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PubMed1999

Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial.

OBJECTIVES: 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. DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

Adult↗
PubMed1999

Modulation of P-glycoprotein function in human lymphocytes and Caco-2 cell monolayers by HIV-1 protease inhibitors.

OBJECTIVES: To determine the effect of the protease inhibitors ritonavir, nelfinavir and indinavir on the P-glycoprotein (P-gp)-mediated transport of saquinavir in Caco-2 cell monolayers. To study the modulation of P-gp function in human lymphocytes by saquinavir, ritonavir, nelfinavir and indinavir. METHODS: We examined the effect of the protease inhibitors on P-gp function in human lymphocytes by using Rhodamine 123 (Rh 123; a fluorescent substrate of P-gp) by flow cytometry. Efflux of Rh 123 correlates with P-gp function and inhibition of P-gp results in dye retention. Verapamil, a P-gp modulator and inhibitor of active transport at 4 degrees C was used as a positive control. The transport of [14C]saquinavir (1 microM) across Caco-2 cell monolayers was investigated, alone and in the presence of verapamil and ketoconazole (500 microM) and the protease inhibitors at 100 microM. Caco-2 cells are an in vitro model of the intestinal epithelium that is widely used for the study of P-gp function. The transport of saquinavir was determined in both the apical to basolateral (AP-BL) and basolateral to apical (BL-AP) directions. RESULTS: Saquinavir and ritonavir (10 microM) markedly inhibited Rh 123 efflux with an increase in fluorescence intensity similar to that obtained with verapamil. A small but statistically significant increase in fluorescence intensity was observed with nelfinavir; however indinavir did not modulate Rh 123 efflux. In Caco-2 cells the apparent permeability coefficient for BL-AP efflux of saquinavir exceeded that for AP-BL efflux by a factor of 26: this is indicative of an active efflux pump. Known P-gp modulators caused a decrease in BL-AP efflux and an increase in AP-BL transport. The protease inhibitors displayed some P-gp modulation with ritonavir having the most potent effect. CONCLUSIONS: We have demonstrated that saquinavir is a substrate for P-gp and that ritonavir, nelfinavir and indinavir modulate P-gp function in both human lymphocytes and Caco-2 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir.

OBJECTIVE: To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development. DESIGN: Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy. METHODS: The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >/= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level. RESULTS: The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity. CONCLUSIONS: Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.

AIDS-Related Opportunistic Infections↗
PubMed2000

Renal toxicity of protease inhibitors.

Introduction of several classes of antiviral agents for the treatment of immunodeficiency virus has led to increased survival and improved quality of life for patients with HIV infection. Protease inhibitors have become the mainstays of current therapy in patient with AIDS. Renal intolerance of indinavir is a rare but important complication in HIV positive patients. The renal function of patients receiving indinavir should be closely monitored. Benign and asymptomatic crystalluria occurs in 4-13% of HIV positive patients. Several cases of acute renal failure, renal atrophy and interstitial nephritis have also been reported. A hydration protocol consisting of one to two liters of fluid should be initiated three hours after each indinavir dose. If significant renal insufficiency persists, temporary indinavir withdrawal or switching to another protease inhibitor should be considered.

Crystallization↗
PubMed1999

Insulin resistance in HIV protease inhibitor-associated diabetes.

BACKGROUND: Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy. OBJECTIVE: To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes. DESIGN: Cross-sectional evaluation. PATIENTS: 8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir. MEASUREMENTS: Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell function in vitro. RESULTS: In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat beta-cells. CONCLUSIONS: The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery.

Adult↗
PubMed2005

HIV protease inhibitors block adipocyte differentiation independently of lamin A/C.

