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Efficacy and safety of twice-daily versus three-times daily saquinavir soft gelatin capsules as part of triple combination therapy for HIV-1 infection
Abstract
The objective of this study was to determine whether a triple therapy regimen incorporating twice-daily saquinavir is as effective as a three-times daily regimen.
This was an open-label, Phase III, multicentre, 48-week study involving 837 HIV-1-infected patients randomised to one of the following: saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1,600 mg twice-daily, plus two NRTIs (arm B); saquinavir SGC 1,200 mg twice-daily and nelfinavir 1,250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was the virological response in arm A versus B and in arm A versus C with respect to the percentage of patients whose plasma HIV-1 RNA levels fell below the level of quantification for the Amplicor assay (<400 copies/ml) at weeks 24 and 48.
At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels <400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the intention-to-treat analysis. The treatment difference between arm B-arm A was -1.8% (95% confidence intervals -10.1, 6.5) and for arm C-arm A was -4.5% (95% confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These differences fell within the maximum allowable difference (+/- 12%) for arm B compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels <400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C).
A twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs was of equivalent efficacy to the three-times daily regimen studied. All regimens were generally well tolerated.
To estimate the cost of the first combination antiretroviral drug therapy (cART) in HIV-infected patients and to determine factors associated with expensive prescriptions, 1698 patients starting cART between September 2002 and September 2007 were selected from the Dat'AIDS cohort. A multivariate linear regression model was used to assess associations between the cost of first cART and patient characteristics, clinical centre and cART adequacy. At cART initiation, the median age was 39 years, median CD4 count was 223 cells/mm(3), median viral load (VL) was 5.2 log copies/mL and 18.3% presented with AIDS. cART was concordant with the French guidelines in 88.7%. The mean cost of cART varied from €26.69/day/person in 2002-2003 to €32.23 in 2006-2007 (P < 0.0001), cost was associated with previous AIDS diagnosis (€31.83/day/person) versus (29.49; P < 0.0001), baseline VL > 5 log copies/mL (€30.99/day/person) versus (28.33; P < 0.0001) and centre. cART regimen not concordant with guidelines were more expensive (€38.31/day/person) versus (29.07; P < 0.0001). After adjusting for the year of initiation, the previous AIDS diagnosis, VL and recommended cART regimen, differences were still found between centres (from €27.81/day/person) to (33.12; P < 0.0001). Cost should be considered when choosing a first cART regimen, especially when considering clinically equivalent regimens.
The maturation of newly formed human immunodeficiency virus type 1 (HIV-1) virions is a critical step for the establishment
of productive infection. We investigated the potential of saquinavir (SQV), a protease inhibitor (PI) used in highly active
antiretroviral therapy (HAART), as a candidate microbicide. SQV inhibited replication of clade B and clade C isolates in a
dose-dependent manner in all cellular models tested: PM-1 CD4 T cells, peripheral blood mononuclear cells (PBMCs), monocyte-derived
macrophages (MDMs), and immature monocyte-derived dendritic cells (iMDDCs). SQV also inhibited production of infectious virus
in cervical, penile, and colorectal explants cocultured with T cells. Moreover, SQV demonstrated inhibitory potency against
trans infection of T cells by in vitro-derived dendritic cells and by primary dendritic cells that emigrate from penile and cervical tissue explants. No cellular
or tissue toxicity was detected in the presence of SQV, suggesting that this drug could be considered for development as a
component of an effective microbicide, capable of blocking viral maturation and transmission of HIV-1 at mucosal surfaces.
To evaluate the long-term efficacy and safety of saquinavir soft gelatin capsules (SQV-SGC) (Fortovase) in twice-daily, with or without nelfinavir (NFV), and three-times-daily regimens. This was an extension of a 48-week study, with follow-up to 100 weeks.
Patients were randomized to one of three treatment arms: arm A, SQV-SGC 1200 mg three times daily plus two nucleoside reverse transcriptase inhibitors (NRTIs); arm B, SQV-SGC 1,600 mg twice daily plus two NRTIs; or arm C, SQV-SGC 1200 mg twice daily plus NFV 1250 mg twice daily plus one NRTI. At week 48, patients could either withdraw or continue in the study to the common study closure date. Antiretroviral activity was assessed by changes in HIV-1 RNA values and CD4 cell counts from 48 weeks until 100 weeks.
In the modified intention-to-treat population, the proportion of patients with HIV-1 RNA values <400 copies/ml was statistically different between arms A and C (49 vs 28%, P=0.017), and arms B and C (48 vs 28%, P=0.027). Continued suppression of HIV-1 replication (HIV-1 RNA <400 copies/ml) was observed through 100 weeks in 83% (30/36), 73% (29/40) and 62% (16/26) of patients in treatment arms A, B and C, respectively, in the on-treatment (OT) population. At 100 weeks, sustained increases were achieved in mean CD4 cell counts of +361, +273 and +309 cells/mm3, respectively (OT population). No additional adverse events or increase in the proportion of patients reporting adverse events were observed from 48 weeks to 100 weeks.
