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)

Long-term alterations to body metabolism have become apparent with the prolonged use of antiretroviral nucleoside analogue reverse transcriptase inhibitors (NRTIs). The NRTIs differ in the mechanisms, potency and probably also tissue specificity of mitochondrial toxicity. One group of NRTIs, the so-called "d-drugs" (zalcitabine> didanosine>stavudine) are relatively strong inhibitors of g-polymerase and thus cause a time- and dose-dependent decrease in the intracellular levels of mitochondrial DNA (mtDNA). The most important target organs of d-drugs are the liver, skeletal muscle, peripheral nerves and probably also the subcutaneous adipose tissue of lipoatrophic subjects. Hyperlactataemia may be observed. Zidovudine is an inhibitor of the mitochondrial adenine nucleotide translocator, binds to adenylate kinase and may also be converted into stavudine triphosphate in vivo. Persistent hyperlactataemia, mtDNA depletion and isolated cases of mitochondrial encephalomyopathies have been observed in babies under perinatal exposure with zidovudine. Nucleotide analogues such as tenofovir are avidly taken up into renal tubular epithelia. Isolated cases of renal failure and Fanconi syndrome require further investigation. Mitochondrial toxicity cannot yet be adequately monitored and predicted. Drugs with potential additive or synergistic toxicity, such as valproate, should be used with caution. Didanosine interacts with allopurinol, hydroxyurea and ribavirin. In established mitochondrial toxicity, cessation of the offending NRTI remains the most effective therapeutic intervention because vitamin cocktails and l-carnitine have, at best, only a marginal effect.
J HIV Ther 2003 May
PMID:Update on mitochondrial toxicity: where are we now? 1283 62

Didanosine (ddl) has been a cornerstone of HIV management since it was made available in October 1991. Didanosine was originally introduced as an alternative to zidovudine (ZDV) for patients who were intolerant of ZDV or experienced disease progression during ZDV monotherapy. Didanosine is now used extensively as an integral component of multidrug combination regimens in both adults and children with HIV infection, and is now available for once-daily administration in the United States, Canada, and Europe. The recently approved Videx EC is an enteric-coated didanosine capsule dosed as one capsule, once daily. This paper provides an update of recently published studies on the use of ddl in combination anti-HIV therapy. In particular, these studies examine the rationale for the use of ddl as first-line anti-HIV therapy, and describe newer findings concerning its long-term efficacy, side effects, compliance, resistance, and once-daily use. The increased survival of HIV-infected patients is largely attributed to the introduction of the triple combination drug therapy but is probably also due to the long-term clinical efficacy of ddl.
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PMID:Update on didanosine. 1294 65

Both the incidence and prevalence of human immunodeficiency virus infection are increasing in the world. Diseases of ENT districts are more frequent in human immunodeficiency virus-infected patients and involve all the otolaryngological sites. The otorhinolaryngological manifestations in association with HIV infection are mainly atypical, so common in the clinical practice, really aspecific and very frequent in ENT daily routine (such as sinusitis, otitis, etc.) and, therefore, immunodeficiency may not be suspected. In other cases, ENT evidence is more peculiar or unusual, such as opportunistic infections, rare neoplasm and tumours with an unusual course, giving a very high suspect of a human immunodeficiency virus-related infection. The most frequent malignant neoplasm is Kaposi's Sarcoma which is extremely rare in non-human immunodeficiency virus-infected subjects; the second most frequent is non-Hodgkin's lymphoma with 50% in extranodal sites (oral and maxillary sinus). Following a review of the literature, modifications caused by current antiretroviral treatment on head and neck manifestations of human immunodeficiency virus infection have been evaluated. Highly active antiretroviral therapy is a new therapeutic strategy, based on poly-chemo-therapeutic schemes, providing simultaneously two or more anti-retroviral drugs. We have used highly active antiretroviral therapy in human immunodeficiency virus infection since 1997, substituting previous mono-chemotherapy based on Zidovudine or Didanosine alone. Highly active antiretroviral therapy is extremely efficient in reducing the viral load of human immunodeficiency virus and increasing CD4+ T-lymphocyte count. These biological effects are associated with an improvement in immune functions. To evaluate the effects of highly active antiretroviral therapy on otorhinolaryngological manifestations in human immunodeficiency virus infection, we performed a retrospective study on 470 adults, observed over 14 years (1989-2002) and constantly receiving the same treatment, with follow-up from 7 to 80 months. A total of 250 subjects underwent mono-antiretroviral chemotherapy (1989-1996), while 220 underwent highly active antiretroviral therapy (1997-2002). The results of the retrospective study showed that highly active antiretroviral therapy has greatly improved the control of the immune-deficiency (increasing the range of CD4+), reducing the number of otorhinolaryngological manifestations (also tumours). On the other hand, 2 patients presented sudden unilateral hearing loss following treatment: toxicity due to association of new drugs cannot be excluded.
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PMID:Human immunodeficiency virus infection: personal experience in changes in head and neck manifestations due to recent antiretroviral therapies. 1608 Mar 13

