Abstract
Recent data indicate that fosamprenavir/ritonavir as part of an initial antiretroviral regimen in HIV-1 -infected patients is associated with favourable efficacy and tolerability and in the KLEAN study (kaletra versus lexiva with epivir and abacavir in antiretroviral-naive patients) it was found to be non-inferior to lopinavir/ritonavir in association with abacavir/lamivudine. In our open-label, observational study conducted in 82 therapy-naíve HIV-1-infected patients followed-up for 18 months, virological and immunological efficacy was comparable in subjects receiving a fosamprenavir/ritonavir-based and a lopinavir/ritonavir-based treatment (proportions of patients with HIV RNA <50 copies/mL at month 18 were 76.9% and 74.4%, respectively, when discontinuations were counted as failures). At the same time, frequency of treatment discontinuations and adverse events were similar in both groups, whereas incidence of diarrhoea and hypertriglyceridaemia was significantly higher in lopinavir-treated patients than in fosamprenavir-treated ones (53.5% vs. 25.6% and 69.8% vs. 43.6%, respectively; P < 0.01). In subjects with virological failure, no viral protease resistance mutations were detected by genotype analysis.
Introduction
Highly active antiretroviral therapy containing a protease inhibitor (PI) plus two nucleoside reverse transcriptase inhibitors (NRTIs) has dramatically reduced morbidity and mortality associated with human immunodeficiency virus (HIV)-l infection, and is currently a standard of care regimen for initial antiretroviral therapy (ART) in HIV-1-positive subjects.1,2 Moreover, a very high efficacy rate with rare detection of viral protease resistance mutations was shown for ritonavir-boosted PIs in recent studies and most current ART guidelines recommend a boosted-PI for initial treatment of antiretroviral-naíve HIV-1-infected individuals.3–5
Fosamprenavir is a PI prodrug employed for the treatment of HIV-1 infection and developed with the intention of reducing the pill burden associated with amprenavir. In fact, the active moiety, amprenavir, is extensively metabolized by hepatic cytochrome P450 3A4 enzymatic system, and in clinical trials fosamprenavir was at least as effective as amprenavir, with a reduced pill burden. It has demonstrated comparable virological efficacy and clinical safety with comparator PIS, and is associated with limited cross-resistance to other PIS.6–8
Patients and Methods
To assess the efficacy and tolerability of fosamprenavir/ritonavir vs. lopinavir/ritonavir, a cross-sectional evaluation allowed us to identify HIV-1-infected adult patients naive to all antiretroviral agents and starting between January and September 2005 an antiretroviral regimen including two NRTIs plus fosamprenavir/ritonavir (700/100 mg twice daily) or lopinavir/ritonavir capsules (400/100 mg twice daily).
Eighty-two subjects underwent ART with either fosamprenavir/ritonavir (group A) or lopinavir/ritonavir (group B) in our tertiary care centre during this nine-month period and were followed-up for 18 months in our open-label, observational study. The two study groups were comparable with regard to the main baseline demographic-epidemiological features, laboratory parameters and clinical stage of HIV disease (as showed in Table 1), whereas a greater duration of HIV infection was found in group B (P < 0.01). Physical examination (including evaluation of blood pressure, body weight, abdominal circumference and fat redistribution syndrome), adherence assessment (by patients’ self-reports, questionnaires and direct drug distribution and accountability) and laboratory workout (including plasma HIV RNA, CD4 lymphocyte count, lipid and glucose concentrations) were performed every three months. The 10-year risk of myocardial infarction was determined by the Framingham equation. Hypertriglyceridaemia was defined by plasma fasting triglyceride levels >200 mg/dL, hypercholesterolaemia by plasma fasting total cholesterol levels >200 mg/dL and hyperglycaemia by plasma fasting glucose levels >100 mg/dL. Metabolic syndrome was defined as the occurrence of three or more of the following abnormalities: abdominal obesity (waist circumference >102 cm for men and > 88 cm for women), hypertriglyceridaemia (fasting serum triglyceride levels >150 mg/dL), decreased high-density lipoprotein (HDL) cholesterol (fasting serum levels <40 for men and <50 mg/dL for women), arterial hypertension (systolic blood pressure >130 mg/dL and/or diastolic blood pressure >85 mmHg) and hyperglycaemia (fasting glucose levels ≥ 100 mg/dL).
