didanosine and Acidosis--Lactic

The combination of tenofovir and didanosine results in an increase in the didanosine plasma exposure and might augment the risk for didanosine toxicity. Although pharmacokinetic studies support a didanosine dose reduction to 250 mg when used concurrently with tenofovir in patients weighing at least 60 kg, no data are available in lower-weight patients. We describe a case of lactic acidosis and acute liver failure in a low-weight patient receiving tenofovir and a reduced dose of didanosine (200 mg/day). To our knowledge, this is the first case of severe toxicity associated with a reduced dose schedule of didanosine. Previous cases of severe toxicity associated with the combination of tenofovir and didanosine are reviewed.

Topics: Acidosis, Lactic; Acute Disease; Adenine; Anti-HIV Agents; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Liver Failure; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir

Although women account for a substantial proportion of the global population infected with HIV, most clinical trials evaluating the safety and efficacy of specific antiretroviral therapy regimens have been preformed in predominantly male cohorts. Our knowledge of the sex differences associated with responses to these treatments is therefore limited. Potentially sex-specific influences, such as endogenous or exogenous hormones, could impact antiretroviral tolerance. Women also have different pharmacokinetic profiles for selected antiretrovirals compared with men. These factors could influence how women respond and react to antiretrovirals. Several observational studies have described a higher frequency of antiretroviral-related adverse effects among women compared with men. Women appear to be at an especially high risk for lactic acidosis, nevirapine-associated rashes and hepatotoxicity, and fat redistribution after highly active antiretroviral therapy exposure. Although a statistical association between antiretroviral toxicity and pregnancy has not been described, pregnancy may provide an additional influence on the toxicity of several antiretrovirals or antiretroviral combinations. Potential tolerability should be an important component in discussions of antiretroviral options among women.

Topics: Acidosis, Lactic; Anti-Retroviral Agents; Didanosine; Exanthema; Female; HIV Infections; Humans; Liver Diseases; Male; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Randomized Controlled Trials as Topic; Sex Factors; Stavudine

We conducted a retrospective study to identify prognostic factors in the lactic acidosis syndrome (LAS) caused by nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/AIDS. Fifty-eight cases of LAS were included in our analysis, 8 from our hospital spanning the years 1992-2002, and 50 reported in the English language literature from 1986 through 2002. Peak venous lactate level was the best predictor of mortality. Zidovudine was associated with higher lactate levels and higher mortality than stavudine and lamuvidine. Mortality declined progressively after 1986 when the first cases of NRTI-related LAS were described. Increased mortality with zidovudine in this study appears due in part to its greater use prior to 1990 when LAS was not widely recognized as a potential complication of NRTI therapy.

Topics: Acidosis, Lactic; Adult; Didanosine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; New York; Reverse Transcriptase Inhibitors; Stavudine; Syndrome; Zidovudine

Topics: Acidosis, Lactic; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV-Associated Lipodystrophy Syndrome; Humans; Peripheral Nervous System Diseases; Practice Guidelines as Topic; Stavudine

Topics: Acidosis, Lactic; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Hemophilia A; Hemorrhage; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Topics: Acidosis, Lactic; Anti-HIV Agents; Antiviral Agents; Didanosine; DNA, Mitochondrial; Drug Synergism; Hepatitis C; HIV Infections; Humans; Metabolic Clearance Rate; Pancreatitis; Ribavirin

The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL).. In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaïve, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined.. In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event.. The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Australasia; Body Mass Index; Didanosine; DNA, Mitochondrial; DNA, Viral; Europe; Female; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; North America; Polymerase Chain Reaction; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Factors; RNA; RNA, Mitochondrial; RNA, Viral; Sex Factors; South America; Stavudine

This is the first report on the preliminary efficacy of 4 different short-course nucleoside analogue regimens (stavudine [d4T], didanosine [ddI], d4T+ddI, and zidovudine [ZDV]) for the prevention of mother-to-child transmission of HIV-1 (MTCT) in a resource-limited setting.. This prospective open-label, randomized 4-arm study (May 1999 to May 2000) conducted in South Africa enrolled 373 women from 34 weeks of gestation; medication was continued through delivery and for 6 weeks to infants. MTCT rates were ascertained at birth, 6, 12, and 24 weeks of age.. Mean maternal HIV-1 RNA levels decreased rapidly on treatment in all groups. At week 4, the mean decrease was 1.91 log10 copies/mL (c/mL) in the d4T+ddI group, 1.33 log10 c/mL in the ddI group, 1.12 log10 c/mL in the d4T group, and 0.76 log10 c/mL in the ZDV group. Among the 362 evaluable mother-infant pairs, 11 infants in the d4T group, 10 in the ddI group, 5 in the ZDV group, and 4 in the d4T+ddI group were infected by 24 weeks of age. Eleven infections occurred in utero. Treatment with d4T and ddI was not associated with lactic acidosis or hepatic steatosis.. The abbreviated use of nucleoside analogues for the prevention of MTCT appears safe and effective.

