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PubMed2002

Hyperlactataemia in HIV-infected patients: the role of NRTI-treatment.

BACKGROUND: Long-term treatment with nucleoside reverse transcriptase inhibitors (NRTIs) can induce mitochondrial dysfunction, most severely represented by lactic acidosis. Diagnostic tests for mitochondrial dysfunction are lacking, although persistently elevated serum lactate might be a surrogate marker. OBJECTIVES: To determine the occurrence of hyperlactataemia in HIV-infected patients on NRTI-treatment and to evaluate the possible risk factors. METHODS: Cross-sectional analysis of lactic-acid levels in asymptomatic HIV-infected patients. Hyperlactactaemia was considered mild if between 2.0-5 mmol/l, serious if >5 mmol/l and lactic acidosis was defined as lactic acid levels >5 mmol/l with bicarbonate <20 mmol/l. Possible risk factors, such as current and preceding NRTI-treatment as well as treatment with non-nucleoside reverse transcriptase inhibitors or protease inhibitors and concurrent liver disease, were analysed. RESULTS: Two hundred and twenty three asymptomatic HIV-infected patients were studied, including 174 patients (78%) on NRTI treatment, 12 patients (5%) treated without NRTIs and 37 patients (17%) not treated. Mild hyperlactataemia was found in 42 patients (19%), from whom 38/42 (90%) were NRTI-treated and the remaining patients (4/42, 10%) received no treatment (chi2, P<0.05). The significant risk factors for hyperlactataemia in the univariate analysis were NRTI-treatment as a group (P=0.03) and elevated ALT (P=0.008). In multivariate analysis NRTI use (P=0.05) and ALT level (P=0.03) remained a significant determinant of hyperlactataemia. Among the different individual NRTIs, a stavudine-containing (P=0.004) and a zalcitabine-containing (P=0.07) regimen were most notably associated with the development of hyperlactataemia, whereas for the combinations of NRTIs, such association was only found for stavudine/lamivudine (P=0.05). CONCLUSIONS: A correlation between hyperlactataemia and NRTI treatment was found, but the value of routine lactate measurement for individual treatment monitoring remains uncertain.

Acidosis, Lactic↗
PubMed2006

Changing electrolyte and acido-basic profile in HIV-infected patients in the HAART era.

BACKGROUND: HIV-infected patients may develop a variety of underreported metabolic abnormalities that may be classified into HIVAN, specific HIV abnormalities, coincidental renal disorders and anti-retroviral-treatment-induced side effects. METHODS: Our descriptive cross-sectional study evaluates the prevalence of electrolyte and acid base disorders in HIV patients in the HAART era in a tertiary care teaching hospital. All consecutive HIV-infected patients (n = 1,232) presenting at our Department of Infectious Disease over 3 months were included. MEASUREMENTS: All available biochemical data obtained at admission or on the day of the visit were analyzed. We identified risk factors for electrolyte and acid base disorders with univariate regression analysis and multivariate stepwise regression analysis. Variables tested for significance included age, sex, absolute CD4 and CD8 counts, hepatitis B and C antibodies, and use and type of anti-retroviral medication. RESULTS: Most frequent and clinically relevant abnormalities were hyperuricemia in 41.3%, hypophosphatemia in 17.2% and low bicarbonate level in 13.6% of HIV-tested patients. Plasma magnesium was out of the normal range in 38.9% and blood glucose in 25.3% of the tested patients. When CD4 count was below 200/mm3, 9.2% of tested patients experienced low serum calcium (vs. 0.5% if CD4 count >200/mm3, p < 0.002), 11.4% increased creatinine plasma level (vs. 2.3% if CD4 count >200/mm3, p < 0.0001) and 24.5% low serum bicarbonate (vs. 13.7% if CD4 count >200/mm3, p < 0.0001). Protease inhibitor treatment was a significant risk factor of hyperuricemia (p < 0.003). Non-nucleoside reverse transcriptase inhibitor therapy was significantly associated with less hyperuricemia (OR = 0.6, 95% CI 0.38-0.96) and with hypophosphatemia (OR = 2.0, 95% CI 1.1-3.4). CONCLUSIONS: The profile of biochemical abnormalities in HIV-infected patients has changed, hyperuricemia and hypophosphatemia being the most prevalent. Causes are poorly understood. Interpretation of drug-induced side effects in the HIV patient is only meaningful if performed versus a control group of patients.

Acid-Base Equilibrium↗
PubMed2004

Improving HIV infection management using antiretroviral plasma drug levels monitoring: a clinician's point of view.

Due to genetic and environmental factors, there are wide inter-patient differences when measuring drug exposure to a standard dose. If there is a relationship between drug exposure and efficacy or toxicity, this inter-patient variability carries various risks to develop toxicity or failure. Therapeutic drug monitoring is an attempt to adjust the dose to obtain a level within a therapeutic range consisting in a minimum plasma concentration needed to be efficacious and a maximum plasma concentration not to exceed to avoid toxicity. Many studies have shown a relationship between various pharmacokinetic parameters and drug toxicity or efficacy for HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Therapeutic drug monitoring (TDM) proves to be a useful tool to assess adherence, to investigate drug-drug interactions between antiretroviral (ARV) drugs or with co-medications, to prevent some ARV drug toxicities, to adjust the dosage in particular populations, and to increase ARV efficacy of some drugs in naive patients. The integration of virological and pharmacological parameters, using inhibitory quotients, looks promising to improve therapy in ARV-experienced patients. Effective and non-toxic target concentrations will be determined for all present and future antiretroviral drugs covering the extended spectrum of naive patients to multiple failures. In this article, we review the rationale of TDM for antiretroviral drugs, the retrospective and prospective studies assessing plasma drug concentrations in relation with antiretroviral toxicity or efficacy, and the actually recommended or proposed indications for TDM. We also highlight the benefits and limits of this tool as an adjunct in the care of HIV-infected patients.

Anti-HIV Agents↗
PubMed2006

Antiretrovirals induce direct endothelial dysfunction in vivo.

HIV-associated cardiovascular diseases have been widely described, but clinical studies aimed at establishing cause-effect relationships between HIV-associated cardiovascular disease and either the HIV infection or antiretroviral therapy have been problematic. Endothelial dysfunction is a sensitive marker and early event in atherosclerosis, and many have suggested that protease inhibitors promote endothelial dysfunction indirectly by inducing elevations in circulating lipids. To determine whether nucleoside reverse transcriptase inhibitors and/or protease inhibitors induce endothelial dysfunction, and to test whether this effect is dependent upon drug-mediated alteration in plasma lipid concentrations, we treated male Sprague-Dawley rats with pharmacological doses of azidothymidine (AZT), indinavir, or AZT plus indinavir through their drinking water for 1 month and assessed endothelial function in aortic rings using an isometric force measurement. Circulating levels of plasma lipids and endothelin-1, a marker for endothelial injury and/or dysfunction, were also determined. We found that AZT and AZT plus indinavir treatments dramatically reduced endothelium-dependent vessel relaxation. However, AZT treatment did not significantly alter plasma levels of cholesterol or triglyceride. In addition, plasma endothelin-1 levels were elevated in rats treated with AZT plus indinavir. Indinavir treatment alone increased plasma cholesterol levels but had no effect on endothelial function. These findings suggest that in addition to modulating plasma lipid levels, antiretrovirals, particularly AZT and perhaps other nucleoside reverse transcriptase inhibitors, may have direct effects on the vascular endothelium. Together with other increased risk factors for atherosclerosis in HIV patients, AZT-induced endothelial dysfunction may contribute to the cardiovascular diseases associated with HIV antiretroviral therapy.

Animals↗
PubMed2001

Limits of deep salvage antiretroviral therapy with nelfinavir plus either efavirenz or nevirapine, in highly pre-treated patients with HIV disease.

The virological and immunological response to an efavirenz-containing rescue regimen was compared with that of a nevirapine-containing one in a prospective, open-label 12-month study performed in patients previously treated with > or = 12 months of nucleoside analogue monotherapy, and > or = 15 months of indinavir- or ritonavir-containing HAART. Pooled laboratory data were assessed according to change or continuation of nucleoside analogues, at the time of start of salvage treatment. An improvement of markers of HIV disease progression occurred in all 59 evaluable patients (with a higher viral load decrease in the efavirenz over the nevirapine group at the third month), but the virological response was neither complete nor sustained at the end of study, irrespective of efavirenz or nevirapine adjunct, and complete viral suppression was attained in only 16.9% of subjects. A progressively increasing mean CD4+ lymphocyte count characterized the immunological response of all patients. The 35 patients who changed at least one nucleoside analogue when introducing salvage therapy had a better outcome, irrespective of the non-nucleoside reverse transcriptase inhibitor chosen. Rescue strategies are increasingly needed in HIV-infected patients treated for a long time with HAART. The association of nelfinavir, a non-nucleoside reverse transcriptase inhibitor, and dual nucleoside analogues, is popular among patients who fail first-line HAART. When prolonged prior treatment with nucleoside analogue monotherapy and HAART are of concern, and a quite elevated viral load is present, this salvage regimen may not allow a complete and sustained virological response in a 1-year period, while a more favourable immunological recovery can be expected. However, the concurrent change of nucleoside analogues significantly improves treatment outcome.

