Relevant data were derived from neonatal seroprevalence studies, obstetric and paediatric reporting schemes, and review of external information. Sensitivity analyses were performed for certain parameters.
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Three-drug ART (zidovudine or stavudine plus lamivudine plus nevirapine or efavirenz) for children who met national treatment criteria.
In September 2000, two instances of life-threatening hepatotoxicity were reported in health-care workers taking nevirapine (NVP) for postexposure prophylaxis (PEP) after occupational human immunodeficiency virus (HIV) exposure. In one case, a 43-year-old female health-care worker required liver transplantation after developing fulminant hepatitis and end-stage hepatic failure while taking NVP, zidovudine, and lamivudine as PEP following a needlestick injury (1). In the second case, a 38-year-old male physician was hospitalized with life-threatening fulminant hepatitis while taking NVP, zidovudine, and lamivudine as PEP following a mucous membrane exposure. To characterize NVP-associated PEP toxicity, CDC and the Food and Drug Administration (FDA) reviewed MedWatch reports of serious adverse events in persons taking NVP for PEP received by FDA (Figure 1). This report summarizes the results of that analysis and indicates that healthy persons taking abbreviated 4-week NVP regimens for PEP are at risk for serious adverse events. Clinicians should use recommended PEP guidelines and dosing instructions to reduce the risk for serious adverse events.
Retrospective study of a historic cohort of 350 patients, from January 1988 to December 1994. The clinic progression, the immunologic deterioriation and the survival after the ZDV administration were evaluated, like the toxicity of the drug.
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Varying components of the syndrome of human immunodeficiency virus nephropathy (HIVN) have been described, the most pertinent including proteinuria/nephrotic syndrome, progressive azotemia, normal blood pressure, enlarged and hyperechoic kidneys, rapid progression to end-stage renal disease (ESRD), and no response to treatment regimens. The diagnosis of HIVN requires identification of excessive proteinuria or albuminuria, determined by a total protein excretion on a timed urine collection or a high protein/creatinine ratio in a random specimen. Various pathological lesions have been found in HIVN. The lesion of focal and segmental sclerosis (FS/FSS) is most characteristic in adults and usually is associated with a rapid demise. FS/FSS also has been described in approximately one-half of the pediatric patients reported in the literature (31/64). Despite progression to ESRD, the clinical course in children with HIVN is less fulminant than in adults. Other reported histological findings include primarily mesangial hyperplasia as well as minimal change, focal necrotizing glomerulonephritis or lupus nephritis, and hemolytic uremic syndrome. In addition to glomerular pathology, interstitial findings of dilated tubules filled with a unique proteinaceous material, atrophied tubular epithelium, and interstitial cell infiltration are very common. On electron microscopy, most investigators have found tubuloreticular inclusion bodies in endothelial cells of glomerular capillaries. Treatment of patients who develop ESRD remains highly controversial. Most adult patients treated with hemodialysis have succumbed rapidly; peritoneal dialysis has been better tolerated. Transplantation in patients with HIV infection must be considered to be tentative, with reports of acceleration towards full blown acquired immunodeficiency syndrome in some and uneventful 5-year survival in others.(ABSTRACT TRUNCATED AT 250 WORDS)
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A human betaretrovirus has been characterized in patients with primary biliary cirrhosis (PBC). Uncontrolled studies using combination anti-retroviral therapy have reported significant biochemical and histological improvement.
To explore the mitochondrial toxicities induced by zidovudine (AZT) and adefovir dipivoxil (ADV) antiviral drugs using a rat model system.
The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one.
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To assess the efficacy of d4T compared to AZT in combination with one NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI), two additional NNRTIs, or one NRTI and one protease inhibitor (PI), as part of first-line ART for HIV-infected people in low-resource settings.
BACKGROUND--Antimycobacterial therapy for disseminated Mycobacterium avium complex (DMAC) in patients with acquired immunodeficiency syndrome (AIDS) may ameliorate symptoms and decrease bacteremia. However, no studies have demonstrated improved survival in patients with AIDS treated for DMAC. We assessed the effects of treatment of DMAC on the survival of patients with AIDS. METHODS--We retrospectively reviewed records of patients with AIDS and DMAC seen at two San Francisco, Calif, hospitals between January 1, 1988, and January 1, 1990. The treatment group (N = 76) consisted of patients who received 2 weeks or more of antimycobacterial therapy with at least three agents. The untreated group (N = 74) received either no therapy or isoniazid alone. Patients in both groups lived a minimum of 2 weeks after the diagnosis of DMAC. RESULTS--The median survival in the treatment group was 191 days, compared with 80 days in the untreated group. In a multivariate proportional hazards model (N = 145), both treatment of DMAC (relative hazard = 0.34; 95% confidence interval, 0.23 to 0.51) and treatment with zidovudine (relative hazard = 0.54; 95% confidence interval, 0.36 to 0.82) were associated with improved survival. CONCLUSION--Patients with AIDS and DMAC who are treated with antimycobacterial drugs may survive longer than untreated patients. We recommend that a randomized trial be conducted to evaluate the optimal treatment of DMAC.
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: HIV-1-infected, treatment-naive adults were randomized, using a factorial design, to add NVP and/or HU to the triple NRTI backbone of zidovudine plus lamivudine plus abacavir. Primary endpoint was treatment failure, defined as having plasma HIV RNA levels > 50 copies/ml after week 24, or discontinuation of randomized treatment. