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PubMed1999

Use of hydroxyurea in heavily pretreated patients with HIV infection.

This study was designed to assess the potential benefit of hydroxyurea (HU) on virological and immunological markers in heavily pretreated human immunodeficiency virus (HIV)-infected patients. A total of 118 patients received hydroxyurea as treatment added to their current antiviral therapy ('add' group), or as treatment added together with a switched nucleoside reverse transcriptase inhibitor or protease inhibitor or with the introduction of an additional antiviral agent ('add and switch' group). Efficacy of HU was also compared among patients receiving didanosine- and non-didanosine-containing regimens. Results showed that HU was not associated with a significant decline in plasma HIV-1 RNA, and no significant difference in plasma HIV-1 RNA changes was noted between patients who did and did not receive didanosine. The absolute number of CD4 cells, but not the CD4 percentage, declined significantly from baseline. Significantly more grade 3-4 neutropenia occurred among patients receiving HU combined with zidovudine, although the discontinuation rate for haematological toxicity was similar in zidovudine- and non-zidovudine-treated patients.

Adult↗
PubMed1999

Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system.

OBJECTIVE: To study the pharmacokinetic properties and clinical efficacy of the HIV-1 protease inhibitor (PI) indinavir in the central nervous system (CNS). DESIGN: Twenty-five consecutive HIV-1 infected patients on combination therapy that included indinavir, had cerebrospinal fluid (CSF) and plasma samples taken on 32 different occasions, at different times after indinavir administration. CSF and viral load data obtained from these treated patients were compared with those from 36 untreated HIV-1 infected patients of similar immunological and demographic pre-treatment status. METHODS: Concentrations of indinavir were measured in CSF and plasma by high-pressure liquid chromatography with ultraviolet light detection and the data were used in pharmacokinetic modelling. RESULTS: The concentration of indinavir in plasma varied with time over a dose interval by about two orders of magnitude, whereas the concentration in CSF was relatively stable. The median concentration of indinavir in CSF was 210 nmol/l, which is above the 95% inhibitory concentration in vitro. Findings from the pharmacokinetic modelling indicate that indinavir is actively transported out of the CSF (P <0.001 compared with a passive transport-only model). In the PI-treated group there was a reduction in viral load to below 50 copies/ml in most subjects and a normalization of the CSF cell content and IgG-index. CONCLUSIONS: This study has shown that one PI, indinavir, is present in the CSF at therapeutic concentrations, and is likely to contribute to the antiretroviral activities observed within the CNS.

Adult↗
PubMed1999

HPLC-UV method for the quantitation of nevirapine in biological matrices following solid phase extraction.

Nevirapine (VIRAMUNE) is a non-nucleoside reverse transcriptase inhibitor with activity against human immunodeficiency virus type 1 (HIV-1), currently marketed for the treatment of HIV-1 infected adults. A reverse phase HPLC-UV method was optimized and validated for the determination of nevirapine in human plasma, serum, milk and cerebrospinal fluid. The analyte was extracted from 250 microl of biofluid using a bonded silica solid phase extraction column, and resolved chromatographically on a reversed-phase, 15x0.46 cm i.d. 5 microm particle Supelco LC-8 analytical column with an isocratic mobile phase of 63% phosphate buffer (0.025 M, pH 6.0) with 1-butanesulfonic acid as anion-pair reagent: 21.5% methanol: 15.5% acetonitrile. The peaks were detected at a flow rate of 1.0 ml min(-1), at a wavelength of 280 nm, with a run time of 10 min. The assay was linear over a range of 25 to 10000 ng ml(-1). This method has been used for the clinical development of nevirapine.

Adult↗
PubMed2002

Marked dyslipidemia in human immunodeficiency virus-infected children on protease inhibitor-containing antiretroviral therapy.