Adult↗
PubMed2002

Evaluation and management of dyslipidemia in patients with HIV infection.

OBJECTIVE: Persons with HIV infection develop metabolic abnormalities related to their antiretroviral therapy and HIV infection itself. The objective of this study was to summarize the emerging evidence for the incidence, etiology, health risks, and treatment of dyslipidemias in HIV disease. DESIGN: Systematic review of original research with quantitative synthesis. MAIN RESULTS: Dyslipidemia is common in persons with HIV infection on highly active antiretroviral therapy (HAART), but methodologic differences between studies preclude precise estimates of prevalence and incidence. The typical pattern includes elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides, which may be markedly elevated. The dyslipidemia may be associated with lipodystrophy, insulin resistance, and, rarely, frank diabetes mellitus. Exposure to protease inhibitors (PIs) is associated with this entire range of metabolic abnormalities. PI-naïve patients on nucleoside reverse transcriptase inhibitors (NRTIs) may develop lipodystrophy, insulin resistance, hypercholesterolemia, and possibly modest elevations in triglycerides but not severe hypertriglyceridemia, which appears to be linked to PIs alone. Most studies have not found an association between CD4 lymphocyte count or HIV viral load and lipid abnormalities. The pathogenesis is incompletely understood and appears to be multifactorial. There are insufficient data to definitively support an increased coronary heart disease risk in patients with HIV-related dyslipidemia. However, some of the same metabolic abnormalities remain firmly established risk factors in other populations. Patients on HAART with severe hypertriglyceridemia may develop pancreatitis or other manifestations of the chylomicronemia syndrome. Some of the metabolic derangements (particularly hypertriglyceridemia) may improve upon replacing a PI with a non-nucleoside reverse transcriptase inhibitor. The limited experience suggests that fibrates, pravastatin, and atorvastatin can safely treat lipid abnormalities in HIV-infected patients. CONCLUSIONS: Patients with HIV infection on HAART should be screened for lipid disorders, given their incidence, potential for morbidity, and possible long-term cardiovascular risk. Treatment decisions are complex and must include assessments of cardiac risk, HIV infection status, reversibility of the dyslipidemia, and the effectiveness and toxicities of lipid-lowering medications. The multiple potential drug interactions with antiretroviral or other HIV-related medications should be considered in lipid-lowering drug selection and monitoring.

Antiretroviral Therapy, Highly Active↗
PubMed2003

A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects.

OBJECTIVE: To evaluate antiviral activity, tolerability, safety and pharmacokinetics of treatment with TMC125 (a non-nucleoside reverse transcriptase inhibitor), 900 mg twice daily for 7 days. DESIGN: Randomized, double-blind, placebo-controlled, phase IIA clinical trial. SETTING: Two hospital clinics in Moscow and St Petersburg, Russian Federation. PARTICIPANTS: Nineteen antiretroviral-naive, HIV-1-infected subjects. INTERVENTIONS: Randomization (2:1) was to twice daily treatment with either 900 mg TMC125 or matched placebo as monotherapy for 7 days. MAIN OUTCOME MEASURES: Change in plasma HIV-1 RNA from baseline values (primary); change in CD4 cell counts from baseline, and evaluation of safety, tolerability and pharmacokinetics of TMC125 treatment (secondary). RESULTS: A mean decrease from baseline in plasma HIV-1 RNA of 1.99 log10 copies/ml and 0.06 log10 copies/ml was achieved after 7 days in the TMC125 and placebo groups, respectively (P < 0.001). Plasma viral daily decay rates of 0.33 log10 copies/ml and 0.02 log10 copies/ml were observed in the TMC125 and placebo groups, respectively (P < 0.001). A steady-state plasma concentration of TMC125 was attained within 5 days of treatment with a mean minimum concentration of 246 ng/ml and a mean maximum concentration of 419 ng/ml. The majority of subjects did not report any adverse events. No abnormalities consistent with changes in blood chemistry, haematology, urinalysis, electrocardiograph or vital signs were observed. CONCLUSIONS: TMC125 administered as monotherapy for 7 days yielded a 1.99 log10 copies/ml reduction in HIV-1 RNA in antiretroviral-naive, HIV-1-infected subjects. TMC125 was well tolerated and represents a promising and highly potent, next generation non-nucleoside reverse transcriptase inhibitor candidate.

