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PubMedDate not supplied

Efficacy of a nelfinavir- and nevirapine-containing salvage regimen.

PURPOSE: In this study, our purpose was to assess the efficacy of nelfinavir- and nevirapine-containing salvage regimens in nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients virologically failing a protease inhibitor (PI)-based combination. METHOD: A retrospective case note review of all patients virologically failing their PI-based combination who were switched to a regimen containing both nelfinavir (1 g t.d.s.) and nevirapine (200 mg b.d.). CD4 cell counts and viral loads were monitored. Genotypic analysis was performed using RT-PCR sequencing. RESULTS: Nineteen patients commenced a salvage regimen containing nelfinavir and nevirapine. Five patients also changed at least one nucleoside reverse transcriptase inhibitor (NRTI), although in one case this represented recycling. Thirty-eight percent (6/16) of patients achieved a viral load below the level of detection (BLD; <200 copies/mL; complete responders [CR]), 3 achieved <20 copies/mL. Five patients achieved > or =1 log drop (partial responders [PR]) that was not sustained over follow-up, and five failed to respond to therapy (nonresponders [NR]). CRs tended to have wild-type NNRTI and PI sequences relative to PRs and NRs. CONCLUSION: In heavily pretreated patients, a nelfinavir-and nevirapine-containing salvage regimen resulted in a virological response in 38% of patients that was sustained in 31% over 63 weeks.

Adult↗
PubMed2001

Nelfinavir desensitization.

OBJECTIVE: To report the first case of nelfinavir desensitization in an HIV patient who was intolerant to protease inhibitors. CASE SUMMARY: A 43-year-old HIV-positive white man was treated with several protease inhibitors. The patient developed rashes in response to all protease inhibitors. His viral load was controlled only in the presence of a protease inhibitor. The patient tolerated nelfinavir longer than the other agents; therefore, the decision was made to attempt to desensitize him to nelfinavir. A six-hour inpatient protocol was used, and he tolerated the procedure without event. His disease is now well managed without recurrence of the rash. DISCUSSION: The use of protease inhibitors has had a major impact on the morbidity and mortality of HIV-infected patients, Despite their benefits, this class of drugs is not without adverse effects. Allergic reactions in the form of rashes may develop, which can severely limit treatment options in HIV patients. We report the first case of rapid desensitization of nelfinavir in a patient who developed rashes to several protease inhibitors. CONCLUSIONS: Intolerance to protease inhibitors due to rash is a well-documented phenomenon. In HIV patients, this can limit treatment options severely. This case demonstrates how desensitization to nefinavir can be performed successfully.

Adult↗
PubMed2005

HIV-1 genotypes related to failure of nelfinavir as the first protease inhibitor treatment.

Combined antiretroviral therapy results in sustained viral suppression and a decrease in mortality and morbidity due to HIV infection. Intrinsic strength, durability and absence of cross-resistance are key factors in the selection of antiretrovirals. Failure with nelfinavir has been associated with two protease gene mutations, D30N and L90M. The D30N mutation does not result in cross-resistance with other protease inhibitors, and it decreases viral fitness. In order to check for this mutation after failure with nelfinavir, the 246 HIV-1 genotyping test was performed on virus samples from 55 patients with failure of nelfinavir as the first protease inhibitor. Most (84%) of the viral strains were of subtype B. Nucleosides associated with mutations (NAM) were observed in 80% of the tests; no INS69, complex 151, K65R and L74V mutations, which give multi-resistance to nucleoside analogue reverse transcriptase inhibitors to tenofovir and DDI, respectively, were observed. In the tests for protease gene mutations, the D30N mutation was found in 57%, L90M in 18% and the wild-type virus in 25%. These data are similar to published reports, showing that alternative therapies used after failure with nelfinavir may be more successful, as the D30N mutation does not cause cross-resistance to other protease inhibitors.

Drug Resistance, Viral↗
PubMed1999

Nelfinavir, a new protease inhibitor: early clinical results.

Nelfinavir is a potent inhibitor of the HIV-1 protease, which shows good inhibitory activity against HIV-1 in vitro. Initial clinical trials have shown that it has excellent activity in vivo in HIV-infected patients. The combination of 750 mg nelfinavir three times daily with zidovudine and lamivudine has been shown to cause a median reduction in HIV plasma RNA of approximately 2 log10 copies/ml, and to reduce plasma levels of RNA below the limit of detection (< 400 copies/ml) in 50-75% of patients after 12 months of treatment. This combination was associated with a mean increase of almost 200 CD4+ lymphocytes per mm3 at 12 months of therapy. The drug is well-tolerated, with mild diarrhea, which occurs in 12-20% of patients, being the most common side-effect. The pattern of initial protease mutations associated with nelfinavir resistance appears to be different from that seen with resistance to the other protease inhibitors, with the predominant initial mutation occurring at codon 30 of the HIV protease gene. Thus, initial trials indicate that nelfinavir is equivalent to other potent protease inhibitors and can be considered as a component in first-line combination therapy for HIV-infected patients.