OBJECTIVES: To determine the importance of lamin A/C for fat cell differentiation in vitro and for the anti-adipogenic activity of HIV protease inhibitors such as indinavir. METHODS: Lipodystrophy-associated and processing-defective mutants of lamin A were stably expressed at high levels in 3T3-L1 pre-adipocytes. Additionally, 3T3-L1 pre-adipocytes with stable reduction of lamin A/C or emerin were derived. The cells were differentiated for 8 days into mature adipocytes in the presence or absence of indinavir or nelfinavir. RESULTS: 3T3-L1 cells stably expressing high levels of lipodystrophy-associated or processing-defective mutants of lamin A differentiated with comparable efficiencies to control cells. Similarly, cells with dramatically reduced lamin A levels differentiated as efficiently as controls. Although indinavir stimulated the accumulation of unprocessed lamin A, cells with dramatically reduced lamin A/C levels and no detectable prelamin A remained responsive to an indinavir-induced inhibition of adipogenesis. CONCLUSIONS: The ability of HIV protease inhibitor to stimulate the accumulation of unprocessed lamin A is neither necessary nor sufficient to explain their anti-adipogenic activity. Furthermore, lamin A/C plays a minimal role in the differentiation of 3T3-L1.

Adipocytes↗
PubMed2002

Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease.

The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements seen in the second tightest inhibitor complex. This occurs as adaptations in the S1 pocket of one monomer propagate through the dimer and affect the conformation of the S1 loop near P81 of the other monomer. Therefore, structural rearrangements that occur within the protease when it binds to an inhibitor with a single modification must be accounted for in the design of inhibitors with multiple modifications. This consideration is necessary to develop inhibitors that bind sufficiently tightly to drug-resistant variants of HIV-1 protease to potentially become the next generation of therapeutic agents.

Anti-HIV Agents↗
PubMed2006

Quantitative SNP-detection method for estimating HIV-1 replicative fitness: application to protease inhibitor-resistant viruses.

We have improved the methods for the standard competitive growth assay of human immunodeficiency virus type 1 (HIV-1). The cloning step for the mixed viral population and subsequent genotype analysis for arbitrary numbers of clones were excluded from procedures. Instead, a single nucleotide polymorphism (SNP)-detection step was devised for the determination of viral populations. The quantitative SNP-detection method can rapidly estimate the proportion of wild-type and mutant populations with high reproducibility. Consequently, this method allows manipulation of many samples within a short period. Using this new competitive growth assay, replicative fitness of drug-resistant HIV-1 containing an M46I amino acid mutation in the protease was assessed in the presence or absence of indinavir. Without indinavir, replicative fitness of wild-type HIV-1 surpassed that of M46I-mutated HIV-1, and the fraction of mutated virus was reduced to about 10% at passage #9. In contrast, the fraction of M46I-mutated virus increased to >90% at passage #5 in the presence of 26.4 nM indinavir. Almost identical results were obtained for L90M-mutated HIV-1 with or without saquinavir. HIV-1 can survive under indinavir pressure by acquiring M46I mutation, as with acquisition of the L90M mutation under saquinavir pressure. However, these mutations damage viral replicative fitness under natural conditions without any drugs. Subtle differences between wild-type and mutant viruses are thus easily detected using the improved method.

Drug Resistance, Viral↗
PubMed2000

Variability in activity of hepatic CYP3A4 in patients infected with HIV.

STUDY OBJECTIVES: To evaluate hepatic cytochrome P450 (CYP) 3A4 activity in patients infected with the human immunodeficiency virus (HIV) using the erythromycin breath test (ERMBT), and to examine the relationship of the ERMBT to plasma concentrations of indinavir and nelfinavir. DESIGN: Prospective observational study. SETTING: University infectious diseases clinic. SUBJECTS: Thirty-nine HIV-positive patients and 47 healthy controls. INTERVENTION: After the ERMBT in patients and controls, 25 patients received indinavir or nelfinavir. MEASUREMENTS AND MAIN RESULTS: Compared with controls, ERMBT variability was significantly greater in HIV-positive patients, including a subset of 19 patients receiving no concurrent drugs reported to alter CYP3A4 activity. Correlation between the ERMBT and first-dose plasma indinavir concentrations nearly reached statistical significance (p=0.07). CONCLUSION: Variability in hepatic activity of CYP3A4 in HIV-positive patients may be greater than in controls and may explain some between-subject variability in plasma concentrations of indinavir. However, clearance mechanisms for protease inhibitors are complex, and if it is important to assess systemic exposure, the ERMBT is not a substitute for direct measurement of plasma concentrations.