The aim of this prospective study was to determine the adverse effects of antiretroviral therapy in HIV-1 infected children and factors associated with adverse effects. The study was performed in a pediatric and perinatal HIV clinic in a tertiary general hospital. Forty-three HIV positive children from the age group of 5 months to 14 years were started on antiretroviral therapy ART. Thirteen patients (30%) had adverse effects related to the ART. Seven patients (16%) had hepatotoxicity, 5 patients (12%) had raised serum amylase without symptomatic pancreatitis, 5 patients (12%) had zidovudine AZT induced anemia, 4 patients (9%) had Nevirapine NVP induced rash, 1 patient (2%) had Didanosine ddI induced pain in abdomen, 1 patient (2%) had Stavudine d4T induced angioedema, and 1 patient (2%) had hepatic steatosis. Five patients (71%) with hepatotoxicity responded to dose adjustment of ART whereas in 2 patients (29%), the elevated liver enzymes resolved on its own. Two patients (40%) with AZT induced anemia required omission of AZT and remaining 3 patients (60%) responded to dosage adjustment. ddI induced abdominal pain, d4T induced angioedema and hepatic steatosis resolved on omitting the respective antiretroviral drug. NVP induced rash and raised serum amylase subsided without any intervention. Hepatotoxicity was seen at higher viral load (Mean = 118608 copies/ml) whereas elevated serum amylase was seen at lower viral load (mean = 37631 copies/ml), which was statistically significant (p < 0.0001). NVP induced rash was seen in early weeks of therapy, serum amylase abnormalities were seen at a mean interval of 0.9 years after starting therapy, hepatotoxicity was seen at a mean interval of 1.7 years and AZT induced anemia was seen at a mean interval of 2.0 years after starting therapy. Adverse effects with antiretroviral drugs in HIV-infected children are quite common. Hepatotoxicity is the commonest adverse effect noted followed by elevated serum amylase and zidovudine induced anemia. Hepatotoxicity is seen at higher viral load as compared to other adverse effects. Most of the adverse effects are reversible on dosage modification or omitting the offending drug.
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PMID:Adverse effects of antiretroviral therapy in HIV-1 infected children. 1612 3

Despite dramatic reduction of the levels of human immunodeficiency virus type I (HIV-1) virions in blood and seminal plasma of infected patients, highly active antiretroviral therapy (HAART) does not eradicate HIV-1. Three patients, with less than 50 copies/ml of plasma viral RNA, were enrolled in this eradication protocol. Didanosine (DDI) and hydroxyurea (HU) were added to their baseline HAART and after a month of therapy, low dose OKT3, followed by a 2-week course of interleukin 2 (IL-2), was administrated. All antiretroviral therapy was then interrupted and the three patients developed viral rebound in the peripheral blood. The V3 loop region of the HIV-1 gp120 from cell-free viral RNA and proviral DNA in blood and seminal compartments was sequenced in one patient. The two major viral isolates in semen cells were macrophage- tropic (R5) and dual-tropic (R5X4), and these isolates were also present in the PBMCs. Six months after the viral rebound, we demonstrated a shift toward dual tropism in semen cell-associated HIV-1 proviral DNA, with the first appearance of a T-lymphotropic (X4) provirus solely in this compartment. The virus responsible for the blood plasma viral rebound was never found in the semen microenvironment. This study suggests viral compartmentalization of the semen microenvironment after an intensification and stimulatory HIV-1 eradication protocol, with evidence of viral evolution.
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PMID:Seminal reservoirs during an HIV type 1 eradication trial. 1621

