Salvage therapy with abacavir plus efavirenz or nevirapine in HIV-1-infected persons with previous nucleoside analogue and protease inhibitor use.

Abstract

Limited data are available regarding the use of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens for therapy after virological rebound on protease inhibitor (PI) plus nucleoside analogue (NA) therapy, or in persons with low CD4 cell counts. Treatment guidelines suggest the use of new NA plus an agent from a previously unused class to be the best approach to managing these patients [1,2]. In early 1998, a limited release programme (known as study CNA3008) for the new potent NA, abacavir, was commenced at three sites in the UK. Patients entering this programme were required to have had previous exposure to at least two NA and a PI, have a detectable viral load and a history of a CD4 cell count of less than 100/mm3. We retrospectively analysed the response to these abacavir-containing regimens in individuals who entered the programme naive to NNRTI and who included either efavirenz or nevirapine in their new treatment regimen. The choice of NNRTI was at the discretion of the physician and the patient, nevirapine being fully approved and efavirenz available on an expanded access programme at the time. Subsequently, analysis for evidence of phenotypic (by Antivirogram, Virco, Belgium) and genotypic (by Vircogen, Virco, Belgium) resistance was performed on baseline samples, and the number of sensitive agents in the new regimen estimated. A two-tailed Fisher's exact test was used to examine the relationship between treatment response and resistance within groups, logistic regression for response and CD4 cell count and viral load at baseline, and two-sample t-tests were used to compare the NNRTI groups for a change in viral load. One-sample t-tests were used to compare baseline versus on-therapy values within groups for CD4 cell count and log10 viral load. Data are available on 31 patients, 18 of whom received efavirenz and 13 nevirapine as the NNRTI with abacavir. At baseline, the mean viral load and CD4 cell count in the efavirenz group were 5.4 log10 (range 3.7–6.1) and 57 cells/mm3 (range 2–264) and for nevirapine 5.5 log10 (range 4.6–6.4) and 36 cells/mm3 (range 0–110). The majority of patients (28; 90%) received two additional drugs, with two patients receiving three additional and one patient four additional agents. Baseline characteristics were similar between the groups. No relationship was found between virological response and baseline CD4 cell count, viral load, the number of agents received, or the number of sensitive agents received (by pheno- or genotype). The results of treatment are shown in Table 1.Table 1: Change in viral load and CD4 cell count, and proportion of patients achieving a 1 log10 reduction or to less than 500 copies/ml in a cohort of abacavir plus non-nucleoside reverse transcriptase inhibitor-treated patients. Despite small patient numbers, significant differences (P < 0.05) were observed between recipients of efavirenz and nevirapine regarding the magnitude of viral load reduction at weeks 8, 16 and 24, the proportion of patients experiencing a greater than 1 log10 reduction in viral load at week 16 and the proportion of patients being below 500 copies/ml at weeks 8 and 16. The rates of adverse event were similar between the groups and mostly assessed by the investigators as being unrelated to therapy (for the efavirenz group: 63 events, 18 considered to be related; for the nevirapine group: 50 events, 13 considered to be related) with rash reported in one (5%) and four (31%) of the efavirenz and nevirapine recipients, respectively. One nevirapine recipient discontinued because of rash. No events of abacavir hypersensitivity were diagnosed. Five patients died on-study (one efavirenz and four nevirapine recipients), all deaths being secondary to the progression of HIV disease. These data indicate that abacavir plus NNRTI-based regimens are generally well tolerated and provide effective therapy in a substantial proportion of individuals with advanced HIV disease who have failed to maintain virological control with PI-based regimens. The majority of patients did not require multi-drug (or `mega-highly active antiretroviral therapy') regimens to achieve viral suppression. This small, retrospective and non-randomized study suggests that differences favouring efavirenz may exist in efficacy, but not in tolerability, in these circumstances. The observed differences in this uncontrolled retrospective study might relate to unidentified confounding differences between these cohorts or differences in the activity between these agents in NA-resistant individuals. However, this finding requires confirmation in a randomized trial. Graeme J. Moylea Ed Wilkinsb Clifford Leenc Ann Cheesbroughd Brian Reynoldsa Brian G. Gazzarda