Topics: Acidosis, Lactic; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Fatty Liver; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Mothers; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; RNA, Viral; South Africa; Stavudine; Viral Load; Zidovudine

Genetic predisposition to dideoxynucleoside-induced mitochondrial dysfunction might be related to mitochondrial DNA (mtDNA) polymorphisms. Severe hyperlactataemia is probably the best model to assess such a predisposition.. For this exploratory study in White European and Black African HIV-infected adults, hypervariable region 1 of mtDNA samples from peripheral blood mononuclear cells or buccal smears of patients who have developed confirmed severe hyperlactataemia was sequenced. Additionally, 21 single nucleotide polymorphisms and a 9 bp deletion were genotyped to assign mtDNA haplogroups. Finally, entire mtDNA sequencing was performed in a subset of European samples. Samples were obtained from Black African cases and controls recruited from a single centre in Johannesburg, South Africa and from white European cases from Amsterdam, London and Zurich.. A total of 40 cases and 38 controls from Johannesburg were included. All of the cases and 33 controls were receiving stavudine-based therapy at the time of the index date (P=0.024). The distribution of mtDNA haplotypes was not different between cases and controls (P=0.137), and neither were the predicted haplogroups (P=0.751). In total, 11 of the 12 European cases were on stavudine and/or didanosine at the time of the event. No hypervariable region 1 haplotype was consistently found in the European cases. Sequencing of the entire mtDNA from three of these cases supported the absence of any shared mutations other than major alleles frequently seen in the mtDNA database.. We did not find an association between homoplasmic inherited mtDNA polymorphisms and severe hyperlactataemia. Our data do not support the existence of non-synonymous mtDNA mutations that explain an increased predisposition to dideoxynucleoside-induced mitochondrial dysfunction.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Black People; Case-Control Studies; Didanosine; DNA, Mitochondrial; Female; HIV Infections; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Mutation; Polymorphism, Single Nucleotide; Reverse Transcriptase Inhibitors; Sequence Deletion; Stavudine; White People; Zidovudine

Hyperlactatemia and lactic acidosis (LA) are among the most dangerous and life-threatening side effect that occurs during therapy with some nucleoside reverse transcriptase inhibitors (NRTIs), mainly didanosine (ddI) and stavudine (d4T), also known as d-drugs. Therefore, we performed a prospective, follow-up study and aimed to examine the incidence rates (IR) and rate ratios (RR) of hyperlactatemia and LA for each NRTI. Three hundred and ninety-six HIV-patients were included in final analysis comprising 783.8 person-years of follow-up. Between 1st January 2000 and 1st January 2008, 19 cases of hyperlactatemia and 15 cases of LA were recorded. Between regimens with the significant impact for developing hyperlactatemia and LA the lowest IR was for didanosine (IR=2.87 per 100 person-years, 95%CI=0.45-9.25 and IR=4.31 per 100 person-years, 95%CI=1.07-13.91, respectively), and the highest for didanosine+stavudine (IR=10.17 per 100 person-years, 95%CI=1.02-19.76 and IR=7.39 per 100 person-years, 95%CI=1.02-13.05, respectively). Compared to didanosine alone the RR of hyperlactatemia was 2.67 (95%CI=1.11-12.52) for stavudine, and 4.06 (95%CI=1.31-15.48) for didanosine+stavudine. The RR of LA was 3.12 (95%CI=1.13-10.65) for stavudine, and 5.13 (95%CI=1.54-13.37) for didanosine+stavudine in comparison with didanosine alone. Other risk factors for AP were CD4 cell count less than 200 cells/mm³ and female sex. Our results suggest that the use of stavudine alone or in combination with didanosine should not be used as first-line therapy, especially in patients with CD4 cell count less than 200 cells/mm³ and females if other treatment options are available.