This study demonstrates the long-term efficacy and safety of SQV-SGC twice daily, with or without NFV, and three times daily, in triple combination therapy for HIV-1-infected patients. However, the evidence suggests that long-term treatment with SQV-SGC plus NFV may be less acceptable to patients.
To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available.
A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995.
Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999.
The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive.
The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.
Human immunodeficiency virus type 1 (HIV-1) protease inhibitors have dramatically improved treatment options for HIV infection, but frequent dosing may impact adherence to highly active antiretroviral treatment regimens (HAART). Previous studies demonstrated that combined therapy with ritonavir and saquinavir allows a decrease in frequency of saquinavir dosing to twice daily. In this study, we evaluated the safety and pharmacokinetics of combining once-daily doses of the soft-gel capsule (SGC) formulation of saquinavir (saquinavir-SGC) and minidose ritonavir. Forty-four healthy HIV-negative volunteers were randomized into groups receiving once-daily doses of saquinavir-SGC (1,200 to 1,800 mg) plus ritonavir (100 to 200 mg) or a control group receiving only saquinavir-SGC (1,200 mg) three times daily. Saquinavir-SGC alone and saquinavir-SGC-ritonavir combinations were generally well tolerated, and there were no safety concerns. Addition of ritonavir (100 mg) to saquinavir-SGC (1,200 to 1,800 mg/day) increased the area under the concentration-time curve (AUC) for saquinavir severalfold, and the intersubject peak concentration in plasma and AUC variability were reduced compared to those achieved with saquinavir-SGC alone (3,600 mg/day), while trough saquinavir levels (24 h post-dose) were substantially higher than the 90% inhibitory concentration calculated from HIV-1 clinical isolates. Neither increasing the saquinavir-SGC dose to higher than 1,600 mg nor increasing ritonavir from 100 to 200 mg appeared to further enhance the AUC. These results suggest that an all once-daily HAART regimen, utilizing saquinavir-SGC plus a more tolerable low dose of ritonavir, may be feasible. Studies of once-daily saquinavir-SGC (1,600 mg) in combination with ritonavir (100 mg) in HIV-infected patients are underway.
Background: Medication nonadherence in the treatment of chronic diseases compromises the effectiveness of therapy. Little information is available about the extent of medication adherence or determinants of medication adherence in HIV disease, an issue of increasing importance in this new therapeutic era of combination antiretroviral therapy. Methods: We studied 244 HIV-infected Medicaid-insured patients attending an HIV hospital-based clinic regarding the extent of and predictors of adherence to antiretroviral therapy and Pneumocystis carinii pneumonia (PCP) prophylaxis. Patients were asked to report medications being taken, patterns of use, and knowledge and attitudes about HIV therapies. Medical record report of type, dose, and frequency of medication was compared with self-report using the kappa statistic. Urine sulfamethoxazole assay was obtained from patients prescribed sulfamethoxazole-trimethoprim. Results: Among patients prescribed antiretroviral therapy, 60% reported greater than or equal to 80% adherence in the previous 7 days; 49% reported greater than or equal to 80% adherence with PCP prophylaxis in the previous seven days. Seventy-nine percent of patients who reported taking daily sulfamethoxazole-trimethoprim had detectable urinary sulfamethoxazole. In multivariate analysis, greater than or equal to 80% adherence to antiretroviral therapy was associated with taking medication less than or equal to twice a day (odds ratio [OR] = 1.44; 95% confidence interval [CI], 1.01, 1.96), being likely to take medication when not at home, (OR = 1.41; 95%CI, 1.04, 2.00) and patients' belief in their ability to adhere to therapy (OR = 1.57; 95%CI, 1.13, 2.17). For PCP prophylaxis, greater than or equal to 80% adherence was associated with presence of family (OR = 2.39; 95%CI, 1.01, 5.63) and patients' belief in their ability to adhere to therapy (OR = 2.87; 95%CI, 1.44-1.78). Sociodemographic characteristics and belief in the efficacy of medications were not associated with adherence. Conclusions: A relatively low level of adherence to antiretroviral therapy and PCP prophylactic regimens was found. Although our results are principally from patients receiving antiretroviral monotherapy, these findings may have important implications for patients receiving highly active antiretroviral therapy (HAART). Decreasing the complexity of antiretroviral regimens, and working with patients to modify identified barriers to adherence may improve effectiveness of medications and prolong survival.
Objective
To update recommendations for antiretroviral therapy for adult human
immunodeficiency virus type 1 (HIV-1) infection, based on new information
and drugs that are available.
Participants
A 17-member international physician panel with antiretroviral research
and HIV patient care experience initially convened by the International AIDS
Society–USA in December 1995.
Evidence
Available clinical and basic science data including phase 3 controlled
trials; data on clinical, virologic, and immunologic end points; research
conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations
were limited to therapies available (US Food and Drug Administration approved)
in 1999.