Adolescent↗
PubMed2001

The safety and antiviral effect of protease inhibitors in children.

STUDY OBJECTIVE: To determine the safety and antiviral effect of protease inhibitors (PIs) over 36 months in pediatric patients infected with the human immunodeficiency virus (HIV). DESIGN: Observational study SETTING: Pediatric immunodeficiency clinic. PATIENTS: Twenty-one children. INTERVENTION: Demographics, dosage regimens, genotype data, viral RNA and CD4+ lymphocyte counts, adverse drug events (ADEs), laboratory tests, and compliance were evaluated over 3 years. Data were analyzed by chi2, repeated measures analysis of variance, and paired t tests. MEASUREMENTS AND MAIN RESULTS: Twenty-one pediatric patients (aged 3 mo-15 yrs) received PIs over the study period. Average daily doses were ritonavir 26 mg/kg in 12 patients, nelfinavir 94 mg/kg in 16, indinavir 49 mg/kg in 5, and saquinavir 43 mg/kg in 4. Five patients developed resistance to an existing PI. Overall compliance was 70%. Baseline HIV-1 RNA plasma concentrations were significantly higher than average follow-up concentrations during 3-36 months in patients taking ritonavir (p<0.001) and nelfinavir (p<0.001). Sample size was insufficient for indinavir or saquinavir. Sixty ADEs occurred, diarrhea being most common. Of patients with ADEs, 55% required increased monitoring and 43% treatment. Ritonavir was associated with the most ADEs (28), followed by nelfinavir (16), indinavir (11), and saquinavir (5). Significant increases between baseline and follow-up cholesterol levels were found with ritonavir (p=0.02) and nelfinavir (p=0.001), and for serum creatinine (p=0.02) and triglycerides (p=0.02) with ritonavir. Follow-up triglycerides were significantly higher than baseline for indinavir (p=0.003). CONCLUSION: Nelfinavir and ritonavir were effective in decreasing HIV-1 viral loads and improving CD4+ lymphocyte counts. Ritonavir was associated with more ADEs than other PIs. Changes in cholesterol, serum creatinine, and triglycerides were noted with some PIs.

Adolescent↗
PubMed2005

Effects on immunological and virological outcome of patients using one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor in a triple antiretroviral therapy: normal clinical practice versus clinical trial findings.

We compared the response of two standard 3-drug regimens containing two-nucleoside reverse transcriptase inhibitor (Zidovudine +Lamivudine) plus either a protease inhibitor (PIs) (Indinavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTIs) (Efavirenz) among treatment-naïve or treatment-experienced HIV-infected persons. The obtained results will be compared to clinical trial findings. Through a retrospective study, we compared the virological and immunological response of 119 Tunisian HIV-1 infected patients (North Africa) who started for the first time/ in salvage use a triple antiretroviral treatment containing one NNRTI (group A1/group A2) or one PI (group B1/group B2). Viral load (VL) was analysed with Amplicor HIV-1 Monitor test and drug resistance mutations were examined by using two distinct line probe assays (LiPA). The analysis according to the received treatment showed an average of 0.45 log(10) drop in the mean VL among groups A2 and B2. For naïve patients, 62.5% of group A1 reached an undetectable VL versus 53.5% for group B1 (p < 0.001). With regard to the CD4 cell count change, we observed a mean increase of more than 65% versus baseline within group A1 in comparison with 42% for group B1 (p < 0.001). Genotypic resistance assays showed that patients of group A2 had significantly more resistance mutations than those of group B2 (2.66 vs. 0.75 (p = 0.0039)). Finally, 15 patients who were failing were switched to indinavir or efavirenz. When indinavir was replaced by efavirenz, we observed an increase in the plasma VL. With regard to the effects on immunological and virological outcome of patients using PIs or NNRTIs in a triple antiretroviral therapy, our observations in normal clinical practice supported the reported clinical trial findings but are not in favour of replacing indinavir by efavirenz in failing regimen.

