cART prescription trends in a prospective HIV cohort in rural Tanzania from 2007 to 2011

Fabian Christoph Franzeck 0 1 Emilio Letang 0 1 2 Geoffrey Mwaigomole 3 Boniphace Jullu 3 Tracy R Glass 0 1 Daniel Nyogea 0 3 Christoph Hatz 0 1 Marcel Tanner 0 1 Manuel Battegay 1 4 0 Swiss Tropical and Public Health Institute (SwissTPH) , Socinstrasse 57, CH-4051 Basel , Switzerland 1 University of Basel , Basel , Switzerland 2 Barcelona Centre for International Health Research (CRESIB-Hospital Clinic, Universitat de Barcelona) , Barcelona , Spain 3 Ifakara Health Institute (IHI) , Ifakara , United Republic of Tanzania 4 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel , Basel , Switzerland Background: Since 2010, World Health Organization (WHO) guidelines discourage using stavudine in first-line regimens due to frequent and severe side effects. This study describes the implementation of this recommendation and trends in usage of antiretroviral therapy combinations in a cohort of HIV-positive patients in rural Tanzania. Methods: We analyzed longitudinal, prospectively collected clinical data of HIV-1 infected adults initiating antiretroviral therapy within the Kilombero Ulanga Antiretroviral Cohort (KIULARCO) in Ifakara, Tanzania from 2007-2011. Results: This analysis included data of 3008 patients. Median age was 38 (interquartile range [IQR] 31-45) years, 1962 (65.2%) of all subjects were female, and median CD4+ cell count at enrollment was 168 cells/mm3 (IQR 81-273). The percentage of prescriptions containing stavudine in initial regimens fell from a maximum of 75.3% in 2008 to 10.7% in 2011. TDF/FTC/EFV became available in 2009 and was used in 41.9% of patients initiating cART in 2011. An overall on-treatment analysis revealed that d4T/3TC/NVP and AZT/3TC/EFV were the most prescribed combinations in each year, including 2011 (674 [36.5%] and 641 [34.7%] patients, respectively). Of those receiving stavudine in 2011, 659 (89.1%) initiated it before 2011. Conclusions: Initial cART with stavudine declined to low levels according to recommendations but the overall use of stavudine remained substantial, as individuals already on cART containing stavudine were not changed to alternative drugs. Our findings highlight the critical need to exchange stavudine in treatment regimens of patients who initiated therapy in earlier years. - Background The revision of the World Health Organization (WHO) HIV treatment guidelines in 2010 brought several changes to the management of HIV patients [1]. Among them was a strong statement about progressing to less toxic antiretroviral drugs in first-line regimens, i.e. discouraging the use of stavudine in initial drug combinations. This drug was crucial in rolling out combined antiretroviral therapy (cART) in low-income setting as in Sub-Saharan Africa (SSA) for its low price and good efficacy in suppressing replication of HIV. However, severe side effects associated with stavudine use, such as peripheral neuropathy, lactic acidosis and lipodystrophy have been shown to be frequent and accumulating over time in several African cohorts [2,3]. In the United States, stavudine was already removed in 2004 from the list of preferred first-line antiretroviral drugs recommended by the US Department of Health and Human Services (DHHS) [4]. The goal of phasing out stavudine still competes in budgetary terms with other priorities in advancing cART as direct drug costs of stavudine were still at around 50% compared to alternative regimens in 2011 [5]. Recently, prices for generic formulations of more modern pharmaceuticals such as tenofovir have declined substantially. This should assist efforts to achieve the WHO goal of phasing out the use of stavudine containing regimens. In some settings, replacing stavudine with tenofovir or zidovudine was judged cost-effective [6-8] and further price reductions for these pharmaceuticals are to be expected. Many national HIV programs have consecutively adopted the recommendations of the WHO, including the National AIDS Control Program (NACP) of Tanzania: In February 2009, the preferred regimen was changed from d4T/3TC/NVP to AZT/3TC/EFV and TDF/FTC/ EFV was introduced as an alternative option [9]. However, d4T/3TC/NVP was still supported as a valid first-line combination for patients with anemia initiating therapy. No recommendation was issued to replace stavudine in existing prescription if it was tolerated without occurrence of severe side effects. In order to describe how recommendations issued by the WHO eventually permeate to treating clinicians in low-income countries, this study describes prescription trends of antiretroviral therapy combinations in a large cohort of HIV patients in rural Tanzania over a five-year period. Methods We analysed data of HIV-1 infected adults ( 18 years of age) initiating cART within the Kilombero Ulanga Antiretroviral Cohort (KIULARCO) at the chronic disease clinic at the St. Francis Referral Hospital in Ifakara. The hospital is the most important health care facility in the rural Kilombero and Ulanga Districts of the Morogoro Region in Southern Tanzania, providing treatment and care for a population of about 600,000 inhabitants. Demographic, clinical and laboratory data were prospectively collected from consenting patients at each consultation at the clinic. Medical doctors and clinical officers filled in standardized paper forms which consecutively where double entered into an electronic database (DMSys, Sigmasoft, Illinois, USA). Treatment failure was defined clinically or immunologically according to WHO criteria (50% drop in CD4 count from peak value within 6 months, or return to pre-ART baseline CD4 count or lower). Antiretroviral therapy combinations used for cases of treatment failure are referred to as second-line treatment regimens. Data collected from the 1st of January 2007 until the 31st of December 2011 were included in the analysis. In case a subject received > 1 regimen in one calendar year, all combinations prescribed during that year were included in the overall prescription analysis. Patients who initiated cART before 2007 were included in the overall prescription analysis. There was no active tracking mechanism of patients lost to follow-up during the study period. Continuous variables are expressed as median (interquartile range) and frequencies (percentages) for categorical variables. For calculation of p-values for trend, a chi-square statistic for trend was used. All statistical analyses were performed using Stata 11.2 (StataCorp, Texas, USA). Ethical statement All subjects included were given oral and written information about the collection of their clinical data and signed an informed consent form. Ethical approval was granted by the local Ethical Committee of the Ifakara Health Institute and the Medical Research Coordination Committee of the National Institute of Medical Research of Tanzania. Results Patients characteristics This analysis included data of 3008 patients (Figure 1). Of these, 2752 (91.5%) (...truncated)