February 7, 2006
Design: Randomized, double-blinded, 24-week, phase 2 study conducted in two centers in Uganda aimed at examining the issues surrounding tolerability and toxicity of abacavir in an African population.
Population: 600 Ugandan adults with symptomatic HIV and a CD4+ cell count <200.
Main Result: In Ugandan patients with a low CD4+ cell count, there was a trend in the abacavir arm towards a lower rate of severe adverse events, a lower discontinuation rate and a lower rate of grade 4 adverse events. There was considerable overlap in the clinical manifestations of abacavir and nevirapine hypersensitivity reactions. The 2% rate of abacavir hypersensitivity reaction was surprisingly low.
Significance: First study to examine toxicity and tolerability of an abacavir-based, triple-nucleoside regimen in African patients with advanced HIV.
The World Health Organization (WHO) has endorsed combinations consisting of two nucleosides and a non-nucleoside reverse transcriptase inhibitor. Combinations with nevirapine (NVP, Viramune) remain the most common first-line regimens in Africa. However, with women now accounting for more than half of all HIV-infected persons worldwide, the issue of an increased risk of nevirapine hepatotoxicity in women cannot be ignored, nor can the potential for efavirenz (EFV, Sustiva, Stocrin)-induced teratogenicity. Yet these concerns do not necessarily open the door for triple-nucleoside combinations: The high expected rate of hypersensitivity reaction with abacavir (ABC, Ziagen) may limit its use, especially in developing areas where febrile illnesses like malaria are common, since it may be difficult to distinguish hypersensitivity reaction from the symptoms of such illnesses.
The NORA (nevirapine or abacavir) substudy of DART (Development of Antiretroviral Therapy in Africa, sponsored by the Medical Research Council of the United Kingdom) is the first to examine the toxicity and tolerability of an abacavir-based, triple-nucleoside regimen in African patients with advanced HIV. This was a randomized, double-blinded, 24-week, phase 2 study conducted by Paula Munderi and colleagues in two centers in Uganda.
Six-hundred adults with symptomatic HIV and a CD4+ cell count less than 200 were randomized on a 1:1 basis to receive a combination tablet of zidovudine 300 mg/lamivudine 300 mg (AZT/3TC, Combivir) orally twice a day in combination with either:
All drugs were dosed orally, with the nevirapine 200 mg or nevirapine placebo given once daily for the usual two-week induction phase.
From Jan. 5, 2004 to Oct. 28, 2004, 300 patients were enrolled in the blinded abacavir + nevirapine placebo arm (hereafter referred to as B-ABC) and 299 in the abacavir placebo + blinded nevirapine arm (B-NVP). Enrollees were predominantly female (72%), and the median age was 37 years.
Of the 599 total patients, 111 (19%) were very advanced, having stage 4 WHO disease at randomization. The median CD4+ cell count was 99 cells/mL; approximately 25% of the patients in each arm had a CD4+ cell count in the range of 0-49, 50-99, 100-149 and 150-199 cells/mL, respectively.
Most patients (95%) completed 24 weeks of follow-up (289 in the B-ABC arm; 280 in the B-NVP arm), although 4% died (9 in B-ABC; 15 in B-NVP) and 1% were lost to follow-up (2 in B-ABC; 4 in B-NVP). One patient was excluded for past antiretroviral therapy. In addition, 2% in the B-ABC arm and 5% in the B-NVP arm received past antiretroviral therapy, but only as part of a mother-to-child transmission prevention program.
The primary endpoints of this study were serious adverse events, as defined by the International Conference on Harmonisation-Good Clinical Practice guidelines. These were independently adjudicated by blinded clinicians. The secondary endpoints were adverse events leading to drug discontinuation.
A total of 34 serious adverse events occurred in 33 patients, primarily during the first eight weeks after initiating therapy. Twenty were felt to be "definitely," "probably" or "uncertainly" related to the study drug -- 6 (2%) on the B-ABC arm and 14 (4.7%) on the B-NVP arm (primary endpoint: hazard ratio 0.41; P = .06). Fourteen serious adverse events occurred that were deemed unlikely to be related to the study drug; these included seven cases of anemia.
The study authors examined which clinical symptoms could help clinicians in recognizing abacavir hypersensitivity reaction. The serious adverse events reported in 19 (6 in the B-ABC arm; 13 in the B-NVP arm) of 20 patients were consistent with potential hypersensitivity reactions. Similar proportions developed other involvements, as broken down in the following chart:
|Type of Involvement||# Patients on B-ABC Arm||# Patients on B-NVP Arm|
Symptomatic hepatic involvement was seen in only three patients, all of whom were on the B-NVP arm. The only remaining severe adverse event was a case of asymptomatic hepatitis in a patient on the B-NVP arm.
While considerable overlap between the signs and symptoms occurred in both treatment arms, everyone with abacavir hypersensitivity reaction had rash and fever without hepatic involvement. Only 2% of patients were ultimately diagnosed as having abacavir hypersensitivity reaction.
In total, 14 patients (4.7%) discontinued therapy in the B-ABC arm versus 30 (10%) in the B-NVP arm (P = .01). The reasons for discontinuation broke down as follows:
|Reason for Discontinuation||# Patients on B-ABC Arm||# Patients on B-NVP Arm|
|Any toxicity||6 (2.0%)||15 (5.0%)|
|Rash or possible hypersensitivity reaction||6||13|
|Need to start tuberculosis treatment||6 (2.0%)||13 (4.3%)|
Secondary endpoints included 187 grade 4 adverse events (78 on the B-ABC arm; 109 on the B-NVP arm), which occurred in 155 patients (64 on the B-ABC arm; 91 on the B-NVP arm). This accounted for 59 events per 100 person-years at risk in the B-ABC arm and 88 events per 100 person-years in the B-NVP arm. Eight patients -- all in the B-NVP arm -- had grade 4 increases in their liver function tests.
The Bottom Line
In Ugandan patients with a low CD4+ cell count, there was a trend in the abacavir arm towards a lower rate of severe adverse events, a lower discontinuation rate and a lower rate of grade 4 adverse events compared to the nevirapine arm, even though the nevirapine arm is currently the standard of care.
The issue of abacavir hypersensitivity may not be as critical in this study population for two reasons: distinguishing symptoms and low incidence rate. While there was considerable overlap in the clinical manifestations of abacavir and nevirapine reactions, rash and fever without hepatic involvement occurred consistently with abacavir hypersensitivity. The 2% rate of abacavir hypersensitivity reaction was surprisingly low compared to the 5% to 8% generally seen in populations studied in the developed world.
Having shown in this study that the combination of zidovudine/lamivudine/abacavir is well tolerated in this African population, this group of researchers has now turned to the important questions of virologic and immunologic efficacy. The issue of distinguishability of hypersensitivity reaction from endemic systemic febrile illnesses like malaria was not examined in detail by this study and will need to be addressed before this combination can be recommended outside of a research trial setting. This group also plans to explore genetic polymorphisms in this population in an effort to further understand the low rate of hypersensitivity reactions.
All in all, this study opens the door to the possibility that triple-nucleoside combinations may offer better treatment alternatives to the developing world, where issues of cost, compliance, pregnancy and tuberculosis coinfection will continue to set the framework for our antiretroviral choices.
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