Adult↗
PubMed2005

Quantification of antiretroviral drugs in dried blood spot samples by means of liquid chromatography/tandem mass spectrometry.

For the first time approved antiretroviral drugs, i.e. protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI), were quantified in dried blood spots (DBS) from HIV/AIDS patient whole blood samples as the basis for therapeutic drug monitoring (TDM) by a robust simultaneous liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. This study included seven PI (amprenavir, nelfinavir, indinavir, lopinavir, saquinavir, ritonavir, atazanavir) and two NNRTI (nevirapine, efavirenz). LC/MS/MS coupling was realized using a Phenomenex Synergy Max RP LC column (150 x 2 mm, 4 micro) in combination with a tandem mass spectrometer (API 2000, Applied Biosystems/MDS Sciex Concord) operating in positive and negative multiple reaction monitoring (MRM) mode with reserpine as internal standard. DBS samples were punched out and extracted with 50:50 MeOH/0.2 M ZnSO4 (v/v) as extraction reagent. The method performance data for the drugs in DBS like limits of detection (LOD, 8-70 ng/mL), lower limits of quantification (LLOQ, 41-102 ng/mL), linearity (R2, 0.9981-0.9999), linear concentration ranges (41-10.000 ng/mL), accuracies (92-113%), recoveries (62-94%), and ion suppression were investigated and are comparable to data obtained from human plasma, which is the current standard matrix for TDM of PI and NNRTI. In this case, off-line plasma sample preparation was performed by means of simple protein precipitation with 80:20 methanol/0.2 M ZnSO4 (v/v) as precipitation reagent. Significant correlations between real patient plasma and DBS were obtained for samples containing lopinavir, atazanavir, ritonavir, saquinavir, and efavirenz. DBS preparation as sampling alternative is well suited and practicable for TDM minimizing the high infection risk of HIV/AIDS samples and may facilitate sample mailing.

Acquired Immunodeficiency Syndrome↗
PubMed2001

ACTG (AIDS Clinical Trials Group) 384: a strategy trial comparing consecutive treatments for HIV-1.

ACTG (AIDS Clinical Trials Group) 384 is designed to evaluate different strategies for antiretroviral treatment in HIV-1-infected individuals with no previous exposure to antiretroviral treatment. The study is a randomized, partially double-blinded, controlled trial with 980 subjects at 81 centers in the United States and Italy. The study has a factorial design that addresses the following scientific questions: (1) Does the best initial choice of therapy include both a protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) in a four-drug combination with nucleoside analogue (NRTI) drugs, or should these agents be used sequentially in three-drug combinations?; (2) Which sequence is best in a three-drug regimen-PI followed by NNRTI or NNRTI followed by PI ?; (3) Which is the best sequence of dual NRTI combinations-zidovudine plus lamivudine followed by didanosine plus stavudine, or the converse? Subjects in the three-drug combination arms are offered a salvage regimen after failure of their second regimen; subjects in the four-drug combination arm are offered a salvage regimen after failure of their first regimen. The primary endpoint of the study is the time until salvage; secondary endpoints include time to virological failure and time to toxicity-related discontinuation of therapy. A Division of AIDS Data and Safety Monitoring Board will review the trial for safety and efficacy. Control Clin Trials 2001;22:142-159

Adolescent↗
PubMed2000

A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVE: To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DESIGN: Prospective randomized controlled trial. SETTING: Multicenter community-based clinical trials network. PATIENTS: One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. INTERVENTIONS: Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. MAIN OUTCOMES MEASURES: Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. RESULTS: The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. CONCLUSION: In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Anti-HIV drug distribution to the central nervous system.

