of anemia. In light of the increasing number of patients receiving HAART in resource-limited settings, future studies are needed to determine the long-term safety and efficacy of such ART substitution strategies.
Acknowledgements
The authors are grateful to the research nurses, data management team and all the clinical and research staff at the YRG Centre for AIDS Research and Education, VHS, Chennai, India, for their facilitation of the study. The authors would like to thank Brown University's AIDS International Research and Training Program of the Fogarty International Center at the National Institutes of Health (NIH), USA (grant No. D43TW00237) and ACTG-ICTU/NIH-Chennai site (grant No. U01AI069432) for supporting this study.
Ethical approval: Data were collected with the approval of YRG CARE's freestanding institutional review board.
Conflict of interest: No conflict of interest to declare.
References
- World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach (2006 revision). Available at: www.who.int/hiv/pub/guidelines/adult/en/index.html (accessed January 2009).
- Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 (accessed January 2009).
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- World Health Organization. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents, and adults in resource-limited settings: recommendations for a public health approach. Available at: http://www.who.int/hiv/pub/guidelines/ctx/en/index.html (accessed January 2009).
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- . Prevalence and cumulative incidence of and risk factors for anemia in a multicenter cohort study of human immunodeficiency virus-infected and -uninfected women. Clin Infect Dis. 2002;34:260–266
- Highly active antiretroviral therapy associated with improved anemia among HIV-infected women. AIDS Patient Care STDS. 2001;15:473–480
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- The changing natural history of HIV disease: before and after the introduction of generic antiretroviral therapy in southern India. Clin Infect Dis. 2005;41:1525–1528
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PII: S1201-9712(09)00072-1
doi:10.1016/j.ijid.2008.11.030
© 2009 International Society for Infectious Diseases. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 6 , Pages e360-e364, November 2009