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Adult; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Incidence; Lactic Acid; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Sex Factors; Stavudine

Topics: Acidosis, Lactic; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; DNA, Mitochondrial; Fatal Outcome; HIV Infections; HIV-1; Humans; Male; Middle Aged; Stavudine

The objectives of our study were to describe the characteristics of a subset of patients who had been prescribed serum lactate in clinical practice within a large cohort of HIV-infected patients and to determine the factors associated with hyperlactataemia. Hyperlactataemia (> or =2 mmol/l) was found in 219 [29% (95% confidence interval: 25.3-31.7)] of the 768 HIV-infected participants. In multivariate analysis (logistical regression), an increased risk of hyperlactataemia was associated with increasing age, CD4 count <500/mm3, triglycerides >2.2 mmol/L, lipoatrophy and stavudine use. In a second model coding for the NRTI-based drug combinations, only those including stavudine were associated with an increased risk of hyperlactataemia. In a third model including exposure duration to NRTIs, we estimated a 20% increased risk of hyperlactataemia per year of exposure to didanosine or stavudine. The risk of hyperlactataemia could increase over time in patients treated with these drugs and is also closely associated with increased age, decreased CD4 count, lipodystrophy and increased plasma triglycerides. It could be proposed that patients having one or more of these risk factors undergo regular monitoring of plasma lactate and renal function to prevent lactic acidosis.

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Adult; Age Factors; Anti-HIV Agents; CD4 Antigens; Cohort Studies; Didanosine; Drug Therapy, Combination; HIV-Associated Lipodystrophy Syndrome; Humans; Lactic Acid; Longitudinal Studies; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Triglycerides

Plasma lactate measurements are typically performed in real time, limiting their usefulness in multicenter or longitudinal studies. To determine the stability of lactate specimens, blood was drawn in sodium fluoride/potassium oxalate tubes from 13 volunteers before and after 5 min of handgrip exercise to intentionally increase lactate concentrations. Plasma was stored at -70 degrees C. Aliquots were assayed in real time and after 1, 3, 6, 9, 12, 18, and 24 months. Real-time lactate concentrations measured at baseline ranged from 0.52 to 2.23 mmol/L before and from 2.91 to 11.04 mmol/L after handgrip exercise. Using a linear mixed model, the estimated change from baseline at month 24 was 1.67% (95% confidence interval, -0.70% to 4.03%) for pre-exercise samples and 0.39% (95% CI, -1.13% to 1.91%) for post-exercise samples. Stored serial specimens from 232 HIV-infected subjects in a multicenter trial of antiretroviral therapy were also assayed centrally. Among those, median plasma lactate increased from baseline to 64 weeks by 0.4 mmol/L with zidovudine+lamivudine treatment and by 0.6 mmol/L with didanosine+stavudine (each p<0.001 from baseline; p=0.04 for difference between groups over time). When performed as in this study, frozen storage with central batch lactate analysis is appropriate for prospectively collected samples in multicenter trials.

Topics: Acidosis, Lactic; Anti-HIV Agents; Blood Preservation; Blood Specimen Collection; Didanosine; HIV Infections; Humans; Lactates; Lamivudine; Multicenter Studies as Topic; Oxalates; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Sodium Fluoride; Specimen Handling; Stavudine; Time Factors; Zidovudine

(1) In patients who are infected with both HIV and hepatitis C virus (HCV), treatment of hepatitis C slightly increases the risk of lactic acidosis associated with antiretroviral treatment, especially when the latter includes didanosine. (2) If a modification in antiretroviral treatment is needed and if treatment for hepatitis C is likely to be necessary, then it is best to avoid didanosine. However, systematic replacement of didanosine is not necessary, given the small magnitude of risk of lactic acidosis. (3) Fatigue, digestive problems, weight loss and dyspnea are signs of lactic acidosis.

Topics: Acidosis, Lactic; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Comorbidity; Contraindications; Didanosine; Drug Interactions; Drug Therapy, Combination; Hepatitis C; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Recombinant Proteins; Reverse Transcriptase Inhibitors; Ribavirin

The "D drug" HIV reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase-gamma compared with the "non-D drugs" zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV-infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV-infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment-related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non-D drug patient and significantly (P =.017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV-infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation.

Topics: Acidosis, Lactic; Adult; Cross-Sectional Studies; Didanosine; DNA, Mitochondrial; Female; Hepatitis C, Chronic; HIV Infections; Humans; Lactic Acid; Liver; Male; Reverse Transcriptase Inhibitors; Stavudine; Zalcitabine

Lactic acidosis is an uncommon but potentially life-threatening adverse effect of didanosine. When given concomitantly with tenofovir disoproxil fumarate (DF), the area under the concentration-time curve of didanosine is increased by 48-60%. A 63-year-old man with human immunodeficiency virus (HIV) infection tolerated several didanosine-containing antiretroviral regimens. He developed generalized weakness, loss of appetite, weight loss, nausea, and vomiting 1.5 years after tenofovir DF was added to his didanosine-containing regimen. He was diagnosed with lactic acidosis and died after a 13-day hospital stay, when his lactate level increased to 189.7 mg/dl and his arterial blood gas pH value fell to 6.75. Health care providers should maintain a high index of suspicion for lactic acidosis in patients with HIV infection who receive didanosine and tenofovir DF concurrently. For patients receiving antiretroviral regimens containing this drug combination, it would be prudent to monitor lactate levels periodically. This is especially important when patients experience symptoms suggestive of lactic acidosis, such as weakness, abdominal pain, weight loss, nausea and vomiting, and shortness of breath.

