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Anti-human immunodeficiency virus type 1 activity and resistance profile of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine in vitro.

2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T) has been identified as a novel nucleoside analog with potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity and weak cytotoxicity in cell cultures. 4'-Ed4T proved to be 5- to 10-fold more active than its structurally related compound, stavudine (d4T). However, the drug resistance profile of 4'-Ed4T was different from those of d4T and other existing HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs). Approximately 6- to 11-fold decreases in susceptibility to 4'-Ed4T were observed for HIV-1 carrying NRTI-associated mutations (D67N, K70R, T215F, and K219Q) or the lamivudine (3TC)-resistant mutation M184V. In contrast, the susceptibility of the virus carrying the K65R mutation or the multidrug-resistant mutation with the Q151M complex (A62V, V75I, F77L, F116Y, and Q151M) was not altered. Furthermore, the activity of 4'-Ed4T appeared to be enhanced in the presence of K103N, a major nonnucleoside reverse transcriptase inhibitor-resistant mutation. Although 4'-Ed4T was 4.5- to 17.5-fold less active against multidrug-resistant clinical isolates than against a reference strain isolated from a treatment-naïve patient, it was still inhibitory to these isolates at low concentrations. Analysis of 4'-Ed4T-resistant HIV-1 obtained through in vitro selection revealed that the virus was also resistant to 3TC and had two amino acid mutations (P119S and T165A) in addition to the M184V mutation. Since 4'-Ed4T has increased anti-HIV-1 activity, decreased cytotoxicity, and a different resistance profile, it should be considered for further development as a new member of NRTIs.

Anti-HIV Agents↗

Effect of prior nucleoside use on the two-year virological response to an initial protease inhibitor regimen in HIV-infected patients.

PURPOSE: This retrospective study investigates the effect of prior nucleoside (nucleoside reverse transcriptase inhibitor [NRTI]) experience on 2-year virologic response to an initial protease inhibitor-highly active antiretroviral therapy (PI-HAART) regimen. METHOD: 152 patients who started a PI (excluding saquinavir hard gel capsule [hgc] as a sole PI) with two NRTIs between January 1996 and May 1998 at two HIV treatment sites were included. RESULTS: 109 patients (71%) were NRTI experienced. 106 patients received two new NRTIs, and 32 received one new NRTI. Overall, 51% of patients had a virologic response (HIV viral load <400 copies/mL); the mean follow-up was 28 months. Virologic response was associated with the use of at least one new NRTI (relative risk [RR] 2.1; p =.031) but not with prior NRTI experience (p =.19). A complete virologic response was most likely to occur when two new NRTIs were used (RR 2.3) rather than one new NRTI (RR 1.8), but this was not significant (p =.12). CONCLUSION: This study suggests that prior nucleoside experience is not a key predictor of 2-year virologic response in patients who receive at least one new NRTI in an initial PI-HAART regimen.

Adult↗

Anti-human immunodeficiency virus type 1 activities of U-90152 and U-75875 in human brain cell cultures.

Antiviral activities of the reverse transcriptase inhibitors U-90152 and 3'-azido-2',3'-dideoxythymidine and the protease inhibitor U-75875 were compared in two culture models of human immunodeficiency virus type 1 brain infection. In a model involving acutely infected microglial cells, U-90152 was the most active, whereas in a model using chronically infected promonocytes, U-75875 was the most active.

Antiviral Agents↗

The clinical significance of viral fitness.

Increasing evidence indicates that antiretroviral drug resistance is associated with impaired viral fitness and that this impairment can translate, at least transiently, into a virological and immunological benefit. The optimal strategies for exploiting the fitness cost associated with drug resistance remain to be determined. For highly drug-experienced patients receiving salvage therapy with a detectable viral load and with limited or no remaining drug options, continuing the current regimen may be a useful strategy to delay disease progression. In this context, it remains controversial whether it is preferable to continue failing therapy with nucleoside reverse transcriptase inhibitors, protease inhibitors or both.

Anti-HIV Agents↗

HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription.