Consensus Process
The panel assesses new research reports and interim results and regularly
meets to consider how the new data affect therapy recommendations. Recommendations
are updated via full-panel consensus. Guidelines are presented as recommendations
if the supporting evidence warrants routine use in the particular situation
and as considerations if data are preliminary or incomplete but suggestive.
Conclusions
The availability of new antiretroviral drugs has expanded treatment
choices. The importance of adherence, emerging long-term complications of
therapy, recognition and management of antiretroviral failure, and new monitoring
tools are addressed. Optimal care requires individualized management and ongoing
attention to relevant scientific and clinical information in the field.
Background
The introduction of combination antiretroviral therapy and protease inhibitors has led to reports of falling mortality rates among people infected with HIV-1. We examined the change in these mortality rates of HIV-1-infected patients across Europe during 1994-98, and assessed the extent to which changes can be explained by the use of new therapeutic regimens.
Methods
We analysed data from EuroSIDA, which is a prospective, observational, European, multicentre cohort of 4270 HIV-1-infected patients. We compared death rates in each 6 month period from September, 1994, to March, 1998.
Findings
By March, 1998, 1215 patients had died. The mortality rate from March to September, 1995, was 23·3 deaths per 100 person-years of follow-up (95% Cl 20·6–26·0), and fell to 4·1 per 100 person-years of follow-up (2·3–5·9) between September, 1997, and March, 1998. From March to September, 1997, the death rate was 65·4 per 100 person-years of follow-up for those on no treatment, 7·5 per 100 person-years of follow-up for patients on dual therapy, and 3·4 per 100 person-years of follow-up for patients on triple-combination therapy. Compared with patients who were followed up from September, 1994, to March, 1995, patients seen between September, 1997, and March, 1998, had a relative hazard of death of 0·16 (0·08–0·32), which rose to 0·90 (0·50–1·64) after adjustment for treatment.
Interpretation
Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the begining of 1998 were less than a fifth of their previous level. A large proportion of the reduction in mortality could be explained by new treatments or combinations of treatments.
Background: PISCES (SV14604) was the largest study of antiretroviral therapy to assess clinical end-points. The study data provides a repository of important information, much of which remains relevant today. This paper reviews the results of the PISCES study, placing the findings in context with today's treatment practices.Objective: To determine the antiretroviral efficacy of saquinavir hard gelatin capsule (SQV; Invirase) plus two nucleoside analogues [zidovudine (ZDV) and zalcitabine (ddC)] using clinical end-points.Design: Prospective, randomised, double-blind international study.Patients: HIV-1-infected individuals (CD4 50 to 350 cells/µl) who were antiretroviral-naïve or minimally pretreated with zidovudine (ZDV; 16 weeks) were randomised.Interventions: Patients received: (i) SQV + ZDV + ddC, (ii) SQV + ZDV, (iii) ZDV + ddC, or (iv) ZDV for 80 weeks or until the common closure date, at daily oral dosages of SQV 1800mg, ddC 2.25mg and ZDV 600mg. After 14 months, ZDV monotherapy patients were reallocated to receive additional SQV + ddC in a double-blinded manner.Main Outcome Measure: Time to clinical end-point of first AIDS-defining event (ADE) or death.Results: A total of 3591 patients were randomised, and 3485 received therapy. Median duration of study therapy was 58.4 to 63.3 weeks and mean duration of follow-up was 73.9 to 75.6 weeks. The time to first ADE or death was significantly reduced with triple therapy relative to ZDV + ddC (p = 0.0001, log rank test). The proportion of patients progressing to the primary clinical end-point was 8.0% for the triple therapy group compared with 15.1% for ZDV + ddC. Initiating triple therapy reduced the risk of progression by 50% relative to ZDV + ddC [risk ratio 0.502; (95% CI 0.379-0.663) p = 0.0001). Patients with prior ZDV therapy for <8 weeks achieved the greatest clinical benefit. HIV-1 RNA was reduced more by triple therapy than by either dual therapy (p = 0.0001), and this reduction explained 64% of the treatment effect. In an exploratory analysis, the primary end-point was reached by 8.0% of patients receiving immediate triple therapy, compared with 17.8% receiving initial ZDV monotherapy followed by triple therapy (p = 0.0001).Conclusions: This study was the first to show the benefit of triple therapy over dual therapy using clinical outcome measures; treatment with SQV + ZDV + ddC producing a statistically significant prolongation of time to first ADE or death in antiretroviral-naïve/minimally pretreated patients, compared with combined nucleoside analogues only. The study also confirms the outcome benefit (time to first ADE or death) of immediate triple therapy over delayed triple therapy and the prognostic value of monitoring HIV-1 RNA (but not CD4 count). The potential of patient/clinician perception of therapy to influence study outcome was also demonstrated.
Objectives: To compare the efficacy and safety of saquinavir soft gelatin capsules (SQV-SGC) and nelfinavir (NFV), with or without two concomitant nucleoside reverse transcriptase inhibitors (NRTIs), in an exploratory objective to identify populations most likely to benefit from quadruple therapy.
Design: Phase II/III, open-label, randomized, parallel-arm, multicenter trial.
Participants: Enrollment included 157 protease inhibitor-naive adults (>=13 years) with HIV-1 RNA >=10,000 copies/ml; 132 participants completed 48 weeks of therapy.
Interventions: SQV-SGC 1200 mg, NFV 750 mg, SQV-SGC 800 mg plus NFV 750 mg, all with two NRTIs, and SQV-SGC 800 mg plus NFV 750 mg alone, all three times daily for 48 weeks.
Main outcome measures: Proportion of participants with HIV-1 RNA <50 copies/ ml (16 and 48 weeks); time to virologic relapse (48 weeks).
Results: Proportions of patients with HIV RNA <50 copies/ml were not statistically significantly different between arms at 16 or 48 weeks, although trends favored the quadruple-therapy arm. In patients experiencing virologic relapse, time to relapse was statistically significantly longer in the quadruple-therapy arm than in the other three arms (p = .007). Quadruple therapy provided benefit in NRTI-experienced patients and those with viral loads above the median value at baseline. Adverse events were mainly mild gastrointestinal disorders in all treatment arms.
Conclusions: Quadruple therapy, including SQV-SGC and NFV, gave a more durable response than triple therapy with either single protease inhibitor. Quadruple therapy might particularly benefit NRTI-experienced patients and those with high baseline viral loads.
(C) 2000 Lippincott Williams & Wilkins, Inc.
Objective: A Phase II, open-label, randomized, parallel-arm, multicentre trial to compare the antiviral activity and safety of two formulations of saquinavir (SQV), soft gelatin (SQV-SGC) and hard gelatin (SQV-HGC) capsules, in combination with two nucleoside reverse transcriptase inhibitors (NRTI), in antiretroviral-naive, HIV-1-infected individuals.
Participants: A total of 171 people of ≥ 13 years, with plasma HIV-1 RNA levels ≥ 5000 copies/ml, who had received no protease inhibitor therapy, ≤ 4 weeks NRTI therapy and no antiretroviral treatment within 28 days of screening. Eighty-one people were randomized to the SQV-HGC group and 90 to the SQV-SGC group. A total of 148 patients completed 16 weeks of therapy.
Intervention: Therapy for 16 weeks with either SQV-SGC 1200 mg or SQV-HGC 600 mg, both three times a day, in combination with two NRTI.
Results: Using an on-treatment analysis, patients taking SQV-SGC had a larger reduction in plasma HIV-1 RNA than those taking SQV-HGC (-2.0 versus -1.6 log10 copies/ml). Eighty per cent of those on SQV-SGC had < 400 copies HIV RNA/ml, compared with 43% in the SQV-HGC group (P = 0.001). A statistically significant difference in the area under the curve (AUC) values between the SQV-SGC and SQV-HGC arms (-1.7 versus -1.5 log10 copies/ml, respectively; P = 0.0054) was observed when withdrawals prior to week 12, major protocol violators and patients with < 75% compliance were excluded from the analysis; however, the difference between the values for the intent-to-treat population was not significant (P = 0.1929). Adverse events (mostly mild) included diarrhoea and nausea.
Conclusions: SQV-SGC was generally well tolerated and gave significantly more potent suppression of plasma HIV-1 RNA in antiretroviral-naive patients than SQV-HGC.
Objective: To correlate self-reported antiretroviral adherence with virologic suppression.
Design: Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA.
Setting: Five university-affiliated HIV clinics.
Patients: A group of 173 HIV-infected patients with a mean baseline CD4 count of 142¥106 cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively.
Intervention: Individualized, unrestricted antiretroviral therapy.
Measurements: Patients were classified into four groups by adherence to therapy in the previous 4 weeks (<80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly.
Results: Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P=0.009 for linear trend). Patients reporting <80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19¥106 CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72¥106 CD4 cells/l in those reporting 100% adherence (P=0.02).
Conclusion: Self-reported poor adherence (<80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.
National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997.
Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid.
The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.
The literature was reviewed in an effort to relate frequency of dosing and other influences with patient compliance in medication taking. Once-a-day and twice-a-day regimens were associated with significantly better compliance (73% and 70%, respectively) than were three-times-daily (52%) and four-times-daily (42%) regimens. Compliance is not related to income, social class, occupation, or educational background, and it cannot be accurately predicted by physicians. Unintentional errors in taking medication are made by 50% to 90% of patients.
A Phase II, open-label, randomized, parallel-arm, multicentre trial to compare the antiviral activity and safety of two formulations of saquinavir (SQV), soft gelatin (SQV-SGC) and hard gelatin (SQV-HGC) capsules, in combination with two nucleoside reverse transcriptase inhibitors (NRTI), in antiretroviral-naive, HIV-1-infected individuals.
A total of 171 people of > or = 13 years, with plasma HIV-1 RNA levels > or = 5000 copies/ml, who had received no protease inhibitor therapy, < or = 4 weeks NRTI therapy and no antiretroviral treatment within 28 days of screening. Eighty-one people were randomized to the SQV-HGC group and 90 to the SQV-SGC group. A total of 148 patients completed 16 weeks of therapy.