OBJECTIVE: To assess the effects of antiretroviral combination therapy that contains protease inhibitor (PI) on carbohydrate and lipid metabolism in human immunodeficiency virus (HIV)-infected children. METHODS: A cross-sectional, descriptive clinical study was conducted in an outpatient clinic. Thirty-seven HIV-infected children who ranged from 1 to 17 years of age received nucleoside reverse transcriptase inhibitor treatment together with PI (PI group, n = 25) or without PI (non-PI group, n = 12). Age, gender, weight, length, CD4 cell count, and viral load did not differ between groups. Nonfasting total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, glucose, lactate, and blood gases were determined. In addition, c-peptide, insulin, hemoglobin A1c, free fatty acids, lipoprotein a, and apolipoproteins A1 and B were evaluated after fasting. PI and non-PI group values were compared with normal values taken from healthy children. RESULTS: In nonfasting and fasting conditions, children of the PI group had higher total cholesterol (fasting PI group: 235 +/- 71 mg/dL; non-PI group: 176 +/- 25 mg/dL, mean +/- standard deviation), triglycerides (156 +/- 89 vs 87 +/- 31 mg/dL), and LDL cholesterol levels (159 +/- 58 vs 113 +/- 23 mg/dL) compared with the non-PI group. High-density lipoprotein cholesterol and apolipoprotein A1 levels did not differ in both groups; there was a trend toward higher apolipoprotein B levels in the PI group. After fasting, 8 (47%) of 17 patients in the PI group presented with hypercholesterolemia as a result of an increase of LDL cholesterol and 11 (65%) had hypertriglyceridemia. It is interesting that the non-PI group showed no pathologic deviations. Compared with normal values, lipoprotein a and free fatty acids were increased in the PI and non-PI groups. Glucose, lactate, blood gases, c-peptide, insulin, and hemoglobin A1c were normal in both groups. CONCLUSION: PI-containing antiretroviral treatment of HIV-infected children was associated with hypercholesterolemia, hypertriglyceridemia, and an increase of LDL cholesterol. The long-term complications of dyslipidemia are of major concern in the growing HIV-infected child.

Ambulatory Care↗
PubMed2002

S-acyl-2-thioethyl (SATE) pronucleotides are potent inhibitors of HIV-1 replication in T-lymphoid cells cross-resistant to deoxycytidine and thymidine analogs.

The biological evaluation of mononucleotide prodrugs (pronucleotides) of various nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT), zalcitabine (ddC) and lamivudine (3TC) was reported in human T-lymphoid MOLT-4/8 cells which were grown continuously for more than 1 year in a medium containing cytarabine (Ara-C). In this cell line, expression of deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) was decreased in comparison to parental cells (3.8 and 2.9-fold, respectively). The lower mRNA level of TK1 correlated significantly with lower enzyme activity, whereas no dCK activity was detectable. In Ara-C-resistant cells, anti-HIV-1 effects of ddC, 3TC and AZT were more than 100-fold lower compared with parental cells. In contrast, the corresponding mononucleoside phosphotriesters bearing S-acyl-2-thioethyl (SATE) groups as biolabile phosphate protection retained anti-HIV-1 activity due to their ability to bypass the first monophosphorylation step catalyzed by dCK or TK1. The results demonstrate that in vitro selection of T-lymphoid cells in the presence of Ara-C results in cross-resistance to deoxycytidine (ddC, 3TC) and thymidine (AZT) analogs and that these cellular resistance mechanisms can be bypassed by the use of bis(SATE) pronucleotides.

Anti-HIV Agents↗
PubMed2000

Viral dynamics in primary HIV-1 infection. Karolinska Institutet Primary HIV Infection Study Group.

