Compliance is the appropriateness of patient behaviour to therapeutic prescriptions. Good compliance increases treatment efficacy although its constraints may harm quality of life. Factors affecting compliance are related to the patient, the disease, health-care workers, family and treatment itself. Psycho-sociologic theories have attempted to explain patient behaviour. In clinical trials, compliance has to be optimized, i.e. in the protocol, during the study and the statistical analysis. In real life, compliance concerns all those involved in health-care, particularly for education, training and motivation of the patients and their immediate environment. Observational surveys relating to compliance are needed to determine prioriites and to develop a "compliance approach" based on improving information and the use of tools for better therapeutic adherence. Evaluation of the quality of life and patient satisfaction aspects is necessary to validate this approach.

ABSTRACTThe objective of this study was to evaluate the antiretroviral efficacy and safety of ritonavir (600 mg twice a day [b.i.d.])-saquinavir (400 mg b.i.d.) compared to ritonavir (600 mg b.i.d.) in patients pretreated and receiving continued treatment with two nucleoside analogs. The study was placebo controlled, randomized, and double blind. Inclusion criteria included protease inhibitor naive status and a viral load of >10,000 copies/ml. The main end point was viral load at week 24. Forty-seven patients were included (25 given ritonavir and 22 given ritonavir-saquinavir) and monitored until week 48. At inclusion, 23% had had at least one AIDS-defining event. Previous treatment durations (mean and standard deviation) were 42 ± 25 and 37 ± 23 months, viral loads were 4.75 ± 0.62 and 4.76 ± 0.50 log10copies/ml, and CD4 cell counts were 236 ± 126 and 234 ± 125/mm3in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, viral loads were 2.81 ± 1.48 and 2.08 ± 1.14 log10copies/ml (P= 0.04) and CD4 cell counts were 330 ± 151 and 364 ± 185/mm3(P= 0.49) in the ritonavir and ritonavir-saquinavir groups, respectively. Similar results were observed at week 48. Moreover, at week 48, 40 and 68% (P= 0.05) and 28 and 59% (P= 0.03) of patients achieved viral suppression at below 200 and 50 copies/ml in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, six patients in the ritonavir group but only one in the ritonavir-saquinavir group had key mutations conferring resistance to protease inhibitors. Clinical and biological tolerances were similar in both groups. In nucleoside analog-pretreated patients, ritonavir-saquinavir has higher antiretroviral efficacy than and is as well tolerated as ritonavir alone.

Background Since eradication of HIV is unlikely, long‐term management of the disease necessitates careful evaluation of the combinations of currently available drugs to determine the most potent and useful rational sequencing of regimens. Objective To determine the antiretroviral efficacy and tolerability of saquinavir soft gelatin capsule (SQV‐SGC) plus zalcitabine (ddC) and stavudine (d4T), as first‐line treatment in HIV‐infected patients. Design Multicentre, open‐label, non‐comparative study. Patients and methods Thirty‐five asymptomatic, HIV‐infected adults with no prior antiretroviral treatment, a CD4 count ≥ 250 cells/μL and baseline ≥ 5000 HIV RNA copies/mL were included in the study. Patients received SQV‐SGC 1200 mg three times a day (tid), ddC 0.75 mg tid and d4T 30 or 40 mg twice a day (bid) for 24 weeks. Plasma HIV RNA, CD4 and CD8 cell counts, HIV reverse transcriptase and protease resistance genotypes, SQV plasma concentration and tolerability were evaluated. Results At baseline, median HIV RNA (interquartile range) was 4.99 (4.81–5.48) log 10 copies/mL, and median CD4 count was 370 (318–504) cells/μL (n = 35). At week 24, the median decrease in HIV RNA was 3.05 (2.19–3.68) log 10 copies/mL. A viral load below the level of quantification (200 copies/mL and 20 copies/mL) was achieved in 63% and 34% of patients, respectively (intent‐to‐treat analysis). The only mutations detected were L90M substitutions in two patients. At week 24, the median CD4 count increased (P < 0.0001), and CD8 cell counts decreased (P < 0.0001), relative to baseline. In total, there were five cases of peripheral neuropathy (14%). Mean triglyceride and cholesterol levels remained within normal ranges. Conclusions Triple therapy with SQV‐SGC plus ddC and d4T is a reasonably well tolerated regimen that markedly and rapidly reduces viral load with immunological improvement. This combination is an effective additional therapeutic option, with an efficacy that compares favourably to other triple regimens used in HIV treatment.