Therapy for 16 weeks with either SQV-SGC 1200 mg or SQV-HGC 600 mg, both three times a day, in combination with two NRTI.
Using an on-treatment analysis, patients taking SQV-SGC had a larger reduction in plasma HIV-1 RNA than those taking SQV-HGC (-2.0 versus -1.6 log10 copies/ml). Eighty per cent of those on SQV-SGC had < 400 copies HIV RNA/ml, compared with 43% in the SQV-HGC group (P = 0.001). A statistically significant difference in the area under the curve (AUC) values between the SQV-SGC and SQV-HGC arms (-1.7 versus -1.5 log10 copies/ml, respectively; P = 0.0054) was observed when withdrawals prior to week 12, major protocol violators and patients with < 75% compliance were excluded from the analysis; however, the difference between the values for the intent-to-treat population was not significant (P = 0.1929). Adverse events (mostly mild) included diarrhoea and nausea.
SQV-SGC was generally well tolerated and gave significantly more potent suppression of plasma HIV-1 RNA in antiretroviral-naive patients than SQVHGC.
The introduction of combination antiretroviral therapy and protease inhibitors has led to reports of falling mortality rates among people infected with HIV-1. We examined the change in these mortality rates of HIV-1-infected patients across Europe during 1994-98, and assessed the extent to which changes can be explained by the use of new therapeutic regimens.
We analysed data from EuroSIDA, which is a prospective, observational, European, multicentre cohort of 4270 HIV-1-infected patients. We compared death rates in each 6 month period from September, 1994, to March, 1998.
By March, 1998, 1215 patients had died. The mortality rate from March to September, 1995, was 23.3 deaths per 100 person-years of follow-up (95% CI 20.6-26.0), and fell to 4.1 per 100 person-years of follow-up (2.3-5.9) between September, 1997, and March, 1998. From March to September, 1997, the death rate was 65.4 per 100 person-years of follow-up for those on no treatment, 7.5 per 100 person-years of follow-up for patients on dual therapy, and 3.4 per 100 person-years of follow-up for patients on triple-combination therapy. Compared with patients who were followed up from September, 1994, to March, 1995, patients seen between September, 1997, and March, 1998, had a relative hazard of death of 0.16 (0.08-0.32), which rose to 0.90 (0.50-1.64) after adjustment for treatment.
Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the beginning of 1998 were less than a fifth of their previous level. A large proportion of the reduction in mortality could be explained by new treatments or combinations of treatments.
To compare the efficacy and safety of indinavir 800 mg three times a day, ritonavir 600 mg twice a day, and a combination of ritonavir 400 mg twice a day and saquinavir 400 mg twice a day, when administered with two nucleoside analogues.
A randomized, open-labelled, controlled trial. Two hundred and eighty-four patients started randomized treatment. The primary end-point was the proportion of patients with HIV RNA of 200 copies/ml or less (Roche Amplicor) and HIV RNA of 20 copies/ml or less (Roche ultradirect assay) at 6 months. Analysis was performed as intent-to-treat, and missing values were accounted for as failures.
As of 1 May 1998, 269 patients should have completed 24 weeks of treatment. The proportion of patients with HIV RNA of 200 copies/ml or less was 71% (indinavir), 67% (ritonavir), and 82% (ritonavir + saquinavir), P = 0.07. In antiretroviral drug-naive patients (n = 119), the corresponding figures were 63, 57, and 89% (P < 0.01), whereas among drug-experienced patients (n = 165) 77, 74, and 77% had HIV RNA of 200 copies/ml or less (P = 0.90). The same pattern was observed in the ultradirect analysis. All three regimens were generally safe, but significantly more patients in the ritonavir group (37%) stopped treatment because of adverse drug reactions compared with the indinavir group (8%) and the ritonavir plus saquinavir group (16%) (P < 0.001).
Treatment with saquinavir plus ritonavir in combination with two nucleoside analogues is generally safe, and has superior short-term antiviral efficacy compared with indinavir and ritonavir also combined with two nucleoside analogues in antiretroviral drug-naive patients. Further follow-up is needed to determine the durability of the viral response.
To compare efficacy and tolerability of saquinavir soft gelatin capsule (SQV-SGC) formulation and indinavir, both given as part of a triple drug regimen containing zidovudine and lamivudine, in HIV-1-infected individuals.
Randomized, open label, multicentre study.
A total of 70 patients who were antiretroviral-naive and who had a CD4 cell count < 500 x 10(6)/I and/or > 10000 HIV RNA copies/ml plasma and/or HIV-related symptoms. Subjects were assigned randomly to zidovudine 200 mg three times per day plus lamivudine 150 mg twice per day plus either SQV-SGC 1200 mg three times per day (SQV-SGC group) or indinavir 800 mg three times per day (indinavir group). Data are presented for all patients up to week 24.