Topics: Acidosis, Lactic; Adenine; Anti-HIV Agents; Area Under Curve; Comorbidity; Didanosine; Drug Interactions; Fatal Outcome; Female; HIV Infections; Humans; Lactates; Male; Middle Aged; Organophosphonates; Organophosphorus Compounds; Tenofovir

We describe the prevalence, risk factors and outcome of hyperlactataemia (HL) in a cohort of 140 HIV-infected patients.. Patients were enrolled consecutively within a 3-month period (July to September 1999) and followed until 31 October 2000. One hundred and forty HIV-infected patients had venous plasma lactate levels measured. HL was defined at baseline by two consecutive lactate levels > 2.1 mmol/L (upper limit of normal). We compared baseline demographic characteristics, immuno-virological parameters, antiretroviral therapy and outcome between patients with HL (cases) or without HL (controls). We described the clinical features of patients with HL.. Among 129 patients included in the analysis, HL was found in 11 patients (8.5%), all of whom were receiving nucleoside reverse transcriptase inhibitors (NRTIs). Cases were more likely than controls to receive didanosine or stavudine (82% vs. 19%, P= 2.7 x 10(-6) and 82% vs. 48%, P= 0.03, respectively). Only 4/11 cases (36%) had symptoms consistent with HL. After a median follow-up of 15 months, lactate level returned to normal in all three patients who discontinued NRTIs, but in only 2/8 patients who did not (P = 0.06). Only one case experienced lactic acidosis and died during follow-up. Mortality rate was similar in cases and controls.. HL is associated with NRTI use, in particular didanosine and stavudine, and discontinuation of NRTIs seems to be associated with rapid resolution of HL. Lactic acidosis remains rare and the long-term outcome of patients with HL does not seem to be poorer than controls.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Didanosine; Female; Follow-Up Studies; HIV Infections; Humans; Lactic Acid; Male; Middle Aged; Prevalence; Prognosis; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Didanosine; Female; HIV Infections; HIV-1; Humans; Pregnancy; Pregnancy Complications, Infectious; Stavudine

Severe hepatotoxicity is a rare but potentially life-threatening side effect of antiretroviral therapy. In this case report we describe an HIV-positive patient who was admitted to our clinic with evidence of severe acute pancreatitis 18 months after the introduction of antiretroviral treatment, which included stavudine and didanosine. Shortly afterwards, she developed lactate acidosis and acute hepatic failure associated with renal failure. Renal support (hemofiltration) was required for three days. The patient subsequently developed grade III encephalopathy, as well as a large pleural effusion and ascites. Although the reported outcome of patients with liver failure due to antiretroviral treatment is poor, with a high mortality rate, our patient fully recovered after intensive supportive care and cessation of the antiretroviral agents. Liver biopsy revealed microvesicular steatosis and giant mitochondria, which are the typical hallmarks of mitochondrial damage, the presumed mechanism of antiretroviral drug toxicity. More than three years later the patient has an excellent clinical status with a stable HIV infection and no need for antiretroviral treatment. This case report indicates the need for increased awareness of the potential hepatotoxicity of an antiretroviral therapy, as severe side effects may occur more frequently with increasing use of such treatment.

Topics: Acidosis, Lactic; Acute Disease; Adult; Anti-HIV Agents; Biopsy; Critical Care; Didanosine; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Liver; Liver Failure; Pancreatitis; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography; Zidovudine

We describe a 49-year-old man with human immunodeficiency virus infection and stable chronic renal insufficiency who developed acute oliguric renal failure and severe lactic acidosis and who died several weeks after tenofovir was added to an antiretroviral regimen that included didanosine. Although the role of tenofovir in precipitating acute renal failure is unclear, progressive accumulation of the drug and pharmacologic interaction that caused increased levels of didanosine were the likely antecedents of increased mitochondrial toxicity that led to lactic acidosis.