Clinical Trials as Topic↗
PubMed2001

AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients.

The objective of our randomized, multicentre, double-blind, placebo-controlled study was to investigate the safety, tolerability, and antiretroviral and immunological effect of double and triple combination therapy regimens. A total of 105 antiretroviral therapy-naive patients were randomized to receive either zidovudine (300 mg twice per day) plus lamivudine (150 mg twice per day) plus nelfinavir placebo (three times per day) (n=52), or zidovudine/lamivudine (dose as before) plus nelfinavir (750 mg three times per day) (n=53) for 28 weeks. After this time, patients were allowed to switch to open-label zidovudine/lamivudine/nelfinavir. The overall log10 reduction from baseline in plasma HIV-1 RNA was significantly greater in the zidovudine/lamivudine/nelfinavir group than the zidovudine/lamivudine group (P=0.001; median treatment difference, -1.01 log10 copies/ml; 95% confidence interval -1.23 to -0.79), as measured by the average area under the curve minus baseline over 28 weeks. Increases from baseline in CD4 cell counts were statistically significantly greater in the zidovudine/ lamivudine/nelfinavir group (101.5 cells/ml) than the zidovudine/lamivudine group (47.0 cells/ml; P=0.027) at week 28. Of note, the addition of nelfinavir from weeks 28-52 led to an increase in the proportion of subjects with plasma HIV-1 RNA <400 copies/ml from 17% (9/52 patients on zidovudine/lamivudine) to 50% (13/26 patients who switched to zidovudine/lamivudine/nelfinavir). Incidence of drug-related adverse events was similar in the two groups, except for nausea (more common in zidovudine/lamivudine group; 40 versus 17%) and diarrhoea (more common in zidovudine/lamivudine/nelfinavir group; 45 versus 14%). In conclusion, our study confirms the efficacy of triple combination therapy with two nucleoside analogues and a protease inhibitor compared with double-nucleoside therapy. Interestingly, the addition of nelfinavir to zidovudine/lamivudine, even after 6 months of double nucleoside therapy, led to a substantial virological benefit that was sustained over 24weeks in a subset of patients.

Administration, Oral↗
PubMed2003

[Immunological, virological and clinical response in patients infected with HIV after highly active antiviral therapy with nelfinavir: prospective cohort study].

INTRODUCTION: To assess the long-term effectiveness, safety and response-related factors in a cohort of HIV-infected persons receiving antiretroviral therapy containing nelfinavir. Design and setting. Prospective, non-randomized multicenter study. METHOD: A total of 792 patients were included: 254 (32.1%) treatment-naive patients and 538 (67.9%) patients previously treated with protease inhibitors who were switched to a nelfinavir-containing regimen due to virological failure or intolerance. Factors related to virological response and to treatment failure were assessed by standard survival techniques and Cox proportional risk models. RESULTS: Nelfinavir was well tolerated; treatment had to be interrupted in only 57 patients (7.1%) because of toxicity. During a median follow-up of 12 months, 31 patients (3.9%) experienced a new AIDS-defining event or death, and 463 (58.4%) showed immunological response. Overall, 52% patients achieved plasma HIV-1 RNA levels below 500 copies/mL (57% of naive and 49% of previously treated patients), but a high rate of virological rebound (24% and 49%, respectively) was observed. Low baseline viral load and few prior treatments were factors related to virological response. Naive treatment status and a high increase in CD4 cell count were predictive of longer viral response. CONCLUSIONS: Highly active antiretroviral therapy with a nelfinavir-containing regimen was associated with favorable virological response in nearly half of previously treated patients, and most experienced clinical and immunological benefits. Nevertheless, the limited duration of virological response indicates the need for new alternative drugs.

Adult↗
PubMed2005

Safety of nelfinavir use during pregnancy. An experimental approach in rats.