Mean baseline CD4 cell counts (+/- SE) were 301+/-29 x 10(6) cells/l and 310 +/-43 x 10(6) cells/l in the SQV-SGC and indinavir groups, respectively. The log10 median baseline HIV RNA load was 5.00 copies/ml in the SQV-SGC group and 4.98 copies/ml in the indinavir group. No difference in antiretroviral effect between the treatment arms could be demonstrated. Intention-to-treat analysis (last observation carried forward [LOCF]) at week 24 revealed that RNA levels decreased to < 50 copies/ml in 74.3% of patients in the SQV-SGC group and in 71.4% of the patients in the indinavir group (P = 0.78). In the on-treatment analysis the proportion of patients < 50 copies/ml at week 24 was 88.0% in the SQV-SGC group and 84.6% in the indinavir group (P = 0.725). Intriguingly, the mean increase of CD4 cells in the first 24 weeks was 162+/-20 x 10(6) cells/l in the SQV-SGC group and 89+/-21 x 10(6) cells/l in the indinavir group (P = 0.01), but preliminary data indicate that this difference in CD4 cell count gain may disappear after 24 weeks of treatment. Both regimens were generally well tolerated.
During the first 24 weeks of the study, we found no difference in antiviral potency between the indinavir group and the SQV-SGC group. A significantly higher CD4 response in the SQV-SGC group was observed.
The prevalence and severity of lipodystrophy syndrome with long-term therapy for HIV-1 infection that includes a protease inhibitor is unknown. We studied the natural course of the syndrome to develop diagnostic criteria and identifying markers that predict its severity.
We assessed 113 patients who were receiving HIV-1 protease inhibitors (mean 21 months) and 45 HIV-1-infected patients (28 with follow-up) never treated with a protease inhibitor. Lipodystrophy was assessed by questionnaire (including patients' rating of severity), physical examination, and dual-energy x-ray absorptiometry. Body composition and fasting lipid and glycaemic variables were compared with data obtained 8 months previously. Oral glucose tolerance was investigated.
There was 98% concordance between patients' reports of the presence or absence of lipodystrophy (reported by 83% of protease-inhibitor recipients and 4% of treatment-naïve patients; p=0.0001) and physical examination. Patients' ratings of lipodystrophy were significantly associated with declining total body fat (p=0.02). Lower body fat was independently associated with longer duration of protease-inhibitor therapy and lower bodyweight before therapy, and more severe lipodystrophy was associated with higher previous (p < 0.03) and current (p < or = 0.01) triglyceride and C-peptide concentrations, and less peripheral and greater central fat (p=0.005 and 0.09, respectively). Body fat declined a mean 1.2 kg over 8 months in protease-inhibitor recipients (p=0.05). The prevalence of hyperlipidaemia remained stable over time (74% of treated patients vs 28% of naïve patients; p=0.0001). Impaired glucose tolerance occurred in 16% of protease-inhibitor recipients and diabetes mellitus in 7%; in all but three patients these abnormalities were detected on 2 h post-glucose load values.
Diagnosis and rating severity of lipodystrophy is aided by the combination of physical examination, patient's rating, and measurement of body fat, fasting triglycerides, and C-peptide. Weight before therapy, fasting triglyceride, and C-peptide concentrations early in therapy, and therapy duration seem to predict lipodystrophy severity. Lipodystrophy was common and progressive after almost 2 years of protease inhibitor therapy, but was not usually severe. Hyperlipidaemia and impaired glucose tolerance were also common.
To correlate self-reported antiretroviral adherence with virologic suppression.
Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA.
Five university-affiliated HIV clinics.
A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively.
Individualized, unrestricted antiretroviral therapy.
Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly.
Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02).
Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.
The aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibitor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empirical mathematical modelling.
A randomised, non-blind, multicentre, dose-ranging 8-week study of monotherapy with 400, 800 or 1200 mg of saquinavir-SGC or 600 mg of the hard gelatin capsule (HGC) formulation, both administered 3 times daily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, were fitted to 2 measures of systemic drug exposure, the area under the plasma concentration-time curve (AUC) and trough plasma concentration (Cmin), using 6 exposure-response models of progressively increasing complexity. Akaike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic-pharmacodynamic relationship.
A total of 88 patients were randomised; pharmacokinetic and pharmacodynamic data were available for 84 patients. In terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-parameter maximum effect (Emax) model, which predicted a typical maximum reduction in viral load of 1.94 log10 copies/ml [coefficient of variation (CV) 12%], with a half-maximal antiviral response occurring at a Cmin of 50 micrograms/L (CV 40%). Saquinavir-SGC 1200 mg administered 3 times daily produced a median AUC to 24 hours (AUC24) of approximately 20,000 micrograms/L.h, corresponding to 85% of the maximum achievable antiviral effect as defined by the model. None of the models yielded a satisfactory fit for CD4+ cell count.
Empirical mathematical modelling confirmed that, when administered 3 times daily, the optimum dose of saquinavir-SGC is 1200 mg, corresponding to 3600 mg/day.
Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen.
The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours).
Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001). The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent) to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts increased significantly with all combinations (range of increases, 180 to 201 cells per cubic millimeter). More patients discontinued treatment because of adverse events in the group given indinavir and two nucleoside reverse-transcriptase inhibitors than in the group given efavirenz and two nucleoside reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005).
As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.
The objective was to compare the compliance of hypertensive patients treated with captopril twice daily or trandolapril once daily. After a 2-week placebo period, hypertensive patients (diastolic BP 95–115 mm Hg) were randomly allocated to trandolapril 2 mg once daily or to captopril 25 mg twice daily for 6 months. Trandolapril and captopril were packed in electronic pill-boxes equipped with a microprocessor that recorded date and time of each opening (MEMS®). Patients’ compliance was assessed both by standard pill-count and by electronic monitoring. Blood pressure was measured using a validated semi-automatic device at the end of the placebo period and of the treatment period.
One hundred sixty-two patients entered the study. Compliance data were evaluable for 133 patients (62 in the captopril group and 71 in the trandolapril group). Treatment groups were comparable at baseline except for age (P = .046). Using electronic pill-box, overall compliance was 98.9% in the trandolapril group and 97.5% in the captopril group (P = .002). The percentage of missed doses was 2.6% in the trandolapril group and 3.3% in the captopril group (P = .06). The percentage of delayed doses was 1.8% in the trandolapril group and 11.7% in the captopril group (P = .0001).
The percentage of correct dosing periods, ie, a period with only one correct recorded opening, was 94.0% in the trandolapril group and 78.1% in the captopril group (P = .0001). Results were unchanged when adjusted for age. At the end of the study, 41% of patients in the trandolapril group and 27% in the captopril group (NS) had their blood pressure normalized (systolic BP <140 and diastolic BP <90 mm Hg). In this 6-month study, the electronic pill-box allowed refined analysis of compliance of hypertensive patients. Patients’ compliance with once daily trandolapril was higher than with twice daily captopril. The between-group difference is mainly explained by an increase in delayed doses in the twice daily group.
To compare the efficacy and safety of saquinavir soft gelatin capsules (SQV-SGC) and nelfinavir (NFV), with or without two concomitant nucleoside reverse transcriptase inhibitors (NRTIs), in an exploratory objective to identify populations most likely to benefit from quadruple therapy.
Phase II/III, open-label, randomized, parallel-arm, multicenter trial.
Enrollment included 157 protease inhibitor-naive adults (> or = 13 years) with HIV-1 RNA > or = 10,000 copies/ml; 132 participants completed 48 weeks of therapy.
SQV-SGC 1200 mg, NFV 750 mg, SQV-SGC 800 mg plus NFV 750 mg, all with two NRTIs, and SQV-SGC 800 mg plus NFV 750 mg alone, all three times daily for 48 weeks.
Proportion of participants with HIV-1 RNA <50 copies/ ml (16 and 48 weeks); time to virologic relapse (48 weeks).
Proportions of patients with HIV RNA <50 copies/ml were not statistically significantly different between arms at 16 or 48 weeks, although trends favored the quadruple-therapy arm. In patients experiencing virologic relapse, time to relapse was statistically significantly longer in the quadruple-therapy arm than in the other three arms (p = .007). Quadruple therapy provided benefit in NRTI-experienced patients and those with viral loads above the median value at baseline. Adverse events were mainly mild gastrointestinal disorders in all treatment arms.
Quadruple therapy, including SQV-SGC and NFV, gave a more durable response than triple therapy with either single protease inhibitor. Quadruple therapy might particularly benefit NRTI-experienced patients and those with high baseline viral loads.
This is an open-label, single-arm, phase 3b study (part of phase 3 development) to evaluate the efficacy and safety of Fortovase-soft gelatin formulation (saquinavir-SGC), combined with zidovudine (ZDV) and lamivudine (3TC), human immune deficiency virus type 1 in (HIV-1)-positive, antiretroviral-naive individuals. Forty-two HIV-1-positive adults with plasma HIV RNA >10,000 copies per milliliter (Roche Amplicor HIV Monitor assay) and CD4 cell count >100 cells/mm(3) were treated with SQV-SGC, 1200 mg three times per day; ZDV, 300 mg; and 3TC, 150 mg each twice per day for 48 weeks. High proportions were drug users (26%), demonstrated psychiatric disorders (alcohol abuse [14%]/depression [14%]), or were inadequately housed (5%). At 48 weeks, 50% of patients achieved viral suppression <400 copies per milliliter with 43% <20 copies per milliliter using an intent-to-treat analysis (missing values counted as virological failures). Corresponding proportions for patients remaining on therapy at 48 weeks were 91% <400 copies per milliliter and 78% <20 copies per milliliter. Most adverse events were mild. Saquinavir-SGC combined with ZDV and 3TC, achieved potent and durable HIV RNA suppression and was well tolerated over 48 weeks in an antiretroviral-naive population including high proportions of individuals considered difficult to treat, such as drug users, people with psychiatric problems and homeless individuals.