Topics: Acidosis, Lactic; Acute Kidney Injury; Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Drug Synergism; Fatal Outcome; Humans; Male; Middle Aged; Mitochondria; Organophosphonates; Organophosphorus Compounds; Tenofovir

A case-control study was undertaken to determine risk factors for lactic acidosis in human immunodeficiency virus-infected patients treated with nucleoside reverse-transcriptase inhibitors (NRTIs). From May 1996 to June 2000, 9 patients with lactic acidosis (defined as a plasma lactic acid level of >5 mM and plasma pH of <7.38) were identified. Control patients were randomly selected from among a large cohort of patients who initiated a dual NRTI regimen in 1996 or after. Two factors were associated with an increased risk of lactic acidosis: first, a creatinine clearance of <70 mL/min before lactic acidosis (OR, 15.8 [range, 3.0-86.5], P<10(-4)), and, second, a low nadir CD4+ T lymphocyte count before the inception of NRTI therapy (OR, 8.4 [range, 1.2-infinity], P=.03). The total cumulative exposure to NRTIs was not associated with an increased risk of lactic acidosis, nor was the cumulative exposure to any of the 4 NRTIs studied. According to these results, monitoring of creatinine clearance, especially in patients with a low nadir CD4+ T lymphocyte count, could lead to modifications in antiretroviral therapy in order to diminish the risk of occurrence of lactic acidosis.

Topics: Acidosis, Lactic; Adult; Case-Control Studies; Didanosine; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine

We report a case of antiretroviral therapy-related fatal lactic acidosis occurring in a vertically infected HIV-positive 17-year-old patient. While receiving antiretroviral therapy with stavudine, didanosine, tenofovir and amprenavir, the patient developed severe acidosis and rapid neuromuscular and respiratory failure mimicking Guillain-Barré syndrome.

Topics: Acidosis, Lactic; Adenine; Adolescent; Antiretroviral Therapy, Highly Active; Carbamates; Diagnosis, Differential; Didanosine; Disease Progression; Drug Therapy, Combination; Fatal Outcome; Female; Furans; Guillain-Barre Syndrome; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Organophosphonates; Organophosphorus Compounds; Risk Assessment; Severity of Illness Index; Stavudine; Sulfonamides; Tenofovir

Pancreatitis and lactic acidosis are severe and life-threatening adverse events associated with nucleoside analogue antiretroviral therapy used to treat HIV infection. The drug from this class most commonly associated with these adverse events is stavudine, although zidovudine and didanosine have also been implicated. Ribavirin is a nucleoside analogue used in combination with interferon alfa to treat hepatitis C. Because of similar mechanisms of action, the combination of these 2 drugs could potentially increase such toxicity. A case of fatal lactic acidosis and pancreatitis is described in an HIV-infected patient coinfected wtih hepatitis C on a didanosine-containing antiretroviral regimen after treatment of hepatitis C was initiated with ribavirin and pegylated interferon alfa-2b. Extreme caution should be exercised when didanosine and ribavirin are used concomitantly because of the increased risk of mitochondrial toxicity and the syndrome of severe metabolic acidosis with elevated lactic acid levels.

Topics: Acidosis, Lactic; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Synergism; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Pancreatitis; Recombinant Proteins; Ribavirin; Risk Factors; Viral Load

Lactic acidosis is a life-threatening event during antiretroviral therapy (ART). Hyperlactataemia may be a prelude to acidosis. Our database study suggested that female gender, intercurrent illness and didanosine (ddI)-based regimens may increase risk of lactic acidosis. The aim of this matched case-control study was to identify risk factors for hyperlactataemia requiring screening.. Cases were defined as patients with two consecutive lactate samples > or =3.5 mmol/L taken more than 1 week apart. Cases were matched to two controls on gender, use of ddI and total duration of therapy using a 6-month window on either side. Controls never had raised lactate >2.5 mmol/L. A conditional logistic regression analysis using the PHREG procedure in SAS (SAS Institute Inc, Cary, NC) was performed with a discreet logistic model stratified by matching variables.. Twenty-one cases were matched to 42 controls. In the univariate model, current use of stavudine (d4T), total cholesterol >5.3 mmol/L and glucose levels > or =5.2 mmol/L gave increased likelihood of persistent hyperlactataemia. The multivariate model showed current use of d4T to be a significant independent predictor of persistent hyperlactataemia.. The results of this case-control study indicate that, when controlling for ddI use, d4T use is an additional risk factor for hyperlactataemia.

Topics: Acidosis, Lactic; Anti-HIV Agents; Case-Control Studies; Didanosine; Female; HIV Infections; Humans; Lactic Acid; Male; Multivariate Analysis; Risk Factors; Sex Factors; Stavudine

To describe the first pediatric case of fatal lactic acidosis in an antiretroviral-treated child with human immunodeficiency virus (HIV) infection.. Case report.. Pediatric intensive care unit.. A patient with fatal antiretroviral therapy-associated type B lactic acidosis.. None.. We report the case of a 5-yr-old girl with HIV infection, receiving ritonavir, stavudine, and didanosine, who presented with a 10-day history of nausea and vomiting. Severe lactic acidosis was found. Her clinical condition worsened, with progressive increase in serum lactate, despite aggressive supportive therapy, including intravenous alkali and continuous arteriovenous hemodiafiltration.. Fatal lactic acidosis is a complication of antiretroviral therapy in pediatric HIV patients, which has not been previously reported in children. Early recognition of mitochondrial dysfunction in these patients could prevent the development of fatal lactic acidosis.