This experimental study aimed to evaluate the safety of nelfinavir when administered in normal up to high doses during the entire period of rat pregnancy. The renal and liver compartments of both mothers and fetuses were studied. For this purpose, three groups of pregnant rats were treated with nelfinavir (E1 = 40 mg/kg; E2 = 120 mg/kg; E3 = 360 mg/kg; no. = 10 in every group) from "zero" up to the 20th day of gestation. These doses were divided into two daily administrations by gavage. Controls (no. = 10) received distilled water in the same schedule. At term-pregnancy, the rats were deeply anesthesized and blood samples were collected for alanine and aspartate aminotransferases, creatinine and urea determinations. Fragments of maternal and fetal livers and kidneys were taken and processed for histopathological study. In all groups blood transaminases were within the normal limits, as were the levels of creatinine and urea, thus indicating that the treatment with nelfinavir during the entire gestation was essentially devoid of liver or kidney effects which could result in altered metabolic parameters. Morphological (light microscopy) studies revealed that no significant effects of the drug could be detected regarding either maternal or fetal organs of the E1 and E2 groups. However, the maternal hepatocytes in the E3 group showed heterochromatic nuclei. In addition, there was some fatty infiltration, congested sinusoids and portal dilatation. It is concluded that only doses of nelfinavir used during the entire gestation in doses well above the usual human doses could be considered to be potentially hepatotoxic for the pregnant rat.

Animals↗
PubMed2006

Safety, efficacy, and tolerability of nelfinavir-containing antiretroviral therapy for patients coinfected with HIV and hepatitis C undergoing methadone maintenance.

The safety, efficacy, and tolerability of nelfinavir (NFV)-containing antiretroviral therapy were evaluated in patients coinfected with HIV and hepatitis C undergoing methadone maintenance at an urban outpatient opioid treatment program serving a minority adult population. Eligibility covered methadone-maintained patients coinfected with HIV and hepatitis C who had received or were currently receiving NFV. The yield was 51 case patients. Parameters examined looked into safety, efficacy, and tolerability. Nelfinavir was discontinued in 2 patients for liver function abnormalities but resumed in 1 patient. One patient developed laboratory abnormalities during NFV therapy that were not present before NFV therapy; in 12 case patients, pre-NFV therapy liver function abnormalities resolved completely during NFV therapy. There was a statistically significant increase in CD4 count during NFV therapy. Viral load decreased or was unchanged in 10 case patients and increased in 8, of whom 5 had a CD4 count increase during NFV therapy. Three patients had diarrhea and 4 patients had constipation. Nelfinavir was not discontinued -- neither was dose adjusted -- in any of these patients. Patients who had received NFV > or =36 months had a smaller increase in mean methadone dose as compared with patients who had received NFV <36 months. The results show that NFV is safe, efficacious, and well tolerated.

Adult↗
PubMed2003

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir.

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.

Administration, Oral↗
PubMed2001

High-performance liquid chromatographic assay to determine the plasma levels of HIV-protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) and the non-nucleoside reverse transcriptase inhibitor (nevirapine) after liquid-liquid extraction.

A single HPLC assay was developed for therapeutic drug monitoring of 5 HIV protease inhibitors (indinavir, amprenavir, saquinavir, ritonavir, nelfinavir) and a non-nucleoside reverse transcriptase inhibitor (nevirapine) in human plasma. After liquid-liquid extraction in a mixture ethyl acetate-hexane, compounds are separated on a C18 column with a gradient elution of solvent A [acetonitrile and 0.025 M tetramethylammonium perchlorate in 0.2% aqueous trifluoroacetic acid (55:45 (v/v))] and solvent B [methanol and 0.025 M tetramethylammonium perchlorate in 0.2% aqueous trifluoroacetic acid (55:45 (v/v))]. The compounds are detected at various wavelengths: 320 nm (nevirapine), 259 nm (indinavir), 254 nm (amprenavir, nelfinavir, saquinavir) and 239 nm (ritonavir). The intra-day and inter-day precision and accuracy are lower than 15%. The limits of quantitation are 0.05 mg/l (amprenavir), 0.2 mg/l (indinavir, saquinavir, nelfinavir) and 0.4 mg/l (ritonavir, nevirapine). This method which allows to estimate simultaneously plasma levels of protease inhibitors and nevirapine can be used for therapeutic drug monitoring.

Calibration↗
PubMed2003

Drug resistance mutations and outcome of second-line treatment in patients with first-line protease inhibitor failure on nelfinavir-containing HAART.

