Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since 1996 indinavir in combination with zidovudine + lamivudine has been the standard regimen in the treatment of HIV infection. Although protease inhibitor (PI) containing therapies are very potent, many problems have now been identified that reduce quality of life such as a high pill burden, multiple daily dosing and dietary constraints. In addition, adverse events, such as lipodystrophy and lipid metabolism changes are being reported more frequently as long-term experience with PI therapy is gained. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be potent partners for antiretroviral combined therapies. Efavirenz is one of the most recent NNRTIs to be developed. Evidence to date suggests that given its potency, convenience and tolerability, efavirenz will have a major role to play in first-line, PI-sparing regimens and long-term suppressive therapy. However, many questions remain unanswered and future research should attempt to address these issues.
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PMID:Review of NNRTIs: 'today and tomorrow'. 1062 38

Amprenavir is a new peptidomimetic inhibitor of the HIV protease enzyme. Amprenavir has a twice daily dosing schedule and can be administered with or without food making it a convenient dosing regimen among the protease inhibitors (PIs). It is currently being investigated in combination with various nucleoside reverse transcriptase inhibitors (NRTIs) and initial results are promising. Amprenavir may also be useful for salvage therapy in patients failing PI-containing regimens as little cross-resistance has been observed so far with nelfinavir, indinavir or saquinavir. However, amprenavir resistant strains show cross-resistance with ritonavir. Clinical evidence indicates amprenavir is generally well tolerated. However, there is little information to date regarding the ability of amprenavir to cause lipodystrophy or other disturbances of lipid metabolism.
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PMID:Coming therapies: amprenavir. 1062 44

Highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1 (HIV-1) and prophylactic therapy for opportunistic infections have increased survival. Adverse effects of HAART include lipid profile alterations, diabetes mellitus, and fat redistribution. These metabolic and physical changes are called the HIV-associated lipodystrophy syndrome. A link to protease inhibitors has been suggested, and more recently to nucleoside reverse transcriptase inhibitors and factors related to duration of HIV-1 infection itself.
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PMID:HIV-associated lipodystrophy syndrome. 1064 72

Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/microL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir. In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-line option. Indinavir is being studied as a twice daily and once daily regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug interaction and patient compliance/adherence issues. Indinavir-containing triple therapy has demonstrated positive effects not only on surrogate markers of disease progression, but also on clinical end-points of mortality and morbidity in patients with HIV disease. Protease inhibitors are a significant advance in the care of patients with HIV infection, and, in an era of evidence-based medicine, indinavir represents an important component of antiretroviral treatment strategies.
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PMID:Indinavir: a review of its use in the management of HIV infection. 1065 94

A recent prospective clinical study has shown that antiviral therapy with HIV protease inhibitors (PIs) is associated with a syndrome of peripheral fat wasting (lipodystrophy) and disordered glucose and lipid metabolism (Carr et al. 1999). We have studied the effects of indinavir and saquinavir, two HIV protease inhibitors, on cultured primary human preadipocytes and report that these compounds inhibit their differentiation. However, we find that these agents do not inhibit either transcriptional activation or adipocyte P2 gene induction by the PPARgamma/RXR nuclear receptor heterodimer. Together, our findings suggest that impaired adipogenesis is the basis of PI-associated lipodystrophy, but that this occurs via a PPARgamma/RXR-independent mechanism.
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PMID:HIV protease inhibitors block human preadipocyte differentiation, but not via the PPARgamma/RXR heterodimer. 1065 60

Lipodystrophies, characterized by reduction of subcutaneous fat over part or all of the body surface, are uncommon. Their causes are unknown. Recently, lipodystrophy has been reported in human immunodeficiency virus (HIV)-infected patients taking protease inhibitors, which have been recommended since 1996 as standard therapy for HIV disease in combination with nucleoside analogues. In these cases, lipodystrophy consists of an association of peripheral lipoatrophy with central adiposity. We report four HIV-infected men on protease inhibitors who developed a disfiguring lipodystrophy. In three of them, the protease inhibitor was administered for a mean duration of 21.5 months (range 19-23) with good immunological and virological responses. Patient 4 had been treated for 2 years with successive combinations of protease inhibitors with nucleoside analogues without success. The four patients progressively developed an increase in abdominal girth associated with fat wasting of the face and legs. Two of them had recurrent paronychia of the great toes. Triglyceride levels were moderately increased in all patients, and one had a slightly increased cholesterol level. One patient had elevated glucose and insulin plasma levels during a glucose tolerance test. In two patients, a deep biopsy taken from the thigh showed thinning of the subcutaneous fat without other morphological changes. Computed tomographic scans of the face and abdomen confirmed the loss of almost all subcutaneous fat of the cheek and temporal regions, and abdominal perivisceral fat accumulation. For patients 1-3, the protease inhibitor was replaced by a non-nucleoside reverse transcriptase inhibitor. Nine months later, dysmorphic changes had not regressed, but lipid abnormalities had returned to normal and the paronychia had disappeared.
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PMID:Lipodystrophy associated with protease inhibitors. 1073 57

