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)

Mycophenolic acid (MPA) enhances the in vitro activity of abacavir (ABC) and other nucleoside analog reverse transcriptase inhibitors (NRTIs) against sensitive and NRTI-resistant HIV-1. This may occur via depletion of intracellular deoxyguanosine triphosphate (dGTP). Mycophenolate mofetil (MMF) 500 mg twice daily was added as a single agent to the antiretroviral regimens of five patients failing maximal available therapy. Therapy included ABC, and in most cases didanosine (DDI) and tenofovir (TDF). At entry, mean plasma HIV-1 RNA (VL) was 5.02 log copies/mL (median 4.78, range 4.71-5.63) and mean CD4 count was 106/microL (median 117, range 11-174). MMF was well tolerated. CD4 cell counts did not change significantly from baseline for up to 60 weeks of follow-up. Three of five subjects had VL declines of >0.5 log copies/mL immediately after adding MMF; a fourth subject had a sustained decline of >0.5 log copies/mL after week 8. Declines of >0.5 log copies/mL were lost in two patients at 6 and 8 weeks, and persisted in two patients at 36 and 60 weeks of follow-up, respectively. An increase in the ratio of carbovir triphosphate (CBV-TP), the active antiviral metabolite of ABC, to dGTP was documented in 3 of 4 subjects in temporal association with decreased VL. Trough plasma MPA levels ranged from 0.26-1.67 microg/mL; peak levels 90 minutes after dosing from 1.20-7.77 microg/mL. AUC of MPA appeared little changed when measured over 28 weeks of therapy. Declines in VL were observed in association with measurable changes in the CBV-TP/dGTP ratio in some patients, whereas MPA AUC was below the 30-60 microg*hr/mL range targeted in organ transplantation. The possibility that MMF may enhance the effect of selected NRTIs and be tolerated in late stage HIV disease deserves careful randomized study.
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PMID:The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. 1235 49

Chronic viral hepatitis has emerged as one of the leading causes of morbidity and mortality among HIV-positive patients. These individuals are at risk for aggressive chronic active hepatitis, cirrhosis, and hepatocellular carcinoma, and eventually, death. Currently available therapies for hepatitis B are limited and include interferon-alpha, lamivudine (3TC), and adefovir. Tenofovir (TDF), a recently approved drug for the treatment of HIV, is also active against hepatitis B. We report the case of a HIV-positive patient with liver cirrhosis secondary to chronic hepatitis B virus (HBV) with evidence of resistance to 3TC. The patient was initially accepted as a liver transplant candidate. However, when TDF was added to his treatment, a remarkable virologic and histopathologic improvement was achieved. The patient was subsequently removed from the liver transplant program and has not suffered from any further hepatic complications.
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PMID:Management of chronic hepatitis B in an HIV-positive patient with 3TC-resistant hepatitis B virus. 1458 80

Previous investigational data using abacavir (ABC), lamuvidine (3TC), and zidovudine has suggested the possibility of triple nucleoside analogue reverse transcriptase inhibitors (NRTI) therapy as an option in the treatment of HIV infection. We performed a pilot study to assess the potency of once daily ABC+ 3TC+ tenofovir (TDF) in the treatment of HIV-infected naive patients. CD4 and HIV-viral load (VL) were followed monthly. Patients were considered to be nonresponder/failing if there was no reduction in VL by >/= 2 log(10) by week 8 and/or a rebound in VL after initial suppression. Resistance testing was then obtained. Nineteen patients naive to antiretroviral therapy (3 women and 16 men) were enrolled, of whom, 2 did not return (withdrew from study at week 2). Median VL and CD4 count at baseline were 147,167 copies per milliliter (5.16 log(10); [range, 7650->750,000]) and 277 cells/mm(3) (range, 59-598). Eight patients had VL > 100000 at baseline. Of 17 patients eligible for follow-up, 5 (27%) were responders (virologic success). Twelve patients (63%) were considered nonresponders and/or with virologic failure. The study was prematurely interrupted because of a high rate of treatment failure. Resistance testing available for 11 nonresponders (58%) showed: 2 patients with wild-type, 5 patients with M184V (reducing susceptibility to 3TC and ABC), 4 patients with M184V+K65R (K65R is responsible for reducing susceptibility to ABC, 3TC and TDF), and none with K65R alone. In conclusion, the combination of ABC, 3TC and TDF cannot be recommended for the initial regimen in HIV treatment-naive patients.
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PMID:Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients. 1698 45

Tenofovir (TDF) co-administered with didanosine (ddI) 400 mg increases ddI plasma concentrations by up to 60%, raising concerns over toxicity. To limit this interaction, the dosage of ddI may be reduced to 250 mg once daily when co-prescribed with TDF. In this clinical cohort, highly active antiretroviral therapy regimens containing TDF and ddI 250 mg were significantly better tolerated than combinations with TDF and ddI at a dose of 400 mg. Low-dose ddI 250 mg once daily plus TDF as part of antiretroviral therapy was effective.
HIV Med 2005 May
PMID:The durability of virological success of tenofovir and didanosine dosed at either 400 or 250 mg once daily. 1587 80