OBJECTIVE This study was undertaken to determine the placental transfer of the human immunodeficiency virus protease inhibitor saquinavir. STUDY DESIGN An ex vivo perfused human placental cotyledon model was used. Ten placental perfusion studies were performed, with concentrations of saquinavir in the maternal compartment ranging from 322 to 2197 ng/mL (within reference therapeutic ranges). Drug concentrations were determined by high-performance liquid chromatography. RESULTS The mean (+/- SD) fetal transfer rate of saquinavir was 1.8% +/- 1.6%, and the mean (+/- SD) clearance index was 0.05 +/- 0.05. A mean (+/- SD) of 1.6% +/- 3.1% of the perfused saquinavir was retained by the cotyledon. The small amount of saquinavir that crossed the placenta corresponded to the fraction not bound to human serum albumin. CONCLUSION The low rate of placental transfer of saquinavir suggests that use of this antiretroviral drug by pregnant women may not lead to significant exposure of the fetus.

ABSTRACTThe MIKADO trial was designed to evaluate the efficacy of stavudine-zalcitabine-saquinavir (soft gel capsule) [d4T-ddC-SQV(SGC)] in 36 naive patients (−3.3 log10units at week 24 [W24]). Among the 29 patients remaining on d4T-ddC-SQV(SGC) until W24, 10 harbored a virological failure (viral load of >200 copies/ml at W24) (group 1). To determine the reasons for therapeutic failure, genotypic and phenotypic resistance test results and SQV concentrations in plasma were analyzed and compared to those in successfully treated patients (viral load of <200 copies/ml at W24) (group 2). Reverse transcriptase and protease genotypic analyses in group 1 revealed the acquisition of only one SQV-associated mutation (L90M) in only two patients. There was no significant increase in the 50 or 90% inhibitory concentration of SQV in patients with or without the L90M mutation. However, the fact that two patients developed an L90M mutation only 4 weeks after relapse points to the need for genotypic resistance testing in the context of an initial failure of the antiretroviral regimen. At W24, the median SQV concentration in group 1 (71 ng/ml) was significantly lower than in group 2 (475 ng/ml), and the plasma SQV concentration was correlated with the viral load at W24 (r= −0.5;P< 0.05) and with the drop in viral load between day 0 and W24 (r= −0.5;P< 0.01). These results and the fact that the plasma SQV concentrations in the two groups prior to relapse (W12) were not significantly different strongly suggest that the early failure of this combination is not due to viral resistance but to a lack of compliance, pharmacological variability, and drug interactions or a combination of these factors.

Background: Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly increases saquinavir bioavailability, In this study we assessed the safety and antiretroviral efficacy of the combination of these two compounds in patients pretreated and receiving continued treatment with zidovudine and lamivudine who were protease inhibitor naive and who had a CD4 cell counts below 200/mm(3).Methods: In this 48-week pilot study, all patients received 600 mg ritonavir and 400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was continued without a change in previous doses. Viral load, CD4 cell count, and the emergence of resistance to the two protease inhibitors were evaluated repeatedly up to week 48.Results: Sixteen patients were included in the study. Previous nucleoside analog treatment duration was 48 +/- 22 months (mean +/- SD), Two patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose had to be reduced in 10 other patients because of side effects. Between inclusion and week 48, plasma viremia varied from 4.87 +/- 0.43 to 3.00 +/- 1.29 log(10) copies/mL and CD4 cell counts ranged from 98 +/- 61 to 250 +/- 139/mm(3). Ten patients (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50 copies/mL. A single key mutation that conferred ritonavir resistance I84V and V82A/V developed in two patients. A mutation at codon 54 developed in another patient. These mutations were associated with repeated cessations of antiretroviral treatment. No lipodystrophy was observed.Conclusion: Ritonavir and saquinavir in combination are quite well tolerated and induce a high and sustained antiretroviral efficacy. A four-drug combination that includes these two protease inhibitors should be considered as a first line of treatment in patients with low CD4 cell counts.