Topics: Acidosis, Lactic; Child, Preschool; Didanosine; Fatal Outcome; Female; HIV Infections; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine

To evaluate the safety and efficacy of rechallenging patients who have recovered from nucleoside reverse transcriptase inhibitor (NRTI)-induced symptomatic hyperlactatemia or lactic acidosis with alternative NRTI-containing regimens.. Data in this case series was collected from patients followed at the UCSD Owen Clinic from July 1998 through September 2002. Cases of symptomatic hyperlactatemia were HIV-infected adults receiving NRTI who had symptoms compatible with hyperlactatemia and two lactates > 2 times the upper normal limit. Lactic acidosis was defined as lactate > 5 mmol/l with bicarbonate < 20 mmol/l. The suspected offending NRTI in the prior regimen were replaced with other NRTI thought to have equivalent antiviral potency but less mitochondrial toxicity.. Ten patients diagnosed with symptomatic hyperlactatemia and two with lactic acidosis were later restarted on antiretrovirals that included new NRTI. The NRTI that patients were receiving when symptomatic hyperlactatemia or lactic acidosis was diagnosed included stavudine and lamivudine (n = 6), stavudine and didanosine (n = 4), and stavudine and abacavir (n = 2). The median (range) peak lactate was 5.4 (4.7-19.1) mmol/l. Five patients were rechallenged with abacavir and lamivudine, five with zidovudine, abacavir and lamivudine, and two with zidovudine and lamivudine. Among the 12 patients contributing over 22 years of cumulative reexposure to NRTI-containing therapy, one developed symptomatic hyperlactatemia again yielding a recurrence rate of 45.5 cases/1000 patient-years. Virologic control was maintained in all patients.. This data supports the strategy that in cases of symptomatic hyperlactatemia or lactic acidosis in which the toxicity is associated with stavudine, didanosine or both, it is safe and efficacious to reintroduce NRTI that are less potent inhibitors of mitochondria.

Topics: Acidosis, Lactic; Adult; Alanine Transaminase; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Lamivudine; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine; Time Factors; Zidovudine

To evaluate the prevalence, outcome and possible risk factors for hyperlactataemia and lactic acidosis in HIV-positive persons receiving antiretroviral therapy.. Cross-sectional and longitudinal data from a prospectively collected clinical database. Associations with antiretroviral regimen, clinical and laboratory parameters were assessed using univariate and multivariate Cox's proportional hazards model.. Patients naive to therapy and patients on current therapy for a minimum of 4 months were assessed. Median lactate was 1.1 mol/l in 253 untreated individuals and 1.4 mmol/l in 1239 patients stable on therapy for at least 4 months. At least two on-therapy samples were available for 750 of the 1239 individuals, taken a median 92 days apart. Lactate measurement showed a low positive predictive value of 38.9% but a high negative predictive value (98%) for normal values. Lactate was elevated > or = 2.4 mmol/l in 102 individuals on at least one occasion. In the multivariate Cox's proportional hazards model, no demographic characteristics were associated with hyperlactataemia. Didanosine-containing regimens doubled the relative hazard of hyperlactataemia compared with those sparing didanosine. Abacavir-containing regimens reduced the hazard of hyperlactataemia. Choice of thymidine analogue did not influence risk. Hyperlactataemia was associated with acid-base disturbance. Use of didanosine and female sex were over-represented amongst nine patients with severe hyperlactataemia (> 5 mmol/l) or lactic acidosis.. Screening of lactate is of limited use in asymptomatic individuals on antiretroviral therapy. Raised lactate represents part of a spectrum of lactate and acid-base disturbance that infrequently includes lactic acidosis. Didanosine appears associated with an increased risk of hyperlactataemia.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Lactic Acid; Longitudinal Studies; Male; Multivariate Analysis; Prospective Studies; Reproducibility of Results; Risk Factors; Sex Factors; Thymidine

We report the case histories of two HIV-1 positive women in the third trimester of pregnancy who presented with acute lactic acidosis and acute pancreatitis, respectively. One case was fatal for mother and baby. Both women had been stable on regimens containing stavudine and didanosine for at least 2 years before their acute presentations. We speculate on the differential diagnosis, discuss possible reasons for an increased risk of these presentations in pregnant women taking antiretrovirals, and advocate increased vigilance of these women, particularly in the last trimester.