Adult↗
PubMed2002

Longitudinal use of phenotypic resistance testing to HIV-1 protease inhibitors in patients developing HAART failure.

An "in-house" recombinant virus protease inhibitor susceptibility assay was carried out (median of 3 per patient) retrospectively in 26 patients failing HIV protease inhibitor based therapy at regular intervals to the initiation of the first protease inhibitor. Patients were treated with either indinavir (N = 6), ritonavir (N = 10), or saquinavir (N = 10) and two nucleoside analogues. Second line therapy was based on single or dual protease inhibitor regimens occasionally containing nelfinavir. Clinically relevant resistance cut-offs associated with a poorer virological outcome from 6 months on and the clinical outcome from 3 months on were determined tentatively as 4- to 8-fold resistance for indinavir and ritonavir and 2.5- to 8-fold to saquinavir. In addition, the degree of cross-resistance at the time of the change of protease inhibitor was associated with the response in viral load at 6 months to the second line therapy (P = 0.018). Cross-resistance (> or = 8-fold) between ritonavir and indinavir was common (78 and 100%). Cross-resistance between indinavir or ritonavir and saquinavir was less frequent (75 and 60% respectively) than the opposite (100%, P = 0.004). Cross-resistance to nelfinavir was encountered more frequently (> 70%) than to amprenavir (9%). The magnitudes of resistance were correlated between each other. In summary, the protease inhibitor susceptibility carried out longitudinally appears to be an earlier prognostic marker than viral load in a context of cross-resistance. The magnitude of resistance, as a marker of cross-resistance, should be useful to guide second line therapy.

Antiretroviral Therapy, Highly Active↗
PubMed1999

Paclitaxel in the treatment of human immunodeficiency virus 1-associated Kaposi's sarcoma--drug-drug interactions with protease inhibitors and a nonnucleoside reverse transcriptase inhibitor: a case report study.

PURPOSE: To describe the pharmacokinetics of paclitaxel and to investigate the interaction potential with protease inhibitors (indinavir, ritonavir, saquinavir) and the nonnucleoside reverse transcriptase inhibitor nevirapine, for which strong theoretical indications for clinically relevant drug interactions exist. METHODS: The 24-h plasma pharmacokinetics of paclitaxel (Taxol, given at 100 mg/m2 by 3-h intravenous infusion) and concomitantly infused antiretroviral drugs were determined in a human immunodeficiency virus 1 (HIV-1)-infected male patient with refractory Kaposi's sarcoma (KS) during high-activity antiretroviral therapy and after discontinuation of this regimen. The plasma pharmacokinetics of paclitaxel, indinavir, ritonavir, saquinavir, and nevirapine were closely monitored. Since all these drugs are extensively metabolized via the cytochrome P450 enzyme system and are substrates for the multidrug transporter P-glycoprotein, investigation of drug-drug interactions was considered important. RESULTS: In this case report study the pharmacokinetics of paclitaxel given concomitantly with various antiretroviral drugs were comparable with those of historical controls who had been treated with single-agent paclitaxel. The pharmacokinetics of indinavir, ritonavir, saquinavir, and nevirapine were also not statistically significantly different from those recorded for historical controls. Paclitaxel was well tolerated and resulted in a significant clinical response in this patient. CONCLUSION: Dose adjustments of paclitaxel, indinavir, ritonavir, saquinavir, or nevirapine are apparently not needed if HIV-1-associated KS is treated with paclitaxel at a dose of 100 mg/m2 as shown in the present case. It is stressed, however, that controlled studies are necessary to substantiate these preliminary case report findings.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Resistance to HIV protease inhibitors.