Allergic reactions to drugs occur more frequently in patients with AIDS than in the general population.1Carr A Cooper DA Penny R. Allergic manifestations of human immunodeficiency virus infection.J Clin Immunol. 1991; 11: 52-64Crossref Scopus (73) Google Scholar HIV-specific protease inhibitors have emerged as critical drugs in triple combination therapy for these patients, and nelfinavir (AG-1343) is one of the most recent and most potent.2Deeks SG Smith M Holodniy M Kahn JO. HIV-1 protease inhibitors. A review for clinicians.JAMA. 1997; 277: 145-153Crossref PubMed Google Scholar Hypersensitivity reactions have been observed with ritonavir and indinavir.3Bonfanti P Capetti A Riva P Testa L Quirino T. Hypersensitivity reactions during antiretroviral regimens with protease inhibitors.AIDS. 1997; 11: 1301-1302PubMed Google Scholar We report here 3 cases of urticaria induced by nelfinavir (Viracept), with positive reintroduction challenges. Two of these patients were successfully desensitized to nelfinavir. Three HIV-infected men (36, 37, and 40 years old) were treated with nelfinavir 750 mg 3 times daily because of a resistance to the 3 other protease inhibitors commercialized in France (ritonavir, indinavir, and saquinavir). They were also all taking zidorudine 250 mg twice daily, didanosine 300 mg daily, and trimethoprim/sulfamethoxazole 80/400 mg daily for over 12 months. They had no personal history of atopic diseases and no history of adverse reactions to any drug. Eight to 10 days after starting nelfinavir, they developed a generalized urticaria. Nelfinavir was withdrawn and antihistamines were started, leading to the disappearance of the cutaneous reaction within 4 to 6 days. Patient 3 also took betamethasone 8 mg daily for 4 days and reintroduced nelfinavir 6 days later at the dose of 250 mg 3 times daily (without informing his physician). Patient 3 experienced similar symptoms within 5 days. We did not perform any skin testing. Because these patients had very low CD4 cell counts (65, 37, and 6/mm3 respectively) and high viral loads (103,125, 370,000, and 363,000 copies/mL respectively) resistant to a 3-drug regimen containing other protease inhibitors (ritonavir, indinavir, and saquinavir), we decided to induce tolerance to nelfinavir. Desensitization protocols were started 12, 2, and 3 weeks, respectively, after nelfinavir was stopped. The drug was given at the following doses as crushed tablets. Patients 1 and 2 received 12 doses of nelfinavir at half-hour intervals (from 25 μg to 1000 mg) on a 1-day protocol (Table I) followed from day 2 by nelfinavir 750 mg 3 times daily. Table IOne-day nelfinavir desensitization protocol*Dose noNelfinavir (μg)Dose noNelfinavir (mg)1257252100850325091004100010250525001150067500121000*Twelve doses were prepared from a crushed 250 mg tablet and given orally at half-hour intervals. Open table in a new tab Patient 3 received 250 mg of nelfinavir the first day and increased his dose by 250 mg every 3 days on a 3-week protocol up to 750 mg 3 times daily. Patients 1 and 2 both experienced a mild and transient rash with pruritus on days 2 and 10, respectively, reinforcing the hypersensitivity diagnosis. Patient 1 refused to carry on nelfinavir desensitization, although his symptoms were well controlled by antihistamines. Patients 2 and 3 were desensitized successfully and still tolerated nelfinavir after 6 months. The most common side effects after nelfinavir treatment are diarrhea (20%) and maculopapular rash (between 3% to 5% in different trials and access programs for over 6500 patients),4Saag M, Knowles M, Chang Y, Chapman S, Clendeninn NJ. Dual effect of Viracept (nelfinavir mesylate, NFV) in triple combination therapy. In: Program and abstracts of the Interscience Conference of Antimicrobial agents and Chemotherapy. Washington (DC): American Society of Microbiology; 1997 September; Toronto, Canada. Abstract I 101.Google Scholar none of which have been documented by reintroduction. Hypersensitivity reactions to other antiproteases (ritonavir and indinavir)3Bonfanti P Capetti A Riva P Testa L Quirino T. Hypersensitivity reactions during antiretroviral regimens with protease inhibitors.AIDS. 1997; 11: 1301-1302PubMed Google Scholar are less frequently observed than with sulfonamides,1Carr A Cooper DA Penny R. Allergic manifestations of human immunodeficiency virus infection.J Clin Immunol. 1991; 11: 52-64Crossref Scopus (73) Google Scholar but such reactions have been observed. Most of them were cutaneous eruptions. Cytochrome P450 metabolites of these drugs2Deeks SG Smith M Holodniy M Kahn JO. HIV-1 protease inhibitors. A review for clinicians.JAMA. 1997; 277: 145-153Crossref PubMed Google Scholar may possibly be involved as they are in sulfonamide hypersensitivity.1Carr A Cooper DA Penny R. Allergic manifestations of human immunodeficiency virus infection.J Clin Immunol. 1991; 11: 52-64Crossref Scopus (73) Google Scholar Bonfanti et al3Bonfanti P Capetti A Riva P Testa L Quirino T. Hypersensitivity reactions during antiretroviral regimens with protease inhibitors.AIDS. 1997; 11: 1301-1302PubMed Google Scholar conducted an observational study in Italy to evaluate the occurrence of such reactions and recently reported 13 hypersensitivity reactions in 238 patients treated with protease inhibitors (7 of 56 with ritonavir, 6 of 132 with indinavir, and 0 of 50 with saquinavir). Mean time to the reaction was 16 and 25 days for ritonavir and indinavir, respectively, which were 1 to 2 weeks longer than our observation with nelfinavir. The authors made a relationship between the different rates of reactions observed (12.5% for ritonavir, 3.7% for indinavir, and 0% for saquinavir) and the degree of interaction that each drug shows with cytochrome P450,3Bonfanti P Capetti A Riva P Testa L Quirino T. Hypersensitivity reactions during antiretroviral regimens with protease inhibitors.AIDS. 1997; 11: 1301-1302PubMed Google Scholar although saquinavir is also metabolized by the 3A4 isoform of the cytochrome P450.2Deeks SG Smith M Holodniy M Kahn JO. HIV-1 protease inhibitors. A review for clinicians.JAMA. 1997; 277: 145-153Crossref PubMed Google Scholar Nelfinavir is also metabolized by cytochrome P450 3A, as shown by in vivo animal studies and in vitro studies in human microsome preparations.5Webber S, Shetty B, Wu E, Zorbas M. In vitro and in vivo metabolism and cytochrome P450 induction studies with the HIV-1 protease inhibitor, Viracept (AG1343). In: Program and abstracts of the Third Conference on Retroviruses and Opportunistic Infections. Alexandria (VA): Foundation for Retrovirology and Human Health; 1996 Jan 28-Feb 1; Washington, DC. Abstract 144.Google Scholar Whether this pathway could be involved in hypersensitivity reactions is unknown. The rashes that patients 1 and 2 experienced after the desensitization protocol were far milder and lasted for a shorter period of time than the original urticarial reactions, strongly suggesting that simply continuing nelfinavir with the addition of antihistamines if patients are seen immediately cannot be recommended. Thus desensitization to nelfinavir can help patients with HIV resistant to other protease inhibitors and hypersensitive to this drug to tolerate and carry on nelfinavir treatment. Moreover, a powder form of nelfinavir is now available in France, which would allow easier protocols. Finally, desensitization implies an IgE mechanism that we did not establish, and test dosing , graded challenge , or tolerance induction may be preferable terms, as they are for sulfonamide hypersensitivity treatment.

