Mitochondrial Toxicity In Children

Hyperlactatemia does occur in the pediatric population (reviewed in ref. 104). There are several concerning reports regarding HIV-exposed but uninfected infants who developed hyperlactatemia from in utero exposure to HAART. One prospective study examined serial lactate levels in 25 infants born to HAART-treated mothers and reported that 92 of infants had elevated lactate levels, with 35 of the cohort demonstrating levels greater than 5 mmol L (105). Only one infant was symptomatic. All of the...

Basic Understanding Of Mitochondria

The most important and critical mitochondrial function is oxidative phos-phorylation, a mechanism by which the energy derived from metabolism of nutrients in the presence of oxygen is transformed into adenosine triphosphate (ATP). Figure 1 describes the mitochondrial oxidative energy metabolism. The system of oxidative phosphorylation includes five multienzyme complexes, designated as electron-transport chain complexes I through V. These enzymes are encoded by either mitochondrial or nuclear...

References

Condra JH, Miller MD, Hazuda DJ, Emini EA. Potential new therapies for the treatment of HIV-1 infection. Annu Rev Med 2002 53 541-555. 2. Graham BS. Clinical trials of HIV vaccines. Annu Rev Med 2002 53 207-221. 3. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995 1 417-422. 4. Lewis W, Copeland WC, Day B. Mitochondrial DNA depletion, oxidative stress and mutation mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Lab Invest 2001 81 777-790. 5. Lewis...

What Laboratory Studies Are Needed For Initiation In Monitoring Of Therapy In Developing Countries

Laboratory tests in Western countries costing between 1000 and 2000 annually are used to provide serial CD4 counts, viral loads, occasional resistance tests, and other laboratory tests for initiating and monitoring HIV care. In many countries in Africa, few laboratory studies are available and most patients have no resources to pay for laboratory studies. As a result, the majority of patients are treated without Western-type laboratory support. Several initiatives need to urgently be taken....

Nnrtiresistant Virus In Treatmentnaive Patients

Transmission of NNRTI-Resistant Virus in Treatment-Naive Patients Transmitted NNRTI resistance is well-documented and is becoming a major problem. High-level resistance can be defined as a 10-fold decrease in susceptibility of the virus to a particular drug. The rate of high-level phenotypic NNRTI resistance in patients recently infected with HIV-1 has been estimated at 7.1 in a retrospective cohort in 10 major cities in infections occurring between 1999 and 2000 (29). Although this high...

Management Of Neuropathy Associated With Nucleoside Reverse Transcriptase Inhibitor Therapy

Complaints of pain or paresthesias in the lower extremities of a patient taking ddI, ddC, or d4T suggests the possibility of a toxic neuropathy and warrants detailed evaluation. Compared with HIV-associated DSP, toxic neuropathies appear more abruptly and progress more quickly, thus, an individual who develops such progressive symptoms within several months after the introduction of a potentially neurotoxic antinucleoside agent is more likely to have a toxic neuropathy. The diagnosis, however,...

Rt Structure And Location Of Nucleoside Resistance Mutations

RT is a heterodimeric protein consisting of 66- and 51-kDa subunits (p66 and p51, respectively). The p66 subunit is composed of all 560 amino acids of the pol gene. The p51 subunit is composed of the first 440 amino acids of the pol gene. Although p51 contains a polymerase active site, p51 is catalytically inactive and predominantly serves as a structural base for the active p66. The three-dimensional conformation of p66 resembles a right hand (Fig. 1). It has a palm containing the active site,...

The Role Of Delavirdine In Clinical Practice Table

According to its package insert, delavirdine is indicated for the treatment of HIV infection in combination with at least two other agents when antiretroviral therapy is warranted from a clinical perspective. Of seven women who became pregnant while receiving delavirdine as part of a clinical trial, three had ectopic pregnancies, one delivered an infant with a small muscular ventricular septal defect, and three had normal deliveries. In light of this (along with limited animal data suggesting...