OBJECTIVES: To study the natural course of viremia during primary HIV infection (PHI). METHOD: Eight patients were followed from a median of 5 days from the onset of PHI illness. Plasma HIV-1 RNA levels were measured frequently and the results were fitted to mathematical models. HIV-1 RNA levels were also monitored in nine patients given two reverse transcriptase inhibitors and a protease inhibitor after a median of 7 days from the onset of PHI illness. RESULTS: HIV-1 RNA appeared in the blood during the week preceding onset of PHI illness and increased rapidly during the first viremic phase, reaching a peak at a mean of 7 days after onset of illness. This was followed by a phase of rapidly decreasing levels of HIV-1 RNA to an average of 21 days after onset. Viral density continued to decline thereafter but at a 5- to 50-fold lower rate; a steady-state level was reached at a median of 2 months after onset of PHI. Peak viral density levels correlated significantly with levels measured between days 50 and 600. Initiation of antiretroviral treatment during PHI resulted in rapidly declining levels to below 50 copies/mL. CONCLUSIONS: This study demonstrates the kinetic phases of viremia during PHI and indicates two new contributions to the natural history of HIV-1 infection: PHI peak levels correlate with steady-state levels and HIV-1 RNA declines biphasically; an initial rapid decay is usually followed by a slow decay, which is similar to the initial changes seen with antiviral treatment.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Type B lactic acidosis: a rare complication of antiretroviral therapy after cardiac surgery.

This report describes a 47-year-old woman with human immunodeficiency virus (HIV) and end-stage renal disease on hemodialysis, treated with combination antiretroviral drug therapy, who developed an acute, severe type B lactic acidosis 24 hours after homograft root replacement for endocarditis. She fully recovered after HIV medication was discontinued, along with administration of riboflavin and supportive measures including hemodialysis. The timing of this complication and previous reports suggest that open heart surgery may be a risk factor for nonischemic (type B) lactic acidosis in patients taking nucleoside analogue reverse transcriptase inhibitors.

Acidosis, Lactic↗
PubMed2003

The role of observational data in monitoring trends in antiretroviral treatment and HIV disease stage: results from the Australian HIV observational database.

OBJECTIVES: To illustrate how human immunodeficiency virus (HIV) observational databases may be used to monitor trends in HIV treatment and HIV disease outcomes through data reported from the Australian HIV Observational Database (AHOD). METHODS: Time trends in the use of antiretroviral treatment, and changes in treatment strategies were calculated in patients recruited to AHOD from HIV specialist clinics including hospitals, sexual health clinics and general practices. These results were then compared to trends reported from other observational cohorts. RESULTS: By September 2001, 1961 patients were recruited to AHOD. Since entering AHOD, 3% of patients have been diagnosed with an AIDS defining illness, and 2% of patients have died, of which, 54% were non-HIV related deaths. The proportion of patients receiving antiretroviral therapy increased from 66% between January and June 1998 and 77% between July and September 2001. The most commonly received treatment regimen was triple therapy including a protease inhibitor (PI), ranging between 36% in January and June 1998 and 31% in July to September 2001. Triple therapy including a non-nucleoside reverse transcriptase inhibitor (NNRTI) more than doubled to 32% between July and September 2001. The proportion of patients receiving either stavudine (d4T) or zidovudine (AZT) treatment regimens decreased from 92% between January and June 1998 to 76% between July and September 2001. Patients receiving ritonavir in combination with another PI increased, as did the proportion of patients interrupting therapy for more than 3 months. CONCLUSION: These findings suggest there have been changes in the way antiretroviral treatments have been used in Australia, and are consistent with the current literature. Furthermore, these findings demonstrate the usefulness of observational cohorts as a surveillance tool monitoring trends in treatment and disease progression.

Anti-HIV Agents↗
PubMed1999

Positive and sustained effects of highly active antiretroviral therapy on HIV-1-associated neurocognitive impairment.