Zalcitabine (ddC), lamivudine (3TC), didanosine (ddI), stavudine (d4T), carbovir (CBV), zidovudine (AZT), tenofovir (PMPA) and its administrated form (tenofovir diisoproxyl fumarate, TDF), are nucleosides currently approved in HIV therapy. To facilitate pharmacokinetics studies, a specific reversed-phase high-performance liquid chromatography (HPLC) method was developed for their analysis in rat plasma. The method involved a quantitative recovery of these drugs from rat plasma by solid-phase extraction on Oasis HLB Waters cartridges followed by optimised HPLC separation on an Atlantis dC18 column with acetic acid-hydroxylamine buffer (ionic strength 5mM, pH 7)-acetonitrile elution gradient. Quantitation was performed by HPLC/UV at 260 nm. Linear calibration curves were obtained within a 30-10,000 ng/mL plasma concentration range. Correlation coefficients (r2) greater than 0.992 were obtained by least-squares regression and limits of quantification were in 30-90 ng/mL concentration range. Quantitative parameters (accuracy, intra-day repeatability and inter-day reproducibility) yielded satisfactory results. Finally, a new buffer, obtained with acetic acid and hydroxylamine, has been tested in HPLC/ESI-MS/MS and appears to be an efficient volatile buffer in the medium 5-7 pH range. Indeed, at pH 7 and low ionic strength (5 mM), its buffer capacity is one hundred times higher to that obtained for the usual acetic acid/ammonia buffer.
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PMID:Simultaneous analysis of several antiretroviral nucleosides in rat-plasma by high-performance liquid chromatography with UV using acetic acid/hydroxylamine buffer Test of this new volatile medium-pH for HPLC-ESI-MS/MS. 1592 78

Concern exists about the risk of nephrotoxicity using tenofovir (TDF) in HIV-infected patients. We performed a retrospective case-control study including 122 consecutive TDF-naive patients who started treatment with TDF-containing regimens and 194 patients receiving antiretroviral therapy with other antiretroviral drugs. During a 12-month observation period 5 (4.1%) patients in the TDF group versus 1 (0.5%) in the control group developed grade 1 or higher serum creatinine elevations (p = 0.018). Only 2 (1.6%) patients discontinued TDF treatment as a result of serum creatinine level elevations. In 4 of the 5 patients developing creatinine elevations TDF was combined with lopinavir-ritonavir. The use of TDF in clinical practice during a 12-month period is associated with low risk of mild renal failure. Further studies to assess long-term renal safety of this drug are needed.
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PMID:Low frequency of renal function impairment during one-year of therapy with tenofovir-containing regimens in the real-world: a case-control study. 1605 98

The liver safety of tenofovir (TDF) was investigated in 142 HIV+ patients exposed to the drug for longer than 12 months. No evidence of liver enzyme elevations were seen, even in 66 patients with chronic hepatitis C virus (HCV) co-infection. Given that TDF is an adenosine analogue, like didanosine, exposure to ribavirin might increase intracellular phosphorylated TDF metabolites, which could result in a higher risk of nephrotoxicity. Signs of tubular dysfunction in blood or urine were not recognized in 17 HCV-HIV co-infected patients exposed to TDF during interferon plus ribavirin therapy.
HIV Clin Trials
PMID:Hepatic and renal safety profile of tenofovir in HIV-infected patients with hepatitis C, including patients on interferon plus ribavirin. 1630 34

Coadministration of didanosine (ddI) and tenofovir (TDF) results in increased ddI serum concentrations, which may lead to increased risk of ddI-associated toxicities. To evaluate the safety and tolerability of ddI/TDF, we performed a retrospective cohort analysis of patients seen in the HIV Outpatient Study, an ongoing dynamic cohort study of HIV-infected persons in clinical care. Study subjects were those who received at least 14 days of combined ddI/TDF before October 2003. Of 260 subjects who received ddI/TDF-based antiretroviral therapy, 155 (60%) received high-dose ddI (400 mg daily dose) and 105 (40%) received low-dose ddI (100-250 mg daily). Forty-two of the high-dose ddI recipients were later switched to low-dose ddI. The median time of observation for those on high-dose ddI only was 5 months, high-dose ddI switched to low-dose ddI was 16 months, and low-dose ddI only was 5 months (p < 0.05). Discontinuations because of toxicity were more frequent on high-dose ddI regimens (34/155, 22%) than on low-dose ddI regimens (9/105, 9%) (unadjusted odds ratio [OR(unadj)] 3.0, 95% confidence interval [95% CI] 1.30-7.09; p = 0.007). Among subjects without preexisting peripheral neuropathy, 12 (12%) of 101 subjects ever on high-dose ddI regimens had treatment-emergent peripheral neuropathy compared to 2 (4%) of 55 subjects on low-dose ddI regimens (OR(unadj) 3.57; 95% CI, 0.72-24.1; p = 0.14). Among patients without a history of pancreatitis, 6 (4%) of 153 subjects developed pancreatitis after starting high-dose ddI regimens, compared to none of the 103 subjects on low-dose ddI regimens (OR(adj) and 95% CIs undefined; p = 0.08). Severe laboratory abnormalities of creatinine, phosphorous, and bicarbonate were not different between the groups. A summary variable for any event--discontinuation for toxicity, treatment- emergent adverse event or abnormal laboratory values--indicated that 44 (28%) of 155 of those on high-dose ddI versus 13 (12%) of 105 on low-dose ddI developed any event (OR(unadj) 2.81; 95% CI, 1.36-5.86; p = 0.004). In conclusion, high-dose ddI/TDF-based therapy was more frequently associated with drug-related toxicity, adverse events, and treatment discontinuation than low-dose ddI/TDF regimens; low-dose ddI with TDF was generally well tolerated in these HIV-infected persons.
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PMID:Short-term safety and tolerability of didanosine combined with high- versus low-dose tenofovir disproxil fumarate in ambulatory HIV-1-infected persons. 1662 22