BACKGROUND:Therapy for hepatitis B virus (HBV) infection is still unsatisfactory, particularly in patients who are co-infected with the human immunodeficiency virus (HIV). Lamivudine, a retroviral inhibitor, has been shown to have activity against HBV replication in vitro, in animal models, and in studies of immunocompetent persons. OBJECTIVE:To assess the efficacy of lamivudine in inhibiting HBV replication during a 12-month period in patients with both HBV and HIV infection. DESIGN:Prospective, open study. SETTING:University hospital. PATIENTS:40 consecutive patients (39 men and 1 woman) infected with both HIV and HBV. All had progressive HIV disease; were refractory to or unable to tolerate therapies other than lamivudine; and received lamlvudine, 600 mg/d or 600 mg/d followed by 300 mg/d, as therapy for HIV disease. MEASUREMENTS:Serum concentrations of HBV DNA were assessed every 2 months by using molecular hybridization. Polymerase chain reaction (PCR) for HBV DNA was done at baseline and was done at months 2, 6, and 12 only if the HBV DNA concentration was less than 5 pg/mL. RESULTS:Two groups were retrospectively identified at baseline: patients with high HBV replication (serum HBV DNA concentrations > 5 pg/mL) (n = 30) and patients with low HBV replication (serum HBV DNA concentrations < 5 pg/mL) (n = 10). After 12 months of treatment, 26 of 27 patients (96.3% [95% Cl, 81% to 99.9%]) who had had high HBV replication at baseline had serum HBV DNA concentrations less than 5 pg/mL. However, PCR could still detect HBV DNA in serum in 11.5% (Cl, 2% to 30%) of these patients. Among patients who had had low HBV replication at baseline, the results of PCR for serum HBV DNA became negative in the 6 patients who had had a positive result on PCR at baseline. No serious adverse events occurred during treatment. CONCLUSION:Although this study was not a randomized, blinded trial, it suggests that lamivudine is active against.