OBJECTIVES: To determine whether highly active antiretroviral therapy (HAART) is effective in HIV-associated neurocognitive impairment. DESIGN: An open label, prospective, observational study. METHODS: Since April 1996, 116 patients with advanced HIV infection, reverse transcriptase inhibitor (nRTI) experienced but protease inhibitor (PI) naive, were screened for the presence of neurocognitive impairment. Ninety patients with confounding neurological illness, opportunistic infections or drug abuse were excluded. The remaining 26 patients underwent comprehensive neuropsychological testing, and laboratory measures before, after 6 and after 15 months of treatment with one PI plus two nRTI. RESULTS: The prevalence of neurocognitive impairment decreased from 80.8% (baseline) to 50.0% (P<0.05) (sixth month) and to 21.7% (P<0.001) (15th month). Among the functions explored, the impairment of concentration and speed of mental processing decreased from 65.4 to 21.7% (P<0.01) and of memory impairment from 50 to 8.7% (P<0.01). Comparing baseline with the sixth and 15th month raw scores, a statistically significant improvement was seen in measures exploring concentration and speed of mental processing (P<0.05), mental flexibility (P<0.05), memory (P<0.05), fine motor functions (P<0.05) and visuospatial and constructional abilities (P<0.01). After 6 months of HAART patients with a normal neuropsychological examination had lower mean plasma viraemia (2.95 versus 3.97 log copies/ml, P<0.05) and greater mean log plasma HIV RNA changes from baseline (-1.84 versus -0.83 log copies/ml, P<0.05) than neuropsychologically impaired subjects. CONCLUSION: HAART produces a positive and sustained effect on neurocognitive impairment in HIV-infected patients. A reduction of plasma viral load was associated with the regression of neuropsychological test abnormalities.

Adult↗
PubMed1998

Regulatory dysfunction of the interleukin-2 receptor during HIV infection and the impact of triple combination therapy.

The interleukin-2 (IL-2)/IL-2 receptor (IL-2R) system is the main regulatory determinant of T cell reactivity. Although it is well known that IL-2 secretion is impaired during HIV infection, up to now IL-2R expression has not been extensively studied in HIV-infected patients despite the use of IL-2 in clinical therapy trials. We show here that IL-2R expression in HIV patients with high viral load (group 1 in the study) is greatly enhanced on B lymphocytes, CD8 T lymphocytes, and monocytes, but not on CD4 T lymphocytes, compared with noninfected individuals. Paradoxically, this modified IL-2R expression does not lead to increased IL-2 responsiveness, except for B lymphocytes. In patients receiving triple combination therapy (TCT, two reverse transcriptase inhibitors and one protease inhibitor) that has triggered a drastic reduction in plasma viral load and an increase in CD4 counts (group 2 patients), IL-2R expression is significantly lower than in group 1 patients. Moreover, cells involved in cellular immunity and CD4 T lymphocytes have the capacity to respond to IL-2 after TCT. These results allow us to anticipate a beneficial role of IL-2 immunotherapy in combination with TCT.

B-Lymphocytes↗
PubMed2003

Clinical, immunological and virological response to different antiretroviral regimens in a cohort of HIV-2-infected patients.

OBJECTIVE: To assess the clinical, immunological and virological response and the emergence of resistance towards antiretroviral therapy (ART) in a cohort of HIV-2-infected patients. DESIGN: Observational study. PATIENTS: HIV-2-infected patients residing in the Netherlands. RESULTS: From 1995 to 2001 seven patients failed various ART regimens. The resistance mutations were analysed retrospectively. Development of mutations proved to be similar to that observed in HIV-1-infected patients, with the exception of a higher occurrence of the Q151M mutation within the reverse transcriptase gene. In a prospective study, comprising 13 consecutive naive HIV-2-infected patients, all patients achieved plasma HIV-2-RNA suppression below the detection limit (500 copies/ml). The antiretroviral regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) and indinavir, with a boosting dose of ritonavir; the median follow-up was 91 weeks. Two patients experienced a temporary virological rebound, while at the same time therapeutic drug monitoring showed sub-therapeutic plasma levels of indinavir. CONCLUSION: Sustained viral suppression in HIV-2-infected patients can be achieved using an antiretroviral regimen of two NRTIs and boosted indinavir or lopinavir.