The introduction, in 1995, of highly active antiretroviral therapy (HAART) dramatically reduced the morbidity and mortality of HIV-infected patients. However, the brain remains a site of viral replication for HIV and thus is still an important target for antiretroviral agents. Consequently, a clear understanding of how the current anti-HIV drugs reach the CNS, and interact at the level of the blood-brain barrier and blood-CSF barrier, is important if we are to maximise viral suppression and improve clinical outcome. It would also contribute to the development of new anti-HIV drugs and the identification of transport inhibitors that could be used as adjuvant therapies. In this review we focus on the role of the blood-brain and blood-CSF barriers in the delivery of the main classes of approved anti-HIV drugs. Among these groups, the CNS distribution of the nucleoside reverse transcriptase inhibitors is the best characterised. It involves probenecid efflux transport mechanisms, which limit their brain delivery and probably their, neurological efficacy. Nevirapine and efavirenz, the commonly prescribed non-nucleoside reverse transcriptase inhibitors, can readily enter the CSF, however, it remains to be seen if a transport system is involved in their distribution. The protease inhibitors have only a limited ability to reach the CNS, with the majority of this class of drugs not even being detected in human CSF after administration. This is partly the result of their removal from the CNS by the efflux transporters; P-glycoprotein, and possibly multi-drug resistance associated protein (MRP).

Animals↗
PubMed2006

Direct and fast determination of antiretroviral drugs by automated online solid-phase extraction-liquid chromatography-tandem mass spectrometry in human plasma.

BACKGROUND: In this study antiretroviral drugs of the classes protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) were quantified for the first time directly in patient plasma samples by means of an automated and validated online solid-phase extraction-liquid chromatography-tandem mass spectrometry (XLC-MS/MS) method using the Symbiosis Pharma system (Spark Holland) for XLC coupled to an API 2000 for MS/MS analysis. METHODS: The PI drugs amprenavir, nelfinavir, indinavir, lopinavir, saquinavir, ritonavir, and atazanavir, and the NNRTI drugs nevirapine and efavirenz in real patient samples were analysed in a 25-microL sample volume, which was only diluted with 200 microL of H2O (containing 500 ng/mL of the internal standard reserpine) to minimise the matrix concentration and to add the internal standard. No additional tedious and time-consuming sample preparation steps such as protein precipitation, centrifugation, and pipetting were per-formed for sample clean-up. RESULTS: The high-throughput method developed allowed the simultaneous analysis of two samples (first analysis 6.6 min, subsequent analyses 3.3 min between injections) and has been validated in terms of the limit of detection (LOD, 2-70 ng/mL), lower limit of quantification (LLOQ, 78-156 ng/mL), linearity (R2, 0.9971-0.9989), linear concentration range (from LLOQ to 10,000 ng/mL), intra- and inter-day precision (< 13.5% at LLOQ, < 7.5% at high concentrations), proficiency testing accuracy (78-127%), laboratory internal accuracy (86-113%), recovery (60-110%), and drug stability (freeze-thaw, short-term temperature, long-term and post-preparative) and inter-subject variability. CONCLUSION: Although direct analysis of diluted plasma was performed, post-column experiments showed efficient matrix minimisation by the XLC-MS/MS technique, which is perfectly appropriate for routine therapeutic drug monitoring of HIV/AIDS patient samples.

Antiviral Agents↗
PubMed2005

Predictors of hypertension and changes of blood pressure in HIV-infected patients.

OBJECTIVE: We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals. METHODS: International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP > or =140 and/or diastolic BP > or =90 mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8 984 patients with a normal BP level at baseline. RESULTS: 73548 BP measurements with a median of 4 per patient (interquartile range [IQR]: 2-6) were recorded over a median follow-up of 2.3 years (IQR: 1.5-2.6). Risk factors significantly associated with a development of higher systolic BP and diastolic BP (differences > or =5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 developed hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval: 68.2-76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher BP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors (P=0.75), protease inhibitors (P=0.92) as well as type of antiretroviral treatment at baseline (P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated < or =10 months and >10 months compared with no exposure; P=0.005). CONCLUSIONS: Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension.

Adult↗
PubMed2005

Evolution of human immunodeficiency virus type 1 protease genotypes and phenotypes in vivo under selective pressure of the protease inhibitor ritonavir.

We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.

Acquired Immunodeficiency Syndrome↗
PubMed2005

[Antiretroviral treatments-related lipodystrophy syndrome: clinico-pathological findings].