Resistance to the HIV-1 protease inhibitor indinavir involves the accumulation of multiple amino acid substitutions in the viral protease. A minimum of 11 amino acid positions have been identified as potential contributors to phenotypic resistance. Three or more amino acid substitutions in the protease are required before resistance becomes measurable (> or = four-fold). Further losses in susceptibility follow the stepwise accumulation of additional amino acid substitutions, indicating that antiviral activity (selective pressure) is maintained despite the appearance of multiple amino acid substitutions in the viral protease. Importantly, the sequential nature of these changes indicates that the effects of these substitutions are additive, and that the evolution of resistance is driven by viral replication. This result has significant implications for therapy. It predicts that viral variants resistant to indinavir are unlikely to pre-exist in protease inhibitor-naive patients, and further, that high-level resistance can only develop if the virus is allowed to replicate in the presence of the drug. The use of indinavir in combination with other antiretroviral agents has been demonstrated to dramatically reduce the incidence of resistance mutations, suggesting that with maximal suppression of viral replication, long-term control of HIV-1 infection may be achievable. Thus, the goal of therapy must be to never to allow the virus to replicate. This can be best accomplished by initiating therapy with a maximally suppressive regimen, to reduce viral replication as much as possible, and by imposing a high genetic barrier to resistance. Previous use of other protease inhibitors or inadequate adherence to therapy may compromise the long-term benefit of indinavir by allowing the virus to gain a foothold through the development of resistance. An understanding of these issues will be critical in realizing the full potential of this potent new drug for the control of HIV-1 infection.

Drug Resistance, Microbial↗
PubMed1998

Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study.

BACKGROUND: Therapies containing two reverse transcriptase inhibitors (RTI) with or without protease inhibitors are used with increasing frequency in pregnant HIV-infected women. OBJECTIVE: To assess the safety of antiretroviral therapy in pregnant women and their newborns. METHODS: All clinical events and laboratory abnormalities in pregnant women on RTI with or without protease inhibitors and in their newborns were collected through an observational study. RESULTS: A total of 37 HIV-infected pregnant women have given birth to 30 children (by 30 April 1998). All received RTI, which were combined with protease inhibitors in 16 cases. Twelve women became pregnant while on treatment. Drugs used were as follows: zidovudine (n = 33), lamivudine (n = 33), stavudine (n = 4), indinavir (n = 9), ritonavir (n = 4), nelfinavir (n = 2) and saquinavir (n = 2). Adverse events during pregnancy were anaemia (n = 15), elevation of transaminases (n = 4), nausea/vomiting (n = 4), glucose intolerance (n = 2), nephrolithiasis (n = 2), diarrhoea (n = 2), hypertension (n = 1), insulin-requiring diabetes (n = 1). Adverse events in neonates were prematurity (n = 10), anaemia (n = 8), cutaneous angioma (n = 2), cryptorchidism (n = 2), transient hepatitis (n = 1). Non-life-threatening intracerebral haemorrhage occurred in a premature baby (33 weeks gestation) exposed during fetal life to zidovudine-lamivudine-indinavir, and in a term baby exposed to stavudine-lamivudine-indinavir. Extrahepatic biliary atresia occurred in one newborn exposed to zidovudine-lamivudine-indinavir. Maternal viral load was below 400 copies/ml in 18 out of 30 patients who delivered. One case of mother-to-child HIV transmission was identified. CONCLUSIONS: In HIV-infected pregnant women treated with two RTI with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies. In newborns, frequent prematurity, one case of biliary malformation and one intracerebral haemorrhage in a term baby are of concern. These observations do not preclude combination therapies during pregnancy but emphasize the necessity to maintain updated registers on their safety.

Anti-HIV Agents↗
PubMed2002

Therapeutic drug monitoring of HIV-protease inhibitors to assess noncompliance.