Adult↗
PubMed1999

Detectable HIV-1 RNA at levels below quantifiable limits by amplicor HIV-1 monitor is associated with virologic relapse on antiretroviral therapy.

OBJECTIVE: To assess the clinical significance of HIV-1 RNA levels detectable using the Amplicor HIV-1 Monitor method but < 400 copies/ml versus levels undetectable by this method. DESIGN: Retrospective cohort study. METHODS: All plasma HIV-1 RNA results over 13 months in our institution were reviewed. The study population comprised all individuals that achieved an HIV-1 RNA level < 400 copies/ml and remained on stable antiretroviral therapy. Results of < 400 copies/ml were stratified as 'below quantifiable limits' (BQL) or 'below detectable limits' (BDL). We examined the incidence of virologic relapse, defined as an HIV-1 RNA level > 400 copies/ml, for individuals with viral loads of BQL or BDL. Cox proportional hazards regression analyses were performed to control for baseline CD4 cell count, the number of antiretroviral medications, and the use of protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI). RESULTS: Virologic relapse occurred in 52 of 168 individuals over 29,576 person-days overall (incidence rate 1.8 cases/1,000 person-days). The relapse rate was three times greater following HIV-1 RNA levels of BQL rather than BDL [crude rate ratio 3.2; 95% confidence interval (CI) 1.8-5.8]. After adjusting for baseline CD4 cell count, number of antiretroviral medications, and use of PI and/or NNRTI, the rate of relapse was nearly four times greater for individuals with HIV-1 RNA levels of BQL (hazard ratio 3.7; 95% CI 2.0-6.7). CONCLUSIONS: In a large clinic population, low-level HIV-1 RNA detected in plasma below the 400 copies/ml limit of quantifiability for Amplicor HIV-1 Monitor was associated with an increased rate of virologic relapse on therapy.

Adult↗
PubMed1998

Neutrophil eccrine hidradenitis in a patient with AIDS.

Neutrophilic eccrine hidradenitis (NEH), first described as a rare, transient, and benign complication of various chemotherapy regimens for acute leukemia, has also been observed in other conditions, including three HIV-positive patients and even in otherwise healthy individuals (1-3). A similar histological pattern was described after intradermal bleomycin injections into normal human skin (4). We report the first case of NEH in a hemophilic HIV infected patient treated with stavudine, a new reverse transcriptase inhibitor.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study.

BACKGROUND: Fat distribution abnormalities have been reported in patients treated with various antiretroviral drug regimens. The LIPOCO study is an ongoing observational study of unselected HIV-infected patients which aims to better characterize such disorders and their metabolic correlations. METHODS: Cross-sectional analysis of data collected at baseline in the first 154 male patients included. Investigators divided patients into four predetermined clinical categories of fat distribution: lipoatrophy, obesity, mixed condition and normal. Body composition (tetrapolar bioelectrical impedance analysis and skinfold thickness), fat distribution [computed tomography (CT) scan], plasma glucose and insulin concentrations both fasting and during an oral glucose tolerance test and endocrine and lipid profile were measured and compared between the four groups. RESULTS: Patients in the lipoatrophy group had significantly decreased abdominal and mid-thigh subcutaneous fat area values and elevated levels of plasma triglycerides. Patients in the obese and mixed groups had significantly increased intra-abdominal fat area values and elevated levels of plasma insulin and C-peptide. The CT scans identified some patients with isolated subcutaneous fat accumulation but no other alterations in fat distribution and no insulin resistance. Visceral adipose tissue measured by CT scan was positively correlated with fasting insulin and the sum of insulin levels (P < 0.0001). Fasting insulin as well as the sum of insulin levels were negatively correlated with the delta HIV-RNA (log(10)). In a multivariate logistic regression model, the use of stavudine significantly correlated with fat wasting in both nucleoside reverse transcriptase inhibitor and protease inhibitor groups: odds ratio (OR), 413 [95% confidence interval (CI), 5.2-999; P = 0.0068] and OR, 2.08 (95% CI, 0.92-7.0; P = 0.058) respectively, when compared with the use of zidovudine. Neither lamivudine or didanosine use, nor the use of protease inhibitors were significantly associated with fat distribution abnormalities or fat wasting. CONCLUSIONS: These preliminary results suggest that three major types of fat distribution abnormalities may occur in isolation or in association in HIV-infected patients undergoing active antiretroviral therapy: a fat depletion or 'lipoatrophy' syndrome which might be related to the use of stavudine; a mixed or fat redistribution syndrome related to an unusual side-product of effective virus control; and a subcutaneous adiposity syndrome reflecting increase in caloric intake.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor.