Emtricitabine Activity And Efficacy Clinical Trials

The antiretroviral activity of emtricitabine was demonstrated in two short-term monotherapy trials in HIV-1-infected adults. Study 101 was a phase I II, open-label, nonrandomized, dose-ranging study in 41 lamivudine- and aba-cavir-naive patients. Emtricitabine was administered at 25 mg twice daily (BID), 100 mg QD, 100 mg BID, 200 mg QD, or 200 mg BID for 14 d (3). At the 200-mg QD dose level, emtricitabine reduced HIV RNA levels by a mean of 1.93 log10 copies mL (21). Study 102 was a phase I...

Factors That May Influence Intracellular Phosphorylation

Because the NRTIs require intracellular activation for antiretroviral activity, influences on the enzymes responsible for activation can modulate drug activity. In vitro, cellular factors have been shown to alter antiretroviral activity. The activation state of the cell may change the relationship between drug triphos-phate and endogenous triphosphate. For instance, in activated cells, the ratios of ZDVTP to deoxythymidine triphosphate (dTTP) and of d4T triphosphate to dTTP are greater than in...

Didanosine

Didanosine (also known as ddI) is available in its original buffered formulations (Videx) and as a delayed-release formulation with enteric-coated beadlets Selected Laboratory and Hematological Abnormalities From Combination Studies of Stavudine (Pooled Data) (6)a Parameter n 467 ( of patients)c Total bilirubin (> 2.6 x ULN) 0 Neutropenia (ANC < 750 mm3) 5 Anemia (hemoglobin < 8 g dL) < 1 Thrombocytopenia (platelets < 50,000 cells mm3) 2 AST, aspartate aminotransferase ALT, alanine...

Info

NVP, nevirapine od, once daily bd, twice daily EFV, efavirenz lab, laboratory value Treatment failure defined as a less than 1 log10 copies mL decline in HIV RNA pVL in first 12 wk, two consecutive pVL levels greater than 50 copies mL from week 24 onwards, a new AIDS-defining illness or death, or a change of allocated treatment Percentage of patients with at least one grade 3 or 4 adverse events (AE) cGrade 3 or 4 elevations in AST, ALT, or total bilirubin levels Excluding isolated (-glutamic...

Nd

Vd, volume of distribution CSF, cerebrospinal fluid ND, not determined Pediatric patients (8-mo to 19-yr old) demonstrate a lower oral bioavailability (25 ), smaller Vd (28 L m2), and shorter half-life (0.8 h) (60,65) Vd, volume of distribution CSF, cerebrospinal fluid ND, not determined Pediatric patients (8-mo to 19-yr old) demonstrate a lower oral bioavailability (25 ), smaller Vd (28 L m2), and shorter half-life (0.8 h) (60,65) Buffered didanosine, the first available formulation of...

Clinical Manifestations Of Mitochondrial Toxicity

Symptomatic Forms of Hyperlactatemia Lactic acidosis is the most dramatic manifestation of NRTI-associated mitochondrial dysfunction. Lactic acidosis has been reported in HIV-infected patients since the early 1990s, but recent clusters of reports increased physicians' awareness about this potentially fatal syndrome. Fortunately, severe lactic acidosis remains a rare occurrence. The typical clinical presentation is one of precipitous occurrence of nausea, vomiting, abdominal pain, severe...

Therapeutic Interventions In The Prevention Of Vertical Hiv Transmission

The initial reports of HIV in children highlighted the fact that this emerging infection could be transmitted from an asymptomatic mother to her newborn child (51), that HIV-infected infants had faster disease progression, and that pediatric AIDS had a high mortality rate (52,53). The poor prognosis of pediatric AIDS led investigators to design strategies to reduce perinatal HIV-1 transmission. ZDV, the only Food and Drug Administration-approved antiretroviral drug in the mid-1980s, was the...

Hiv Rt Crystal Structures

The Architecture of the HIV-1 RT Heterodimer A number of crystal structures of HIV-1 RT have been published during the last 10 years mainly of the full RT heterodimer. In addition, structures of some RT domains have been determined, including the C-terminal HIV-1 RNase H (25) and N-terminal fragments from HIV-1 (26) and murine Moloney RTs (27). The HIV-1 RT heterodimer structures determined, to date, can be divided into three general categories 1. complexes containing nucleic acid, which...