Demographic, epidemiological and laboratory characteristics of the 39 subjects treated with fosamprenavir/ritonavir (group A) as opposed to the 43 treated with lopinavir/ritonavir (group B), at the start of the antiretroviral therapy
NRTIs = nucleoside reverse transcriptase inhibitors; SD = standard deviation; AIDS = acquired immunodeficiency syndrome; HBV= hepatitis B virus; HCV = hepatitis C virus; LDL= low-density lipoprotein; HDL= high-density lipoprotein
Primary endpoints were proportion of patients achieving HIV RNA <50 copies/mL, mean increase in CD4 lymphocyte count and treatment discontinuations because of an adverse event at month 18. Secondary endpoints were clinical and laboratory adverse events, including variations in plasma triglyceride, cholesterol and glucose levels. Mantel-Haenszel chi-square test and Fisher's exact test were used for comparisons of proportions; Student's t-test was used for the comparison of quantitative variables, with significance levels placed at P < 0.05.
Results
Treatment discontinuations, immunovirological responses, adverse events and changes in laboratory parameters observed during the 18-month follow-up are summarized in Table 2. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two study arms: four patients (10.2%) in group A and 6 (13.9%) in group B (Table 2). In group A treatment, discontinuation was caused by a hypersensitivity reaction with skin rash in two cases and grade 3-4 diarrhoea in two cases, whereas in group B ART was discontinued because of grade 3-4 diarrhoea in all six cases. Therefore, the frequency of treatment discontinuations because of grade 3-4 diarrhoea was significantly higher in group B than in group A (13.9% vs. 5.1%; P = 0.008).
Immunovirological responses, clinical adverse events and laboratory changes observed at the end of the 18-month follow-up
SD = standard deviation; conc. = concentration; LDL = low-density lipoprotein; HDL = high-density lipoprotein; ALT = alanine transaminase; n.s. = not significant
At month 18, immunological and virological responses were comparable in both fosamprenavir- and lopinavir-treated patients. Proportions of patients with plasma HIV RNA <50 copies/mL were 76.9% in group A and in 74.4% in group B when discontinuations were counted as failures, whereas mean increases in CD4 lymphocyte count ± standard deviation (SD) were 126 ± 65 cells/mm3 in group A and 138 ± 42 cells/mm3 in group B. In 10 subjects who met the criterion for virological failure, no viral protease resistance mutations were detected by genotype analysis.
Nausea, vomiting, anorexia, abdominal pain and asthenia were the most frequent drug-related adverse events and were reported with similar frequency in both study arms. However, the occurrence of grade 1-4 diarrhoea was significantly more frequent in patients receiving lopinavir/ritonavir than in those receiving fosamprenavir/ritonavir (53.5% vs. 25.6%, P = 0.006). Mean increases in plasma total cholesterol, low-density lipoprotein cholesterol and glucose concentrations occurred at similar frequency in both study groups, whereas mean increase in plasma triglyceride levels ± SD was significantly greater in lopinavir-treated subjects than in fosamprenavir-treated ones (121 ± 69 mg/dL vs. 78 ± 35 mg/ dL, respectively; P = 0.007). Similarly, the frequency of hyper-triglyceridaemia was significantly higher in group B than in group A (69.8 vs. 43.6, respectively; P = 0.008). On the other hand, mean increase in HDL cholesterol ± SD was more remarkable in group A than in group B, but did not reach the statistical significance (16 ± 7 mg/dL vs. 9 ± 4 mg/dL, respectively; P = 0.062). At month 18, the incidence of lipodystrophy syndrome and metabolic syndrome were low and comparable in the two study groups; the 10-year risk of MI was similar in both arms and comparable with that assessed at baseline. Mean changes in serum alanine transaminase levels in patients with chronic HBV or HCV infection were similar in both groups and comparable with those observed at baseline.