PNU-140690 is a member of a new class of nonpeptidic human immunodeficiency virus (HIV) protease inhibitors (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones) discovered by structure-based design. PNU-140690 has excellent potency against a variety of HIV type 1 (HIV-1) laboratory strains and clinical isolates, including those resistant to the reverse transcriptase inhibitors zidovudine or delavirdine. When combined with either zidovudine or delavirdine, PNU-140690 contributes to synergistic antiviral activity. PNU-140690 is also highly active against HIV-1 variants resistant to peptidomimetic protease inhibitors, underscoring the structural distinctions between PNU-140690 and substrate analog protease inhibitors. PNU-140690 retains good antiviral activity in vitro in the presence of human plasma proteins, and preclinical pharmacokinetic studies revealed good oral bioavailability. Accordingly, PNU-140690 is a candidate for clinical evaluation.

Anti-HIV Agents↗
PubMed2004

Minor mutations in HIV protease at baseline and appearance of primary mutation 90M in patients for whom their first protease-inhibitor antiretroviral regimens failed.

The association between minor mutations in human immunodeficiency virus (HIV) protease at baseline and development of common primary mutation 90M at virological failure (conferring some resistance to all protease inhibitors [PIs]) was evaluated in 93 previously drug-naive patients experiencing failure of their first PI-based antiretroviral regimens. In logistic regression analysis, the probability of accumulating a new 90M mutation at virological failure was associated with the presence at baseline of minor mutation 36I (naturally occurring in approximately 25% of HIV clade B and in >80% of HIV non-clade-B viruses) (adjusted odds ratio, 13.5 [95% confidence interval, 1.89-95.6]; P=.009) and, possibly, of 10I/V. This suggests a potential role for the presence of 36I at baseline in predicting the appearance of 90M at virological failure.

Antiretroviral Therapy, Highly Active↗
PubMed1996

Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay.

Anti-viral drug treatment of human immunodeficiency virus type I (HIV-1) and hepatitis B virus (HBV) infections causes rapid reduction in plasma virus load. Viral decline occurs in several phases and provides information on important kinetic constants of virus replication in vivo and pharmacodynamical properties. We develop a mathematical model that takes into account the intracellular phase of the viral life-cycle, defined as the time between infection of a cell and production of new virus particles. We derive analytic solutions for the dynamics following treatment with reverse transcriptase inhibitors, protease inhibitors, or a combination of both. For HIV-1, our results show that the phase of rapid decay in plasma virus (days 2-7) allows precise estimates for the turnover rate of productively infected cells. The initial quasi-stationary phase (days 0-1) and the transition phase (days 1-2) are explained by the combined effects of pharmacological and intracellular delays, the clearance of free virus particles, and the decay of infected cells. Reliable estimates of the first three quantities are not possible from data on virus load only; such estimates require additional measurements. In contrast with HIV-1, for HBV our model predicts that frequent early sampling of plasma virus will lead to reliable estimates of the free virus half-life and the pharmacological properties of the administered drug. On the other hand, for HBV the half-life of infected cells cannot be estimated from plasma virus decay.

Acquired Immunodeficiency Syndrome↗