OBJECTIVES: To determine resistance mutations emerging in HIV-1-infected patients experiencing their first protease inhibitor (PI)-failure on nelfinavir-containing highly active antiretroviral therapy (HAART), and to assess virological response to rescue regimens. METHODS: Plasma HIV-1 RNA from 24 patients failing nelfinavir-containing HAART was sequenced. Failure was defined as two consecutive measurements of viral load > 400 HIV-1 RNA copies/mL. Patients with previous failure on other PIs were excluded. Data on response to second-line treatment was extracted from patient files. RESULTS: At failure primary protease mutations were found in 14 patients (58%). Ten patients had D30N (38%), five patients had L90M (19%), two patients had V82A/F (8%) and two patients had M46I/L (8%). Two patients had both D30N and L90M. Pronounced increases of secondary protease mutations were seen at codon 88 (Delta: 33%), codon 36 (Delta: 30%) and codon 71 (Delta: 17%). Of eight patients with N88D, seven also harboured D30N (P < 0.01). Polymorphisms at codon 63 were detected at baseline in all patients who developed primary resistance mutations at failure (P < 0.01). On rescue regimens, 78% achieved viral loads below limit of detection (BLD). The presence of primary protease mutations was not associated with a higher risk of failure on second-line treatment. CONCLUSION: In patients failing nelfinavir-containing HAART, D30N was detected frequently and L90M occasionally. A pronounced accumulation of the secondary protease mutations N88D, M36I, and A71V/T was found, and D30N was strongly associated with N88D. A high proportion of patients became undetectable on second-line treatment and the presence of primary resistance mutations did not negatively affect the outcome of rescue regimens.

Antiretroviral Therapy, Highly Active↗
PubMed2003

The use of calcium carbonate in nelfinavir-associated diarrhoea in HIV-1-infected patients.

OBJECTIVES: To evaluate the efficacy of oral calcium supplements in HIV-infected patients with nelfinavir (NFV)-associated diarrhoea, and to investigate the influence on the pharmacokinetics of nelfinavir and the active metabolite M8. METHODS: An open-label prospective trial with enrolment of 15 patients with NFV-associated diarrhoea. Study subjects received either calcium carbonate or calcium gluconate/calcium carbonate in addition to highly active antiretroviral therapy (HAART), and were randomized to (i) calcium supplements for 14 days followed by 14 without calcium supplements, or (ii) 14 days without calcium supplements followed by calcium supplements for 14 days. Clinical endpoint was the severity of diarrhoea, graded and summarized for the specific 14 day-period. In the pharmacokinetic evaluation concentrations of NFV and M8 were measured before morning dosing, and 3 h after dosing. RESULTS: Nine patients were treated with calcium carbonate, and six with calcium gluconate/calcium carbonate. In the paired analysis, neither of the groups had a significant improvement in diarrhoea score when treated with calcium supplements (P = 0.34 and 0.46, respectively). We found no significant differences in the concentrations of NFV and M8 between the calcium and control periods. CONCLUSIONS: Oral calcium supplements did not significantly improve nelfinavir-associated diarrhoea. In the pharmacokinetic analysis calcium supplements did not induce major alterations in plasma concentrations of NFV and M8.

Adult↗
PubMed2002

Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir.

OBJECTIVE: Pharmacokinetic interactions are expected when human immunodeficiency virus (HIV) protease inhibitors are coadministered because many are both substrates for and inhibitors of CYP3A4. The goal of this model-based pharmacokinetic analysis was to describe the differences observed in amprenavir pharmacokinetics among treatment arms in the Adult AIDS Clinical Trial Group (AACTG) study protocol 398 and to propose mechanisms to account for them. METHODS: One hundred seventy-six HIV-positive subjects receiving 1200 mg amprenavir twice daily as part of AACTG protocol 398 were included in the pharmacokinetic study. All patients also received background medications efavirenz, adefovir dipivoxil, and abacavir and, depending on the study arm, placebo or one of the following protease inhibitors: nelfinavir, indinavir, or saquinavir. A population pharmacokinetic model was fitted to a total of 565 amprenavir concentration measurements. The blood samples for concentration measurements were drawn at week 2 (12-hour pharmacokinetic study, approximately 7 samples per study; 46 patients) and at week 24 (6-hour pharmacokinetic study, approximately 5 samples per study; 10 patients). In addition, samples were collected at 1 or more follow-up visits (population pharmacokinetic study, 1 to 3 occasions per patient; 150 patients). RESULTS AND CONCLUSION: Amprenavir intrinsic clearance was significantly reduced relative to placebo by nelfinavir (-41%) and indinavir (-54%) but not by saquinavir. The absolute magnitude of amprenavir intrinsic clearance suggests that CYP3A4 inhibition by nelfinavir and indinavir is balanced by enzymatic induction in the presence of the background drug(s), most likely efavirenz. Amprenavir intrinsic clearance apparently increases by more than 30% between weeks 2 and 24, possibly because of the time course of CYP3A4 induction.

