Antiviral Therapy 4: 35–44 Quality of life outcomes of saquinavir, zalcitabine and combination saquinavir plus zalcitabine therapy for adults with advanced HIV infection with CD4 counts between 50 and 300 cells/mm3 Dennis A Revicki1*, Cassandra Swartz1, Albert W Wu2, Richard Haubrich3 and Ann C Collier4 1MEDTAP International Inc., Bethesda, Md., USA 2Johns Hopkins University, Baltimore, Md., USA 3University of California-San Diego, San Diego, Calif., USA 4University of Washington, Seattle, Wash., USA *Corresponding author: Tel: +1 301 654 9729; Fax: +1 301 654 9864; E-mail: [email protected] Background: Benefits in patient health-related quality of demonstrated significantly greater decreases in PHS life (HRQL) have not yet been demonstrated for combi- scores (–4.4±0.6; saquinavir: –1.3±0.6; zalcitabine plus nation antiretroviral therapy with protease inhibitors and saquinavir: –1.7±0.6; P<0.0001) and MHS scores nucleoside analogues. This double-blind study evaluated (–2.2±0.5; saquinavir: –1.0±0.5; zalcitabine plus zalcitabine or saquinavir monotherapy and combination saquinavir: –0.5±0.5; P=0.032) compared to saquinavir saquinavir plus zalcitabine therapy on HRQL of human and zalcitabine plus saquinavir treated patients. No immunodeficiency virus (HIV)-infected adults. differences were observed on the VAS (P=0.172). Nine of Methods: 940 HIV-infected patients (CD4 counts 10 MOS-HIV subscales demonstrated results consistent 50–300 cells/mm3) who had discontinued zidovudine with the primary endpoints. After 48 weeks, a statistically therapy (for intolerance or treatment failure) were significant difference between the saquinavir-treated randomized to one of three regimens: zalcitabine 0.75 groups and the zalcitabine monotherapy group was mg every 8 h; saquinavir 600 mg every 8 h; or combi- observed for PHS scores (zalcitabine: –5.8±0.6; nation zalcitabine 0.75 mg plus saquinavir 600 mg saquinavir: –4.1±0.6; zalcitabine plus saquinavir: every 8 hours. HRQL was measured at baseline, 24 and –3.5±0.6; P=0.014). 48 weeks using the Medical Outcome Study HIV Health Conclusions: Saquinavir monotherapy and combination Survey (MOS-HIV). The primary endpoints were the saquinavir plus zalcitabine demonstrated a benefit in physical and mental health summary scores (PHS; MHS) HRQL relative to zalcitabine monotherapy in patients of the MOS-HIV as well as a global visual analogue with prior zidovudine therapy. The HRQL findings are scale (VAS) score. concordant with improved survival and reduced clinical Results: After 24 weeks, the zalcitabine-treated patients progression of HIV infection found in this study. Introduction Human immunodeficiency virus (HIV) infection results efficacy [14,15]. For some patients treated with in a chronic disease with progressive deterioration of zidovudine, the delay in disease progression may be the immune system, frequent opportunistic infections offset by the decrease in HRQL attributable to side- and death. The introduction of reverse transcriptase effects [16]. The quality of life impact of treatments for inhibitors, including zidovudine [1–3], didanosine HIV-infected patients is an increasingly important [4,5] and zalcitabine [6,7], prophylactic therapies consideration in treatment selection [17–19]. against opportunistic infections [8,9] and most recently In the past few years, therapeutic options for HIV the protease inhibitors [10] and combination therapy disease have expanded rapidly; 12 different antiretro- [11] has extended survival in patients with sympto- viral therapies are now approved for use in the US [20]. matic HIV infection and AIDS. Although treatments Antiretroviral therapies in combination, with or can preserve and improve health, they may also have a without protease inhibitors, have demonstrated negative impact on the patient’s health-related quality improvements in laboratory markers of HIV and delay of life (HRQL). For example, zidovudine monotherapy disease progression [21–23]. Collier et al. [22] found has significant toxicity [12,13] and limited duration of that combination saquinavir, zalcitabine and zidovu- ©1999 International Medical Press 1359-6535/99/$17.00 35 D Revicki et al. dine therapy resulted in greater impact on CD4 cell regimen. Randomization was stratified by screening counts and plasma HIV RNA compared with CD4 cell count (50 to 99, 100 to 300 cells/mm3). Strata saquinavir plus zidovudine or zidovudine plus were weighted 3:1 with more patients entering the zalcitabine treatment. Combination antiretroviral >100 CD4 cell count group. therapy extends survival benefits to patients with The research protocol was approved by each clinical symptomatic HIV disease and AIDS [24–26]. It is centre’s institutional review board and patients provided assumed that