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Acute Disease; Adult; Anti-HIV Agents; Diagnosis, Differential; Didanosine; Fatal Outcome; Female; Humans; Infant, Newborn; Pancreatitis; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Risk Factors; Stavudine

New data suggests that pregnant women may be at increased risk of lactic acidosis from the combination of d4T and ddI.

Topics: Acidosis, Lactic; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine

Topics: Acidosis, Lactic; Anti-HIV Agents; Didanosine; Drug Industry; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Stavudine

We report three cases of hepatic steatosis associated with lactic acidosis occurring in HIV positive patients and due to a toxicity of antiviral nucleoside analogues. The clinico-pathological presentation was similar associating digestive signs (vomiting and abdominal pain), polypnea, lactic acidosis, a lethal clinical course, and an hepatomegaly with a diffuse macrovacuolar steatosis. The ultrastructural study performed in two cases showed mitochondrial alterations in hepatocytes. The toxicity of antiviral nucleoside analogues is due to a mitochondrial DNA polymerase inhibition. The incidence of this disease is actually low but probably underestimated. The diagnosis should be rapidly performed and the treatment immediatly interrupted.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Antimetabolites; Didanosine; Fatal Outcome; Fatty Liver; Female; HIV Seropositivity; Humans; Lamivudine; Microscopy, Electron; Mitochondria, Liver; Stavudine; Zidovudine

As the prevalence of human immunodeficiency virus (HIV) infection continues to rise the clinician is encountered with a diagnostic challenge. Nonsurgical diseases such as acute colitis or enteritis can appear similar to such true surgical emergencies as abscess, perforation, or mesenteric ischemia. We report a case of fulminant hepatic failure associated with didanosine and masquerading as a surgical abdomen and compare the clinical, biologic, histologic, and ultrastructural findings with reports described previously. This entity should be kept in mind when evaluating the acute abdomen in the HIV-positive patient.

Topics: Abdomen, Acute; Acidosis, Lactic; Adult; Anti-HIV Agents; Diagnosis, Differential; Didanosine; Fatty Liver; Female; HIV Infections; Humans; Liver; Liver Failure

The introduction of antiretroviral therapy has led to a significant decrease in the mortality and morbidity associated with human immunodeficiency virus (HIV) infection. Nucleoside reverse transcriptase inhibitors (NRTI) have been widely used as part of the antiretroviral therapy against HIV. However, one recently recognised serious complication of NRTI is the development of lactic acidosis. We report two cases of fatal NRTI-induced lactic acidosis, which occurred within five months of each other. Both were being treated with didanosine (ddI) and stavudine (d4T). Physicians involved in the care of HIV patients should recognise and be alert to the possibility of this highly fatal complication.

Topics: Acidosis, Lactic; Adult; Didanosine; Fatal Outcome; Female; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Stavudine

The prevalence, clinical presentation, and risk factors for hyperlactatemia among patients receiving antiretroviral therapy was determined during a 1-month period for patients in the Swiss HIV Cohort Study. Overall, 73 (8.3%) of 880 patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine (odds ratio, 2.7; 95% confidence interval, 1.5-4.8), as compared with patients who received zidovudine-based regimens. The risk increased with increasing time receiving stavudine with or without didanosine. The association between hyperlactatemia and stavudine with or without didanosine was not biased by these medications being more recently available and, therefore, being given preferentially to patients who had prolonged use of nucleoside analog reverse-transcriptase inhibitors. Hyperlactatemia was associated with lipoatrophy, hyperlipidemia, and hyperglycemia. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia. Determination of lactate levels may prove useful in the screening for mitochondrial toxicity.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Cohort Studies; Didanosine; Female; HIV Infections; Humans; Male; Prevalence; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine; Switzerland; Zidovudine

Topics: Acidosis, Lactic; Didanosine; Drug Therapy, Combination; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Reverse Transcriptase Inhibitors; Stavudine

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Didanosine; Electron Transport; Fatal Outcome; Fatty Liver; Humans; Male; Stavudine

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Carnitine; Didanosine; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Male; Reverse Transcriptase Inhibitors; Saquinavir; Stavudine