HIV-infected patients are living longer since the introduction of highly active antiretroviral therapy. However, coinfection with the hepatitis C virus (HCV) leads to increased morbidity from liver disease and higher overall mortality. The prevalence of chronic hepatitis C among patients with HIV/AIDS ranges from 7% (sexual transmission of HIV) to >90% (injection drug use). Uncontrolled HIV infection seems to accelerate the progression of HCV-induced liver fibrosis. Forty-eight weeks of combination therapy with pegylated interferon alpha (2a or 2b) plus ribavirin achieves a sustained viral response in coinfected individuals in up to 38% with HCV genotype 1 and up to 73% with genotypes 2 or 3. The safety profile of this treatment is similar to therapy in HCV-monoinfected patients with influenza-like symptoms, cytopenia and neuropsychiatric symptoms dominating. However, HIV/HCV-coinfected patients who also take zidovudine develop more profound anaemia than those on other HIV nucleoside analogue therapy. Didanosine and stavudine are associated with rare but serious mitochondrial toxicity, such as pancreatitis or lactic acidosis. It does not appear that the addition of ribavirin increases that risk. There is currently no evidence that in HIV/HCV coinfection one pegylated interferon product is superior to the other. Contrary to common perception, it is also unproven that HIV/HCV-coinfected patients respond less well to therapy with peginterferon alpha plus ribavirin than HCV-monoinfected patients. Given the safety and efficacy of combination therapy with peginterferon plus ribavirin and the deleterious effects of chronic hepatitis C, all HIV/HCV-coinfected patients should be evaluated for therapy.
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PMID:Chronic hepatitis C in patients with HIV/AIDS: a new challenge in antiviral therapy. 1630 19

The plant extract Secomet-V has previously been shown by Kotwal et al. to have potent antiviral activity. It was tested for mutagenicity with the Ames gene mutation test in Salmonella and the chromosome damage (clastogenic) micronucleolus (MN) test in human lymphocytes. These tests predict long-term carcinogenesis activity of the agents tested. Secomet-V (with charcoal added) demonstrated weak clastogenic activity, but powerful mutagenic activity in the Ames test with the addition of exogenous metabolic activation. The mutagenic activity of the conventional antiretroviral drugs AZT, Didanosine (DID), and 3TC alone and in dual combinations was also assessed for the first time for Salmonella mutagenicity without any mutagenic effects. AZT, DID, and 3TC have also been tested for MN induction; DID and 3TC resulted negatively, whereas AZT was positive in a dose-related manner. The dual combinations of AZT and DID, 3TC and DID plus 3TC did not result in any additive or synergistic effect. Purification in the absence of charcoal results in a drastic reduction in extract mutagenicity, which is almost reduced completely by further ultrafiltration (cutoff <3,000 Da). This fraction, which is a mixture of molecules of less than 3,000 Da, still possesses the capability to induce sister chromatid exchanges in human lymphocytes. This could be due to residual mutagenicity or, more likely, to the slowdown of the DNA replication process. These findings open new possibilities for HIV therapy, because this antiviral activity of Secomet-V purified in the absence of charcoal and further filtered through a 3,000-Da filter is devoid of mutagenic activity and therefore safe for long-term use.
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PMID:In vitro mutagenicity studies of the antiretrovirals AZT, Didanosine, and 3TC and a plant antiviral extract Secomet-V derived from the Trifollium species. 1638 97

Effective reduction in maternal-fetal human immunodeficiency virus-1 (HIV-1) transmission has been achieved by administration of nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy, and although most exposed children are clinically normal at birth, mitochondrial dysfunction has been reported. To examine mitochondrial integrity on a molecular level, we evaluated mitochondrial morphology by electron microscopy (EM) and mitochondrial DNA (mtDNA) quantity in umbilical cords and cord blood from NRTI-exposed and unexposed human and monkey newborns. Human subjects included infants born to HIV-1-infected mothers who received Combivir (Zidovudine [AZT] plus Lamivudine [3TC]) (n = 9) or AZT plus Didanosine [ddI] (n = 2) during pregnancy, and infants born to HIV-1-uninfected mothers (n = 7). NRTI-exposed Erythrocebus patas monkey dams (n = 3 per treatment group) were given human-equivalent dosing regimens containing 3TC, AZT/3TC, AZT/ddI, or Stavudine (d4T)/3TC during gestation. Four infants born to unexposed patas dams served as controls. Mitochondria in umbilical cord endothelial cells from NRTI-exposed monkey and human infants showed substantial abnormal pathology by EM, the extent of which was quantified from coded photomicrographs and shown to be different (P < 0.05) from the unexposed monkey and human newborns. Significant (P < 0.05) mtDNA depletion was found in umbilical cords from both human and monkey NRTI-exposed infants and in human, but not in monkey, cord blood leukocytes. For umbilical cords, an increase in mitochondrial morphological damage correlated with reduction in mtDNA quantity in fetal monkeys (r = 0.94). The treatment-induced mitochondrial compromise in infant monkeys ranked as follows: d4T/3TC > AZT/ddI > AZT/3TC > 3TC. The study demonstrates that transplacental NRTI exposures induce similar mitochondrial damage in cord blood and umbilical cords taken from retroviral-uninfected monkey infants and from human infants born to HIV-1-infected women.
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PMID:Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. 1653 87