HIV-positive patients receiving antiretroviral therapy with HIV-1 protease-inhibitors (PI) frequently show insulin-resistance, impaired glucose tolerance, hypertriglyceridaemia and lipodystrophy (LD). LD has often been reported only after the beginning of PI therapy. Some authors link LD to HIV chronic infection, some others suggest that PIs increase pre-existent disturb. Preliminary data of an observational study drawn in IV day-hospital of Spallanzani Institute in Rome showed hypertriglyceridaemia in 36.4% and hyperglycaemia in 11.2% of patients treated with PI. Carr suggests that such drugs should have this lipid-increasing effect because of their inhibition of low density lipoprotein-receptor-related protein, cytoplasmic retinoic-acid binding protein type 1 and P450 3A cytochrome. This theory doesn't explain why both untreated patients and treated with only reverse transcriptase inhibitors show sometimes the same disorders. According to another hypothesis Tumor necrosis factor-alpha, through inhibition of lipoprotein-lipase, would determine high fat-storage in the adipose tissue. Cardiovascular risk factors have always to be assessed before starting a therapy with PI. Glycaemia, triglyceridaemia, cholesterolaemia have to be performed every three months during the treatment and, if necessary, C-Peptide and insulinaemia too. A treatment with lipid-lowering drugs is always recommended in patients with hypertriglyceridaemia > 500 mg/dl and/or hypercholesterolaemia LDL > 190 mg/dl in two following checks. Fibrates have proven to be effective in reducing hypertriglyceridaemia, but there is no certainty that such therapies could have good effects on the LD itself too.
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PMID:[Dysmetabolic syndrome related to HIV-1 protease inhibitors. Review of the literature and personal data]. 1074 53

HIV infection induces an early decrease of cholesterol and a late increase of triglycerides (TG) with a reduction of HDL. These changes are proportional with the lowering of CD4, which reflects the infection's severity. Both the increase of TG synthesis and the decrease of TG catabolism, in relation with a reduction of lipoprotein lipase activity, are responsible of these changes. Moreover, LDL catabolism is enhanced by macrophage scavenger receptors, due to a high proportion of small, dense LDL which are more easily oxidized. Many cytokines (interferon alpha, interleukins, TNF) play probably a pathogenic role in the dyslipidemia. Some HIV patients who received antiproteases may develop lipodystrophy with central obesity, insulino-resistance, glucose intolerance and sometimes diabetes (like in syndrome X). Other patients present a cushingoid, buffalo hump. This complication may be observed also with antiretroviral treatment other than antiproteases. The physiopathology of these findings could be in relation with structural homologies between antiproteases and some important proteins, involved in lipid and adipocyte metabolism. Cardiovascular risk linked to these perturbations is evident. The treatment is not different from the treatment for seronegative, hyperlipidemic patients: struggle against risk factors, diet advices, fibrates or statins. The antiproteases bring huge contribution to the prognosis of AIDS patients but the risk of cardiovascular complications could impair this therapeutic progress. So, it is essential to understand the pathogeny of these complications in order to discover new antiproteases, without these adverse side effects.
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PMID:[Lipids and AIDS]. 1074 83

Since the clinical introduction of protease inhibitors for the treatment of HIV disease in 1996, optimism has grown for the long-term survival of persons living with HIV disease. With the addition of protease inhibitors to highly active antiretroviral therapy, the number of deaths from AIDS has decreased dramatically. However, along with reports of dramatic clinical improvement, many cases of a novel lipodystrophy syndrome associated with high triglyceride levels, diabetes, accumulations of fatty tissue, and alterations in body shape have been reported by researchers, clinicians, and persons living with HIV disease. This article reviews the literature on the defining characteristics and pathogenesis of HIV-related lipodystrophy, summarizes the current state of the science, and discusses related research and clinical implications.
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PMID:HIV-related lipodystrophy: a clinical syndrome with implications for nursing practice. 1075 47

Although effective treatment of antiretroviral-associated metabolic abnormalities ultimately depends on understanding the mechanisms involved, clinicians facing these problems are beginning to feel compelled to do something now to manage treatment-related metabolic complications. Diet and exercise should not be overlooked, because both can be effective in managing these complications without causing further side effects. Fibric acid derivatives such as gemfibrozil and statins can lower HIV-associated cholesterol and triglyceride levels, although further data are needed on problematic interactions between statins and protease inhibitors (PIs). Hypoglycemic agents may have some role in managing glucose abnormalities, although troglitazone cannot be recommended for fat abnormalities alone and metformin may cause lactic acidosis. Growth hormone and anabolic steroids may have some role in treating lipodystrophy, but the cost of growth hormone is prohibitive for many patients and definitive data on efficacy are lacking. Replacing a PI with a reverse transcriptase inhibitor has improved lipid and glucose levels in some studies. However, that strategy begs the question of how the nucleosides might contribute to lipodystrophy.
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PMID:How to manage metabolic complications of HIV therapy: what to do while we wait for answers. 1075 16


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