The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned. Since anecdotal cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI + TDF-containing regimens, we explored the rate of this complication in more detail. Retrospective analysis of plasma glucose levels in patients who completed 12 months of treatment with three different triple antiretroviral regimens including ddI + TDF, TDF, or ddI was done. Patients taking antidiabetic drugs and/or those with baseline glucose levels >125 mg/dl were excluded. Weight, age, concomitant antiretrovirals, and ddI dose were assessed. At 12 months without treatment changes, fasting glucose levels were compared to baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevations. A total of 177 HIV-infected patients were assessed (78 on ddI + TDF, 42 on TDF, and 57 on ddI). Mean baseline features were well balanced between groups for age (mean, 39 years), gender (78% male), CD4+ count (mean, 507 cells/mm3), weight (mean, 67 kg), and glucose level (mean, 95 mg/dl). There were only significant differences between groups for baseline viral load and protease inhibitor (PI) use (13% in the ddI + TDF arm vs. 7% and 9% in the TDF and ddI arms, respectively). At 12 months, 60% of the patients in the ddI + TDF arm were taking ddI 250 mg/day and the rest were on ddI 400 mg/day. At 12 months, hyperglycemia was significantly more frequent in the ddI + TDF arm (33%) when compared to patients on TDF or ddI separately (5% and 10%, respectively). In the multiple linear regression analysis, a lower weight (beta -0.35; 95% CI -0.67 to -0.03; p = 0.033) and use of ddI + TDF (beta: 13.05; 95% CI: 0.2 to 26; p = 0.047) were independently associated with a higher risk of developing hyperglycemia. The risk of hyperglycemia is increased in patients treated with ddI + TDF, particularly in those with lower weight. As high ddI exposure has been associated with endocrine pancreatic dysfunction and diabetes, ddI "overdosing" as result of concomitant TDF use and low weight might explain our findings. These results add a further note of caution to the use of TDF and ddI in combination.
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PMID:Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir. 1662 36

The combination of tenofovir (TDF) and efavirenz (EFV) has not been associated with any pharmakokinetic interaction or with enhancement of neuropsychiatric disturbances. We report nine cases of neuropsychiatric intolerance occurring early after a switch from an antiretroviral regimen without TDF to an EFV and TDF-containing regimen. Nine HIV-1-infected patients were treated with an EFV-containing regimen for a median duration of 31 months without any EFV-related central nervous system (CNS) effects. They were switched to an EFV-TDF-containing regimen because of lipodystrophy (n=2) and/or the wish to simplify to a once-daily regimen (n=9). Moderate to severe neuropsychiatric events occurred immediately (<48 hours) after TDF initiation in five patients and 2 weeks to 24 months after the switch in the remaining four patients. Treatment modifications occurred in six patients (switch to EFV-nevirapine [n=3], TDF-zidovudine [n=2] or treatment discontinuation [n=1]), leading to a marked improvement of CNS intolerance. Treatment remained unchanged in three patients; two patients experienced chronic persistent sleeping disorders and one patient underwent a spontaneous improvement of symptoms within 2 weeks. EFV plasma concentrations, which were available in two patients before the switch and in four patients after the switch, remained in the therapeutic range. Although the exact mechanism of these symptoms remains hypothetical, neuropsychiatric disorders could be either a consequence of an unexplained interaction between EFV and TDF or an infrequent TDF-related side effect. The incidence of these side effects needs to be evaluated in large databases or pharmacokinetic studies.
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PMID:Neuropsychiatric adverse events after switching from an antiretroviral regimen containing efavirenz without tenofovir to an efavirenz regimen containing tenofovir: a report of nine cases. 1664 Jan 7


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