Didanosine, which is a synthetic nucleoside analogue intracellularly phosphorylated to the active metabolite, inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate. Currently, didanosine is mainly provided as an enteric-coated capsule. In vitro, the molecule is active against laboratory strains and clinical isolates of HIV-1 in resting and activated T cells and monocyte/macrophages. Didanosine may select for resistance mutations that may render the drug inactive against the virus; L74V and K65R remain as the main didanosine-related mutations. In vitro, phenotypic susceptibility to didanosine was decreased beyond a defined fold change clinical cut-off (1.7), and it is considered that genotypic resistance exists when five thymidine-associated mutations or four plus M184V are present. In vivo, clinical studies have shown that didanosine retains significant antiviral activity in patients who have up to five nucleoside analogue mutations at baseline. Didanosine is useful in patients with no previous therapy, as well as in experienced patients in whom one or more antiretroviral regimens has failed.Enteric-coated didanosine is taken once daily, its co-administration with food has been recently evaluated and a reduction of the efficacy of the antiretroviral treatment was not observed. Administered with lamivudine (or emtricitabine), it can be considered a good alternative for use in the nucleoside analogue backbone included in combination therapies for antiretroviral-naive patients. Didanosine could be used in initial treatments for patients intolerant of zidovudine, abacavir or tenofovir. It can be included in once-daily combination regimens, which are more convenient and patient friendly.Prospective, observational and open-label studies, as well as clinical trials (with durations between 24 and 96 weeks), have demonstrated the safety and efficacy of didanosine plus lamivudine (or emtricitabine) plus efavirenz (or nevirapine) in previously untreated HIV-1-infected patients. The administration of didanosine to treatment-experienced patients has been evaluated in two different contexts: patients in whom previous therapies have failed (rescue therapy) and those with controlled viraemia who are switched to a didanosine-containing regimen for simplification.Adverse events associated with the administration of didanosine have been well known since the initial clinical trials with the drug. Gastrointestinal intolerance, peripheral neuropathy and hyperamylasaemia/pancreatitis were the most frequently reported. In the highly active antiretroviral therapy (HAART) era, the rate of adverse events has decreased. The tolerability of didanosine has been clearly improved with the development of the enteric-coated capsule. Severe manifestations of mitochondrial toxicity, including lactic acidosis and abnormal fat distribution, are rare complications, and occur most frequently when didanosine is used in combination with stavudine.
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PMID:Didanosine enteric-coated capsule: current role in patients with HIV-1 infection. 1760 Mar 92

Liver disease is currently the second leading cause of death in HIV-infected persons in Western countries. Hepatitis C virus infection accounts for the majority of cases of hepatic illness in this population. Although great progress has been made in the treatment of chronic hepatitis C in HIV-positive patients, many challenges still remain unsolved. The combination of pegylated interferon plus ribavirin is the current treatment of choice in hepatitis C virus/HIV-coinfected patients, regardless of hepatitis C virus genotype. However, the limited efficacy of this therapy in the HIV setting makes necessary the development of new strategies and/or drugs for the treatment of hepatitis C infection. Several anti-hepatitis C virus compounds are currently under investigation, although most are still in the early stages of clinical development. There is a relatively large group of patients who will be unable to be treated with the current hepatitis C virus medication based on interferon, mainly due to contraindications such as serious neuropsychiatric or cardiovascular history. However, for those without contraindications, treatment should be provided with no restrictions at the start (e.g. asking unnecessarily for a liver biopsy), and reassessed at weeks 4 and 12, considering virologic responses. Treatment should only be continued in early virologic responders. The use of standard doses of ribavirin (1000-1200 mg/day) and for at least 12 months seems crucial to maximize the effect of current hepatitis C treatment in the HIV setting, while no further benefit seems to derive from using higher than recommended pegylated interferon dosages. In patients with rapid virologic response (undetectable viremia at week 4) to anti-hepatitis C therapy, shorter periods of therapy (24 weeks) may be advisable in hepatitis C genotypes 2 and 3. Finally, adequate selection of candidates and careful selection of concomitant antiretroviral medications must be encouraged. Patients with low CD4 percentages (< 15%) should be deferred for treatment and HAART prioritized in order to improve CD4 counts. When possible, nucleoside analogs such as zidovudine, stavudine, and abacavir should be replaced by others having no deleterious interactions with ribavirin (e.g. tenofovir, lamivudine, or emtricitabine). Didanosine should never be coadministered with ribavirin due to potential life-threatening complications.
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PMID:Update on the treatment of chronic hepatitis C in HIV-infected patients. 1769 77


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