Antiretrovirals, particularly nucleoside analogue reverse transcriptase inhibitors (RTIs) - DDI, 3TC and D4T, are widely used to effectively control human immunodeficiency virus (HIV) infection. These drugs have several adverse effects including anemia, peripheral neuropathy, pancreatitis and, on rare occasions, lactic acidosis. We describe the case of a 39 year old patient who had severe lactic acidosis after receiving stavudine (D4T) and didanosine (DDI) for an 8 month period. She had never manifested an opportunistic infection and presented a CD4 count of 378 cells/mm3 and an undetectable viral load (< 400 copies/ml). The purpose of the following report is to alert clinicians and infectious diseases specialists to the occurrence of lactic acidosis in asymptomatic HIV patients receiving antiretrovirals for long periods of time.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Female; HIV Infections; Humans; Reverse Transcriptase Inhibitors; Stavudine

We report a case of severe lactic acidosis in an human immunodeficiency virus (HIV)-infected patient treated with combination regimen of stavudine, didanosine and nevirapine. Antiretroviral nucleoside analogs are inhibitors of mitochondrial DNA polymerase gamma, resulting in the dysfunction of the mitochondrial respiratory chain. Despite symptomatic treatments and intravenous L-carnitine supplementation, lactic acidosis persisted, leading to multiorgan failure. The patient died 7 days after admission to the intensive care unit. Retrospective analysis of published cases showed neither specific nor predictive signs of outcome that is usually fatal, with no effective therapy to date. We therefore recommend determining blood lactate in patients with onset of unexplained general fatigue or digestive signs and to stop all antiretroviral treatments in the case of lactate increase.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Didanosine; DNA Polymerase gamma; DNA-Directed DNA Polymerase; Fatal Outcome; Female; HIV Infections; Humans; Mitochondria; Nucleic Acid Synthesis Inhibitors; Stavudine

Type B lactic acidosis occurs without any evidence of cellular hypoxia and is associated with the use of drugs or toxins. We report a 36 years old woman with acquired immunodeficiency syndrome that was admitted to the hospital with a severe lactic acidosis. She had been treated with didanosine, stavudine and efavirenz for four months prior to admission. Despite the use of high bicarbonate doses and vasoactive drugs, the patient had a catastrophic evolution and died in shock and multiple organ failure, 68 hours after admission. (Rev Méd Chile 2000; 128: 1139-43).

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Fatal Outcome; Female; Humans; Oxazines; Severity of Illness Index; Stavudine

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Antimetabolites; Diagnosis, Differential; Didanosine; Dyspnea; HIV Infections; Humans; Liver; Male; Mitochondria, Liver; Reverse Transcriptase Inhibitors; Stavudine; Time Factors

Nucleoside analogues can induce myopathy or hepatitis by means of mitochondrial dysfunction. We report the case of a 31-year-old man infected with HIV who had a severe lactic acidosis without muscle or liver symptoms. He improved after hemodialysis and withdrawal of antiviral drugs. Muscle and liver evaluation allowed us to ascribe lactic acidosis to a mitochondriopathy induced by zidovudine and didanosine.

Topics: Acidosis, Lactic; Adult; Anti-HIV Agents; Antimetabolites; Didanosine; Humans; Male; Zidovudine

Topics: Acidosis, Lactic; Acute Disease; Anti-HIV Agents; Didanosine; HIV Infections; Humans; Male; Middle Aged; Pancreatitis

Nucleoside analogue-induced lactic acidosis is an often fatal condition in patients with HIV. There is only one report of successful treatment with riboflavin. We describe a 30-year-old female with AIDS and nucleoside analogue-induced lactic acidosis that exacerbated shortly after introducing total parenteral nutrition and reversed within hours after the addition of thiamine. Successful treatment of nucleoside analogue-induced lactic acidosis with a high dose of thiamine supports the hypothesis that vitamin deficiency is an important cofactor in the development of this rare and unpredictable condition in patients with HIV. We suggest that high dose B-vitamins should be given to any patient presenting with lactic acidosis under nucleoside analogue treatment.

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Didanosine; Female; Humans; Parenteral Nutrition, Total; Stavudine; Thiamine

We report two cases of fulminant hepatic failure in HIV-1-infected patients treated with didanosine (ddI). Clinical manifestations including vomiting, diarrhoea and dyspnoea were identical in both cases. Biological data mainly revealed hepatic failure and lactic acidosis. Histological examination of liver biopsies showed diffuse microvesicular steatosis. The outcome was fatal in both patients. The only comparable case previously reported (Lai et al., 1991) showed close similarities in the clinical, biological and histological manifestations with microvesicular steatosis. This prompted us to suspect that ddI might be responsible for fulminant hepatitis in all three AIDS patients. This toxic effect may be added to the list of potential adverse events occurring during ddI therapy.

Topics: Acidosis, Lactic; Acquired Immunodeficiency Syndrome; Aged; AIDS-Related Opportunistic Infections; Didanosine; Hepatic Encephalopathy; HIV Infections; Humans; Male; Middle Aged