The current testing of anti-HIV drugs is hampered by the lack of a small animal that is readily available and easy to handle; can be infected systemically with HIV type 1 (HIV-1); harbors the major HIV-1 target cells in a physiological frequency, organ distribution, and activation state; and is established as a pharmacological model. Here, we explored the potential of outbred Sprague-Dawley rats that transgenically express the HIV-1 receptor complex on CD4 T cells and macrophages as a model for the preclinical evaluation of inhibitors targeting virus entry or reverse transcription. The concentrations of the peptidic fusion inhibitor enfuvirtide or the nonnucleoside reverse transcriptase inhibitor efavirenz required to inhibit HIV-1 infection of cultured primary CD4 T cells and macrophages from human CD4 and CCR5-transgenic rats differed by no more than 3-fold from those required for human reference cultures. Prophylactic treatment of double-transgenic rats with a weight-adapted pediatric dosing regimen for either enfuvirtide (s.c., twice-daily) or efavirenz (oral, once-daily) achieved a 92.5% or 98.8% reduction, respectively, of the HIV-1 cDNA load in the spleen 4 days after i.v. HIV-1 challenge. Notably, a once-daily dosing regimen for enfuvirtide resulted in a approximately 5-fold weaker inhibition of infection, unmasking the unfavorable pharmacokinetic characteristics of the synthetic peptide in the context of an efficacy trial. This work provides proof of principle that HIV-susceptible transgenic rats can allow a rapid and predictive preclinical evaluation of the inhibitory potency and of the pharmacokinetic properties of antiviral compounds targeting early steps in the HIV replication cycle.

Animals↗

Factors associated with the successful modification of antiretroviral therapy. HIV Outpatient Study Investigators.

OBJECTIVES: To assess the characteristics of medication regimen modification and the influence of a commercial genotypic resistance assay on the short-term (3-12 weeks) viral load response (> or = 0.5 log reduction) in HIV-1-infected patients extensively treated with antiretroviral therapy (ART). METHODS: A nested cohort study was performed in two clinics from the HIV Outpatient Study of 96 persons with a HIV-1 viral load of 10(4) log copies/ml or greater taking at least two antiretroviral medications. RESULTS: Successful modification was associated with adding at least two new medications [relative risk (RR), 1.5; 95% confidence interval (CI), 1.1-2.2], adding a drug from a previously unused class of agents (RR, 2.0; CI, 1.4-2.9), the initiation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) (RR, 1.7; CI, 1.2-2.4), but not substituting a protease inhibitor or the use of a commercial genotypic resistance assay. CONCLUSION: Incorporating a drug from a previously unused class or changing at least two new medications, but, within the confines of this study, not using a commercial genotypic resistance assay, was associated with the successful modification of ART as measured by a reduction in viral load.

Adult↗

Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy.

We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.

Adipose Tissue↗

Minimizing resistance consequences after virologic failure on initial combination therapy: a systematic overview.

OBJECTIVE: To identify optimal first-line therapies based on the rate of virologic success (VS) and the preservation of future treatment options in antiretroviral therapy (ART)-naive subjects. DESIGN: Systematic overview of genotypic resistance mutations from clinical trials of combination ART. METHODS: Various sources were searched for studies in ART-naive subjects providing virologic response rates and genotypes from subjects with virologic failure. The International AIDS Society-USA genotypic resistance guidelines were used to calculate regimen resistance cost (RCreg) and number of active drug (AD) scores for each regimen and to rank the regimens. RESULTS: Intra- and interstudy comparisons showed higher VS rates for nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens (range: 51%-76%) and boosted protease inhibitor (boosted PI) regimens (range: 55%-79%). Boosted PI failures had the lowest RCreg (range: 0.12-0.21) and the highest AD (range: 19.80-20.18) scores. NNRTI failures had higher RCreg (range: 0.00-1.22) and lower AD (range: 16.83-21) scores. CONCLUSIONS: NNRTI and boosted PI regimens provide the highest rates of VS in treatment-naive HIV-infected persons. Treatment option scores were higher in subjects who failed boosted PI- containing regimens versus NNRTI-containing regimens, however.

Anti-HIV Agents↗

[AIDS; new developments. II. Treatment of HIV infection].

The currently available anti-HIV drugs can be subdivided according to the mechanisms of action into two main groups, viz, reverse transcriptase (RT) inhibitors and protease inhibitors; the former may be subdivided into nucleoside inhibitors and non-nucleoside inhibitors of reverse transcriptase. Combination therapy is preferable to monotherapy because of resistance problems. The 'ideal' combination consists of two RT inhibitors plus one protease inhibitor. Of the RT inhibitors, zidovudine is to be preferred because it slows the development of AIDS dementia. Other RT inhibitors are didanosine, zalcitabine, stavudine and lamivudine. As regards the protease inhibitors; in view of the development of resistance, it is advised to prescribe ritonavir, indinavir or saquinavir. The antiretroviral management should be adjusted as soon as signs appear of toxicity or failure of the treatment due to resistance or poor compliance.