Discussion
Safety and efficacy of a fosamprenavir-based antiretroviral combination in treatment-naive HIV-1-infected patients were assessed in several clinical trials. In the NEAT study, antiviral activity and tolerability of twice daily fosamprenavir (without ritonavir) was compared with nelfinavir in 249 individuals naive to all antiretroviral agents. 9 After 48 weeks of follow-up, the intent-to-treat analysis showed a greater proportion of patients achieving plasma HIV RNA <400 copies/mL in the fosamprenavir group (66%) than in the nelfinavir group (51%). Furthermore, more patients with very high viral load (HIV RNA >100,000 copies/mL) or severe immunodeficiency (CD4 lymphocyte count <50 cells/mm3) at baseline achieved undetectable viral load taking fosamprenavir compared with nelfinavir. Both treatments were associated with a good tolerability profile, but grade 2-4 diarrhoea was significantly more common in the nelfinavir group.
Similarly, in the SOLO study, once-daily antiretroviral treatment with fosamprenavir/ritonavir plus abacavir/lamivudine was found to be non-inferior to nelfinavir plus abacavir/lamivudine in 649 antiretroviral-naïve patients over 48 weeks. 10 The APV30005 is an international, uncontrolled, open-label, follow-on study conducted in 211 patients who have participated in the SOLO study and continued the fosamprenavir/ ritonavir-based therapy for up to 120 weeks. At the end of follow-up, sustained antiviral efficacy and immunological improvement were shown in this study. In fact, at week 120 plasma HIV RNA <400 and <50 copies/mL were achieved and maintained in 75% and 66% of patients, respectively, when missing data and discontinuations were counted as failures. The median increase of CD4 lymphocyte count at week 120 from baseline value was 292 cells/mm3 and the median CD4 lymphocyte count was 451 cells/mm3. At the same time, clinical adverse events and laboratory abnormalities seen by week 120 were comparable with those seen by week 48, although they were less frequent. 11
In the KLEAN study, twice daily fosamprenavir/ritonavir was directly compared with lopinavir/ritonavir, each associated with abacavir/lamivudine, in 878 antiretroviral-naïve patients. At week 48, non-inferiority of fosamprenavir/ritonavir to lopinavir/ritonavir was shown, with 73% and 71% of patients, respectively, achieving plasma HIV RNA <400 copies/mL by the intent-to-treat analysis. Immunological recovery was comparable in both treatment arms, with a median CD4 count increase of 176 cells/mm3 in the fosamprenavir/ritonavir group and 191 cells/mm3 in the lopinavir/ritonavir group. Treatment discontinuations were few and occurred with similar frequency in the two treatment groups (fosamprenavir/ritonavir: 12%; lopinavir/ritonavir: 10%), such as adverse events (represented mostly by diarrhoea, nausea, and abacavir hypersensitivity reaction). Both groups showed similar changes from baseline in fasting lipid values at week 48, and use of lipid-lowering drugs was similar in both arms during the study period. The detection of viral protease resistance mutations was rare, and no patient had a virus that developed reduced susceptibility to fosamprenavir or lopinavir. 12
In our study, fosamprenavir/ritonavir twice daily in treatment-naïve HIV-infected patients provided similar antiviral efficacy, immunological improvement, safety and tolerability as lopinavir/ritonavir after a 18-month follow-up. Moreover, virological results of this antiretroviral regimen were consistent with those reported in clinical trials. On the other hand, lopinavir-based ART was associated with a significantly higher frequency of diarrhoea and hypertriglyceridae-mia when compared with fosamprenavir-based regimen.
Finally, our study presents the limits of cohort analysis (not randomized and not controlled) and the potential problems associated with a small sample size, but it may represent a useful ‘real life’ comparison. Further, enlarged, randomized clinical trials are certainly required to assess efficacy and tolerability of boosted-PI-based antiretroviral combinations and to define the most appropriate guidelines for initial treatment in HIV-1-infected patients.