protease inhibitors in combination with written informed consent before entering the study. other antiretroviral therapy have a positive impact on patient functioning and well-being, but few systemati- Treatment regimen cally collected data are available. Ritonavir combined Patients were randomly assigned to one of three treat- with a variety of antiretroviral therapies demonstrated ment groups: (1) zalcitabine 0.75 mg every 8 h; (2) HRQL benefits in patients with advanced AIDS [27]. saquinavir 600 mg every 8 h; or (3) zalcitabine 0.75 However, the ritonavir study did not specify a partic- mg plus saquinavir 600 mg every 8 h. Placebo ular combination therapy regimen. medications were added to the monotherapy groups This study was designed to compare the effect of so that each patient was required to take equivalent saquinavir monotherapy, zalcitabine monotherapy and numbers of tablets or capsules. Patients who devel- combination saquinavir plus zalcitabine therapy on oped an AIDS-defining event were taken off blinded HRQL in HIV-infected patients with CD4 counts therapy and were offered open label saquinavir 600 between 50 and 300 cells/mm3 with previous zidovu- mg three times daily combined with other available dine treatment. The primary clinical efficacy and safety agents. The median time of study follow-up was 12.7 results from this clinical trial have been reported previ- months. The median time spent on blinded protocol ously [24]; this report focuses on the HRQL outcomes. therapy was 11.2 months for the zalcitabine To improve understanding of the clinical importance of monotherapy group, 12.9 months for the saquinavir the quality of life scores, we examined the magnitude monotherapy group and 13 months for the of change in HRQL scores in relation to changes in zalcitabine plus saquinavir group (P=0.088). Patients CD4 count and occurrence of AIDS-defining events. in the HRQL analysis were evaluated while receiving blinded treatment. Therapy was stopped for AIDS- Methods defining events, treatment limiting toxicity and patient or investigator preference. Concomitant Study design and patient population medications were allowed with the exception of other This was a multicentre, three group, double-blind, antiretroviral agents and drugs with toxicities that randomized clinical trial involving advanced HIV- overlap with zalcitabine or other investigational infected patients with CD4 cell counts between 50 and drugs. Prophylactic and chronic maintenance thera- 300 cells/mm3. A total of 940 patients were recruited pies were allowed for Pneumocystis carinii from 48 clinical centres located throughout the US and pneumonia and other opportunistic diseases. Canada. One clinical centre was dropped from the analysis owing to administrative irregularities; patients Clinical endpoints from this centre were excluded from the intent-to-treat The primary clinical endpoint was the first new or analysis of HRQL outcomes. Male or female patients recurrent AIDS-defining event or death that occurred with documented HIV infection were eligible to partic- during follow-up. Events were included in the analysis ipate if they were aged 18 years or older, had if they occurred at least 2 weeks after the start of study discontinued zidovudine (because of intolerance, therapy, whether or not the patient remained on disease progression or patient choice) and had blinded medication. All AIDS-defining events were Karnofsky Performance Status scores ≥60. Patients confirmed by an independent review committee [24]. were excluded if they had had previous treatment with a protease inhibitor, a history or current evidence of HRQL outcome measures peripheral neuropathy, prior treatment with any anti- HRQL is a multidimensional patient outcome which retroviral agent except zidovudine, evidence of includes physical, psychological and social functioning, malabsorption, severe laboratory abnormalities, active and general well-being [28–30]. For this study, the opportunistic infections, unexplained fever, malig- Medical Outcomes Study HIV (MOS-HIV) [31] and a nancy, or non-Hodgkin’s lymphoma, were receiving visual analogue scale (VAS) were selected to assess radiation or antineoplastic therapy or who were preg- HRQL based on their applicability for measuring HRQL nant or breast feeding. in HIV-infected patients, match with study objectives, Patients were required to have stopped zidovudine psychometric characteristics and ease of administration. at least 28 days prior to starting the study treatment The MOS-HIV was developed to assess HRQL in 36 ©1999 International Medical Press Quality of life and saquinavir Table 1. Baseline demographic and clinical characteristics* Zalcitabine plus saquinavir Characteristic Zalcitabine (n=314) Saquinavir (n=318) (n=308)