Anti-HIV Agents↗

Lactate levels in children with HIV/AIDS on highly active antiretroviral therapy.

A total of 251 venous lactate levels were obtained from 127 children with HIV/AIDS; 104 on highly active antiretroviral therapy, and 23 not on therapy. Asymptomatic hyperlactatemia (> 2 mmol/l) was found in 41 children; no hepatic dysfunction or life-threatening lactic acidosis occurred. Asymptomatic hyperlactatemia is associated with treatment with nucleoside reverse transcriptase inhibitors or protease inhibitors and with undetectable viral loads regardless of treatment regimen, suggesting that elevated lactate levels are useful in evaluating adherence.

Acquired Immunodeficiency Syndrome↗

Premature atherosclerosis in HIV positive patients and cumulated time of exposure to antiretroviral therapy (SHIVA study).

BACKGROUND: With the advent of antiretroviral therapy regimens in HIV positive patients, it is crucial to consider their long-term benefits to risk ratios. The responsibility of treatment in premature atherosclerosis is not clear. Thus, the aim of this study is to evaluate the impact of exposure to reverse transcriptase inhibitors (nucleosidic and non-nucleosidic) and to protease inhibitors on the cardiovascular status of an entire hospital based cohort of patients. METHODS: 154 patients were included. Using a linear analysis, we sought an association between the cumulative time of exposure to these three classes of antiretroviral drugs and the carotid intima-media thickness measured by ultrasonography and a cardiovascular composite score. RESULTS: The study confirms premature atherosclerosis, which not only correlates with the usual risk factors, such as triglyceride level, but also with protease inhibitor exposure, especially that of lopinavir. Nevertheless as regards current drug exposure, the clinical impact was low: five clinical complications of atherosclerosis and only one out of 35 scintigraphic and ECG exercise tests warranted a coronary angiography which was negative. CONCLUSION: These data should not lead to the rejection of protease inhibitors but should strengthen the prevention of cardiovascular diseases as an integral part of the management of HIV patients.

Adult↗

Human immunodeficiency virus protease inhibitors accumulate into cultured human adipocytes and alter expression of adipocytokines.

Lipodystrophic syndrome is a major side effect of highly active antiviral therapy. Fat tissue redistribution is associated with changes in adipocyte gene expression and in circulating levels of adipocytokines involved in the development of insulin resistance. However, the evidence that HIV drugs accumulate into human adipocytes and have a direct effect on the expression of adipocyte-specific genes is still lacking. To address these questions, we used adipocytes derived from adult stem (hMADS) cells isolated from human adipose tissue. We showed by ELISA that two inhibitors of the HIV protease, lopinavir and ritonavir, accumulated at similar levels during the development of hMADS cells in adipocytes, whereas a non-nucleoside reverse transcriptase inhibitor, the nevirapine, accumulated at lower levels. Two fluorescent protease inhibitors then have been generated to investigate their subcellular localization. The data showed that HIV drugs accumulated into adipocytes and displayed various effects on hMADS cell-derived adipocytes. Indinavir, amprenavir, and nevirapine did not alter differentiation of precursor cells. In contrast, lopinavir, saquinavir, and ritonavir inhibited the development of preadipocytes into adipocytes. In adipocytes, amprenavir increased leptin expression and ritonavir was able to up-regulate tumor necrosis factor-alpha, interleukin 6, and leptin expression and down-regulate the expression of peroxisome proliferator-activated receptor gamma and adiponectin. Intracellular accumulation and localization of HIV drugs into human adipocytes strongly suggest that adipose tissues store these drugs. Because ritonavir can alter the expression of insulin resistance-related cytokines in human adipocytes in a way parallel to the situation observed in vivo upon treatment of HIV-infected patients, we propose that protease inhibitors participate in insulin resistance through a direct effect on adipocytes.

Adipocytes↗

[AIDS; new developments. IV. Changes in primary medical care due to new possibilities of treating HIV-infected patients].