Adult↗
PubMed2004

Baseline HIV-1 RNA level and CD4 cell count predict time to loss of virologic response to nelfinavir, but not lopinavir/ritonavir, in antiretroviral therapy-naive patients.

Baseline CD4 cell counts and human immunodeficiency virus (HIV)-1 RNA levels have been shown to predict immunologic and virologic responses in HIV-infected patients receiving antiretroviral therapy. In our randomized, double-blind, comparative trial, 653 antiretroviral therapy-naive patients received lopinavir/ritonavir or nelfinavir, plus stavudine and lamivudine, for up to 96 weeks. The risk of loss of virologic response was significantly higher for nelfinavir-treated patients than for lopinavir/ritonavir-treated patients (Cox model hazard ratio, 2.2; 95% confidence interval, 1.7-3.0; P<.001). For nelfinavir-treated patients, but not for lopinavir/ritonavir-treated patients, higher baseline HIV-1 RNA levels and lower baseline CD4 cell counts were associated with a higher risk of loss of virologic response.

Anti-HIV Agents↗
PubMed2004

Nelfinavir plasma concentrations are low during pregnancy.

Plasma nelfinavir concentration ratios (CRs) were calculated for all pregnant (n=27) and nonpregnant (n=48) human immunodeficiency virus type 1-infected women receiving the drug who visited our outpatient clinic. In pregnant women, mean and median nelfinavir CRs were significantly lower (P=.02 and P=.04, respectively), and 51% of the CRs were below the clinically relevant threshold of 0.90, compared with 35% of the CRs in nonpregnant women. After we adjusted for confounders, we found that the mean nelfinavir CR was 34% lower in pregnant women (P=.02). With targeted interventions, subsequent CRs in pregnant women showed a significant increase (median increase, 0.31; P=.01).

Adult↗
PubMed1999

Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate.

An open-label study was conducted of nelfinavir mesylate, given with reverse transcriptase inhibitors to human immunodeficiency virus 1 (HIV-1)-infected infants and children 3 months to 13 years of age. Doses of nelfinavir mesylate of 20-30 mg/kg yielded drug exposures comparable to those seen in adults. The drug was well tolerated; mild diarrhea was the primary toxic effect observed. Seventy-one percent (39) of the 55 evaluable subjects had an initial decrease in plasma HIV-1 RNA, of at least 0.7 log10 copies/mL; suppression of plasma HIV-1 RNA levels to < 400 copies/mL was observed in 15. Children who began taking at least one new reverse transcriptase inhibitor near the time when nelfinavir mesylate was started, and those with a > or = 24% proportion of CD4 lymphocytes, had a greater chance of achieving and maintaining a decline in plasma HIV-1 RNA to < 400 copies/mL. Suppression of viremia was achieved in children as young as 3 months of age.

Adolescent↗
PubMed2001

Efficacy, tolerance, and pharmacokinetics of the combination of stavudine, nevirapine, nelfinavir, and saquinavir as salvage regimen after ritonavir or indinavir failure.

The high rate of protease inhibitor treatment failure in clinical cohorts makes it necessary to define novel salvage therapies. In a prospective study of 31 HIV-infected patients included in a salvage regimen with stavudine, nevirapine, nelfinavir, and saquinavir, viral load decreased a median of 1.65 log(10) and 1.95 log(10) after 6 and 12 months of treatment, respectively, and 35 and 56% of patients had an HIV RNA level below 50 copies/ml at the same time points. At baseline, the mean number of mutations in the protease gene was 10 (2-19), and the V82A and L90M mutations were present in 54 and 21% of patients. The presence of the V82A mutation did not affect significantly the rate of response (36 vs. 38%), whereas the L90M mutation was associated with treatment failure (0 vs. 43%). Plasma trough levels of nelfinavir (NFV) and saquinavir (SQV), in a twice daily dosing regimen, were above the protein-corrected IC(95) in most patients despite the addition of an enzymatic inducer such as nevirapine, and peak levels were 2- and 5-fold increased with respect to standard doses. However, pharmacokinetics of saquinavir-hard gel capsule (SQV-hgc) did not improve significantly in the three times daily dosing regimen. In conclusion, the combination of stavudine, nevirapine, nelfinavir, and saquinavir increased plasma drug levels and produced an adequate virological response in patients who had failed indinavir or ritonavir therapy. This degree of response is not significantly decreased in the presence of genotypic mutations associated with indinavir/ritonavir (IDV/RTV) resistance.

Adult↗