Effective therapies are available that can stop or slow down the progression of HIV infection. Highly active antiretroviral therapy (HAART) is a combination of antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors. Among the side effects due to these drugs, lipodystrophy is a pathology characterized by fat wasting in face and limbs, accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), insulin resistance, and lactic acidemia. The main clinical features include peripheral fat loss (presumed lipoatrophy in the face, limbs, and buttocks) and central fat accumulation (within the abdomen, breasts, and over the dorsocervical spine, so-called "buffalo hump"). Histopathological features disclose a peculiar type of involutional lipodystrophy. Skin biopsies generally show thinning of the subcutaneous fat, associated with fibrosis, lipogranuloma and sometimes vessel proliferation. There is still an open debate concerning the precise responsibility of HAART as well as the metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. There is no proven therapy for any component of lipodystrophy syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Antiretroviral treatment reduces very-low-density lipoprotein and intermediate-density lipoprotein apolipoprotein B fractional catabolic rate in human immunodeficiency virus-infected patients with mild dyslipidemia.

The relationship between antiretroviral treatment of HIV infection, body fat distribution, insulin resistance, and very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) apolipoprotein-B (apoB) kinetics was investigated in 55 HIV-infected patients taking two nucleoside analogs plus either a protease inhibitor (n = 15) or a nonnucleoside reverse transcriptase inhibitor (n = 25), 15 antiretroviral therapy-naive patients, and 12 HIV-negative controls. Compared with the controls, high-density lipoprotein cholesterol was reduced in all groups (P < 0.01). Plasma triglyceride was increased in patients taking protease inhibitors (P < 0.05). VLDL and IDL apoB fractional catabolic rate (FCR) was lower in all treatment groups (P < 0.05) compared with controls. Trunk fat, VLDL apoB absolute secretion rate, and insulin resistance were not different between groups. Peripheral fat was lower in the treated patients (P < 0.05) and correlated with duration of therapy (r = -0.55; P < 0.001). There was a positive correlation between peripheral fat and VLDL apoB FCR (P = 0.002) and IDL apoB FCR (P = 0.002) and a negative correlation with VLDL apoB pool size, VLDL cholesterol, and triglyceride (P < 0.03; P < 0.01; P < 0.002). These results suggest that mild dyslipidemia resulting from antiretroviral therapy is caused by a decrease in VLDL and IDL apoB FCR, which is associated with a loss of peripheral fat.

Adult↗
PubMed2006

Understanding and avoiding antiretroviral adverse events.

UNLABELLED: To discuss prevention and management of adverse drug reactions which result from antiretroviral use in patients infected with HIV. There are four classes of antiretroviral agents used in the treatment of HIV/AIDS. Side effects to medications are common place and often difficult to avoid. In many cases, research is not able to identify the exact cause of an event. The severity of adverse reactions varies greatly, and some may be difficult to manage; typically, prevention is more desirable than treatment. However, this is not always true. This paper will review class-wide and individual side effects from antiretrovirals and, in some cases, the mechanism of action that results in the event. Class-wide side effects for nucleoside/tide reverse transcriptase inhibitors (NRTIs) include lactic acidosis, peripheral neuropathy and lipoatrophy. Adverse reactions from individual NRTIs, such as abacavir-induced hypersensitivity reactions, will also be discussed. Class-wide side effects to non-nucleoside reverse transcriptase inhibitors include rash and hepatotoxicity, while efavirenz has its own unique CNS reactions. Protease inhibitor side effects include hyperglycemia, lipoaccumulation, dyslipidemia, and gastrointestinal (GI) intolerance. We will also review specific side effects caused by indinavir, ritonavir, and atazanavir. Finally, adverse reactions from the fusion inhibitor, enfuvirtide, will be mentioned. CONCLUSION: Antiretrovirals are an important break-through in the treatment of HIV/AIDS. However, adverse reactions from these drugs can range from mild to life-threatening, and determining which agent is the cause is frequently difficult to discern. Fortunately, side effects can be monitored, treated and in many cases, prevented.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Lipid abnormalities in a healthcare worker receiving HIV prophylaxis.

Healthcare workers (HCWs) worldwide risk occupational exposure to HIV and other blood-borne pathogens. Post-exposure prophylaxis (PEP) may decrease the risk of seroconversion after occupational or sexual exposure. Current guidelines recommend immediate PEP with at least 2 drugs following HIV exposure. In high-risk exposures, the guidelines recommend the use of a protease inhibitor (PI) as well as 2 reverse transcriptase inhibitors. Protease inhibitors have been associated with dyslipidaemias, other metabolic abnormalities and lipodystrophy syndromes in AIDS patients. We report a case of new transient lipid abnormalities in a HCW receiving PEP after HIV exposure. HIV medications may produce occult metabolic abnormalities in HIV-negative individuals receiving PEP. This risk should be considered during follow-up evaluation for PEP.

Adult↗