A combination treatment has recently become available for HIV-infected patients; it consists of two reverse transcriptase inhibitors and one protease inhibitor. This combination therapy has consequences for primary medical care as regards diagnostics, treatment, follow-up and counselling of patients with HIV and AIDS, education of patients requiring the HIV test, information of seropositive patients not yet being treated and the cooperation and task distribution between GPs and AIDS specialists. The new combination method creates new problems for patients, such as medicalization of their lives, side effects and compliance; it also affects their prospects (social reintegration, resumed occupational activity). In the medical management, the focus shifts to early start of treatment, stimulating compliance, monitoring of effect and side effects, if any, of the treatment and coping with the patients' uncertainty about durability of the effect. If the new treatment proves to be successful in the long run as well, HIV infection/AIDS will become a chronic disease, so that the needs of care and the care methods will increasingly resemble those of other chronic diseases. There will be a growing need of extramural care, leading to new requirements regarding the study of medicine and postgraduate instruction of GPs.

Acquired Immunodeficiency Syndrome↗

Patient support and education for promoting adherence to highly active antiretroviral therapy for HIV/AIDS.

BACKGROUND: Highly active antiretroviral therapy is associated with improved health outcomes for people living with HIV/AIDS. Unfortunately, full therapeutic benefit from HAART may require near-perfect adherence to prescribed regimens. OBJECTIVES: To determine the effectiveness of patient support and education interventions for improving adherence to highly active antiretroviral therapy (HAART) in people living with HIV and AIDS. SEARCH STRATEGY: Studies were identified using AIDSLINE, MEDLINE, CINAHL, HEALTHSTAR, PSYCHLIT, SOCIOLOGICAL ABSTRACTS, INTERNATIONAL PHARMACEUTICAL ABSTRACTS, SCIENCE CITATION INDEX, EMBASE, and abstracts from global AIDS meetings, ICAAC, and other major meetings from January 1996 to April 1999. Further information was sought through contact with authors, reference lists, and Collaborative Review Group databases. SELECTION CRITERIA: To be included, studies had to describe a supportive or educational intervention to improve adherence to a HAART regimen in HIV positive patients, and include a comparison group. Eligible HAART regimens were defined as consisting of at least three anti-HIV drugs one of which must be a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. At least one measure of adherence was also required. DATA COLLECTION AND ANALYSIS: Data on study design, participants, interventions, and outcomes were extracted from the reports onto specifically designed data collection forms by at least two reviewers. MAIN RESULTS: One study satisfied the eligibility criteria. It compared a pharmacist-led intervention consisting of educational counseling and availability of follow-up telephone support with conventional dispensing of HAART pills. This intervention significantly improved adherence to HAART, and adherence to HAART significantly predicted undetectable viral load at 24 weeks. However, participating in the intervention did not significantly predict a subsequently undetectable viral load at 24 weeks. REVIEWER'S CONCLUSIONS: Implications for practice Currently a pharmacist-led program of educational and supportive counseling is the only available intervention which has been shown in a controlled study to improve adherence to HAART, with less evidence that viral load is subsequently reduced. Implications for research Controlled trials are urgently needed to determine which interventions can significantly improve adherence to HAART. Whether interventions that improve adherence also suppress viral load and improve clinical outcomes should also be considered.

Acquired Immunodeficiency Syndrome↗

Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection.

The safety and efficacy of a fixed 25 mg pyrimethamine-500 mg sulfadoxine combination supplemented with 15 mg folinic acid twice a week as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis was evaluated in 106 patients infected with the human immunodeficiency virus. All patients had a CD4+ T-lymphocyte count of less than 100 cells/microl at study entry. Efficacy in this single-arm open-label prospective study was analyzed on an as-treated basis. No patient received highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. PCP developed in four patients, one of whom had been noncompliant. No PCP episode occurred in the first year. Probabilities of freedom from PCP were 0.97 (95%CI, 0.92-1) after 24 months and 0.93 (95%CI, 0.84-1) after 36 months. Of 74 (69.8%) patients positive for anti-toxoplasma IgG antibodies, one noncompliant patient developed toxoplasmic encephalitis after 24 months. Allergic reactions were observed in 18 (17%) patients and resulted in permanent discontinuation in 7 (6.6%) patients. One (0.9%) patient who had continued prophylaxis despite progressive hypersensitivity reactions developed a serious adverse reaction (Stevens-Johnson syndrome). The median survival of study participants was 29 months, with relentless progression of AIDS accounting for most deaths. The prophylaxis regimen studied appeared safe and effective for primary prophylaxis of PCP and toxoplasmic encephalitis. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance. Efficacy and safety compare favorably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients failing or intolerant to approved regimens.