OBJECTIVE: To determine plasma concentration ratio limits (CORALS) for HIV-protease inhibitors outside of which random plasma concentrations reflect partial compliance or noncompliance. In the absence of a gold standard for measuring compliance and to avoid complex techniques, measuring plasma concentrations may be an objective and easy way to check noncompliance. METHODS: Pharmacokinetic curves after observed ingestion were recorded in patients on steady-state indinavir 800 mg TID (n = 22), ritonavir 400 mg/saquinavir 400 mg BID (n = 22, ritonavir; n = 17, saquinavir hard-gel capsules), or nelfinavir 750 mg TID (n = 4) or 1250 mg BID (n = 4). Concentration ratios were calculated by dividing the measured concentration by the median population value at the corresponding sampling time. Limits were based on the minimum P(05) (5th percentile) and maximum P(95) of these ratios found during the sampling interval. With these limits the authors determined (1) the proportion of patients falsely judged as noncompliers after observed ingestion, (2) discrimination between compliers and noncompliers, and (3) the absolute percentage of noncompliers. To judge the last two elements, two sets of random plasma samples were included: (1) samples sent in by the physician on suspicion of noncompliance (indinavir, n = 42; nelfinavir, n = 22;) or from a study population stating imperfect compliance in a questionnaire (ritonavir/saquinavir, n = 11); (2) control samples sent in routinely for monitoring therapeutic levels (indinavir, n = 41; nelfinavir, n = 201) or drawn from patients who stated perfect compliance in the questionnaire (ritonavir/saquinavir, n = 35). RESULTS: The following CORALS were found: indinavir <0.23 or >3.3; nelfinavir <0.36 or >2.1; ritonavir <0.18 or >1.9; saquinavir <0.28 or >2.3. In 31% to 55% of the patients suspected of noncompliance a plasma concentration ratio outside these limits was found. If a ratio was outside the limits, there was a 68% to 88% chance that that plasma sample belonged to a patient suspected of noncompliance, compared with the controls (all Chi-squared tests < 0.05). Compared with observed ingestion, these chances ranged from 87% to 92%. CONCLUSION: By using concentration ratio limits (CORALS), plasma samples of protease inhibitors with values outside these limits are highly indicative of partial or noncompliance.

Drug Monitoring↗
PubMed2003

The etiology of urolithiasis in HIV infected patients.

PURPOSE: It is commonly thought that urinary lithiasis in HIV infected patients on protease inhibitor therapy is composed primarily of the protease inhibitor itself. Since many HIV infected patients on protease inhibitors presenting to our institution had nonprotease inhibitor stones, we investigated potential underlying metabolic abnormalities that may account for the lithogenesis. MATERIALS AND METHODS: We retrospectively reviewed all HIV infected patients on protease inhibitors with renal colic and evidence of nephrolithiasis who presented to our institution between June 1996 and January 2001. Patients were evaluated for stone composition and metabolic abnormalities of blood and urine when possible. RESULTS: A total of 24 patients were identified, and all were or had been on protease inhibitors (indinavir 14, ritonavir 3, nelfnavir 2, unspecified 5). Of the 14 patients on indinavir only 4 (28.6%) had indinavir containing stones. The remaining stones in this group and in those not on indinavir contained various amounts of calcium oxalate monohydrate and dihydrate, ammonium acid urate and uric acid. Of 10 patients who underwent 24-hour urine collection for metabolic evaluation 8 (80%) had abnormalities, including hypocitraturia in 5, hyperoxaluria in 4, hypomagnesuria in 4, hypercalciuria in 3, increased supersaturation of calcium oxalate in 3 and hyperuricosuria in 2. Abnormalities in the levels of urinary phosphate and sodium were also observed. CONCLUSIONS: HIV infected patients form many types of stones, which probably are attributable to underlying metabolic abnormalities rather than the use of protease inhibitors. A complete metabolic evaluation is warranted in these patients, as a means of guiding treatment to prevent future stone episodes, while avoiding the need to alter antiretroviral regimens.

Adolescent↗
PubMed2003

Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients.

The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.

Adult↗