Patients with symptomatic gastrointestinal disease due to cytomegalovirus (CMV) were randomized to receive open-label ganciclovir (22) or foscarnet (26). Patients were stratified by disease site and concurrent gut infection. Response was assessed by a visual analogue score of symptoms, endoscopic appearances, histologic inflammation, and numbers of CMV inclusions. In each treatment group, 73% had a complete or good clinical response; 83% of foscarnet-treated and 85% of ganciclovir-treated patients showed response by endoscopy, and inclusion bodies disappeared from follow-up biopsies in 73% of these. Most patients (35) developed further evidence of CMV disease during follow-up. The time to progression was not significantly different between recipients (16 weeks) and nonrecipients (13 weeks) of maintenance therapy, although patients were not randomized to receive maintenance or not. Survival in both treatment groups was < 40 weeks and was unaffected by maintenance treatment. Both ganciclovir and foscarnet are effective first-line treatments for gastrointestinal (GI) CMV infection. Maintenance therapy does not prevent progression of disease.

protective level of immunity (> 10 IU/L) up to 10 years, whereas individuals with initial post-vaccination titres in the range 500-4000 IU/L would need to be given a booster dose at 5 years.With a more probable scenario, in which titre is inversely proportional to time-since-vaccination,' individuals having initial titres greater than 500 IU/L would not need to be revaccinated within 10 years, and perhaps would never need revaccination; this serves to underline our basic position that booster doses within 10 years are largely unnecessary.