How much adherence is enough? A prospective study of adherence to protease inhibitor therapy using MEMSCaps
- D Paterson
- S Swindells
- J Mohr
- M Brester
- E Vergis
- C Squier
- Wagener
- Singh
Paterson D, Swindells S, Mohr J, Brester M, Vergis E, Squier C, Wagener M & Singh N. How much adherence is enough? A prospective study of adherence to protease inhibitor therapy using MEMSCaps. 6th International Conference on Retroviruses and Opportunistic Infections, Chicago, Ill., USA, 31 January–4 Februay 1999, Abstract 92
A comparison of the long-term antiviral efficacy of BID and TID dosing of nelfinavir in combination with stavudine and lamivudine beyond 48 weeks
- A Petersen
- F Antunes
- Kn Aratesh
Petersen A, Antunes F & Aratesh KN. A comparison of the
long-term antiviral efficacy of BID and TID dosing of nelfinavir in combination with stavudine and lamivudine
beyond 48 weeks. Seventh European Conference on
Clinical Aspects and Treatment of HIV-infection, Lisbon,
Portugal, 23–27 October 1999. Abstract 205.
of the NV15355 Study Team Activity of soft gelatin capsule formulation of saquinavir in combination with two nucleosides in treatment-naïve HIV- 1 seropositive persons
- M Thompson
Thompson M, on behalf of the NV15355 Study Team.
Activity of soft gelatin capsule formulation of saquinavir in
combination with two nucleosides in treatment-naïve HIV-
1 seropositive persons. 12th World AIDS Conference,
Geneva, Switzerland, 28 June–3 July 1998. Poster.
Nelfinavir mesylate (NFV) increases saquinavir soft gel capsule (SQV-SGC) exposure in HIV+ patients
- S Kravcik
- J Sahai
- B Kerr
- R Anderson
- N Buss
- I Seguin
- N Bristw
- A Farnsworth
- M Salgo
- P Mastrodonato-Delora
- W Cameron
Kravcik S, Sahai J, Kerr B, Anderson R, Buss N, Seguin I,
Bristw N, Farnsworth A, Salgo M, Mastrodonato-Delora P
& Cameron W. Nelfinavir mesylate (NFV) increases
saquinavir soft gel capsule (SQV-SGC) exposure in HIV+
patients. 4th Conference on Retroviruses and
Opportunistic Infections, Washington, USA, 22–26
January 1997, Abstract 389.
Study Group Quadruple therapy with saquinavir soft gelatin capsules (SQV-SCG) plus nelfinavir (NFV) versus triple therapy with either SQV-SGC or NFV in patients with antiretroviral experience of high baseline viral load
- M Johnson
Johnson M, on behalf of the SPICE (NV15436) Study
Group. Quadruple therapy with saquinavir soft gelatin
capsules (SQV-SCG) plus nelfinavir (NFV) versus triple
therapy with either SQV-SGC or NFV in patients with
antiretroviral experience of high baseline viral load. 6th
International Conference on Retroviruses and
Opportunistic Infections. Chicago, Ill., USA, 31 January–4
February 1999, Abstract 389.
Saquinavir twice-or three-times daily for HIV infection Received 2
Saquinavir twice-or three-times daily for HIV infection
Received 2 November 2001; accepted 30 May 2002
Predictive Value of Response at 12 and 24 Weeks for Durability of Response in a Study of the Soft Gelatin Capsule Formulation of Saquinavir (SQV-SGC) plus 2 Nucleosides in Treatment-Naive HIV-1-Positive Patients
- C Tsoukas
Tsoukas C, on behalf of the nNV15355 study group.
Predictive Value of Response at 12 and 24 Weeks for
Durability of Response in a Study of the Soft Gelatin
Capsule Formulation of Saquinavir (SQV-SGC) plus 2
Nucleosides in Treatment-Naive HIV-1-Positive Patients.
6th Conference on Retroviruses and Opportunistic
Infections, Chicago, Ill., USA, 31 January to 4 February
1999, Abstract and poster 165.
Overview of patient compliance with medication dosing: a literature overview
- Rn Greenberg
Greenberg RN. Overview of patient compliance with
medication dosing: a literature overview. Clinical
Therapeutics 1984; 6:592–599.
Saquinavir soft gel capsule (Fortovase): pharmacokinetics and drug interactions
- N Buss
Buss N. Saquinavir soft gel capsule (Fortovase): pharmacokinetics and drug interactions. 5th Conference on
Retroviruses and Opportunistic Infections, Chicago, Ill.,
USA, 1–5 February 1998, Abstract 354.
Twice daily indinavir trial stopped
AIDSLINE. Twice daily indinavir trial stopped. Treatment
Update 1998; 10:3–4.
Pharmacokinetic (PK) drug interaction with saquinavir soft gelatin capsule
- K Jorga
- Ne Buss
Jorga K & Buss NE. Pharmacokinetic (PK) drug interaction with saquinavir soft gelatin capsule. 39th Interscience
Conference on Antimicrobial Agents and Chemotherapy,
San Francisco, Calif., USA, 26–29 September 1999, Poster
339.