AIDS-Related Opportunistic Infections↗

Antiretroviral Therapy-associated Serious and Life-threatening Toxicities.

In the late 1980s and early 1990s, when HIV/AIDS had become the leading cause of death in 25- to 44-year-old persons in the United States, it was acceptable to prescribe newer antiretroviral therapy such as zidovudine, which has significant bone marrow toxicities but can potentially improve patient survival. Although current antiretroviral therapy is not likely to eradicate HIV-1 infection, the advances in the use of combination antiretroviral therapy (including protease inhibitors and non-nucleoside reverse transcriptase inhibitors) have dramatically improved the overall survival, immune status, and productivity of HIV-infected individuals in developed countries. Instead of prevention and treatment of HIV-associated complications, many of the patients" clinic visits are focused on finding strategies to manage and prevent antiretroviral therapy-associated complications. Because only a few HIV-infected persons fulfilling stringent inclusion criteria were included in premarketing clinical trials and because the US Food and Drug Administration"s (FDA) accelerated approval process for antiretroviral therapy requires only 24-week safety and efficacy data, newly emerging and previously unrecognized adverse effects of antiretroviral therapy continue to surface when these drugs are administered to a larger patient population for a longer duration. Unfortunately, some of these adverse effects can be unpredictable and serious, and, if not recognized early and managed aggressively, can lead to fatality. This article reviews four of the most serious, life-threatening toxicities associated with antiretroviral therapy.

Journal Article↗

Hepatotoxicity and antiretroviral therapy with protease inhibitors: A review.

Highly active antiretroviral therapy including protease inhibitors has led to dramatic decrease in the morbidity and mortality resulting from infection with human immunodeficiency virus-1. However, this combination regimen can be associated with the occurrence of serious toxicities, which may reduce patient compliance. In particular, human immunodeficiency virus-1 protease inhibitors and nevirapine among nonnucleoside reverse transcriptase inhibitors, have the potential for producing hepatotoxicity. We summarise current knowledge of the hepatotoxic effects associated with the commercially available human immunodeficiency virus-1 protease inhibitors based on a literature review of the major retrospective and prospective clinical studies designed to elucidate risk factors for developing hepatotoxicity among human immunodeficiency virus-1-infected patients receiving antiretroviral therapy containing protease inhibitors. Coinfection with chronic hepatitis, a common occurrence in human immunodeficiency virus-1-infected patients, is identified as an independent risk factor for developing hepatotoxicity in antiretroviral-treated human immunodeficiency virus-1-infected patients treated with antiretroviral regimens containing protease inhibitors. The importance of other risk factors for developing protease inhibitor-associated hepatotoxicity and the mechanism underlying the drug-related hepatotoxicity are discussed. The data indicate that the potential for producing hepatotoxicity is variable among the protease inhibitors and suggest that based on differences in drug-related hepatotoxicity, certain protease inhibitors may be preferred for the treatment of human immunodeficiency virus-hepatitis C virus coinfected patients.

Antiretroviral Therapy, Highly Active↗

Determination of atazanavir and other antiretroviral drugs (indinavir, amprenavir, nelfinavir and its active metabolite M8, saquinavir, ritonavir, lopinavir, nevirapine and efavirenz) plasma levels by high performance liquid chromatography with UV detection.

A global method is proposed for therapeutic drug monitoring of atazanavir, a novel protease inhibitor and of all other protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) which are currently used to treat HIV patients. All drugs are extracted after a liquid-liquid extraction and separated on a C18 column with a binary gradient elution except lopinavir which is separated without this gradient. The absorbance is measured at 259 nm except for lopinavir (205 nm) and nevirapine (320 nm). This method is specific, accurate, precise (the intra-day and inter-day imprecision and inaccuracy are lower than 15%) and the limits of quantitation (0.40 mg/L for nevirapine, 0.10 mg/L for indinavir, 0.10 mg/l for M8, 0.05 mg/L for amprenavir, 0.10 mg/L for nelfinavir, 0.10 mg/L for saquinavir, 0.10 mg/L for ritonavir, 0.10 mg/L for efavirenz, 0.10 mg/L for atazanavir and 0.20 mg/L for lopinavir) are consistent with trough plasma concentrations allowing to use this method for therapeutic drug monitoring of PI and NNRTI.

Atazanavir Sulfate↗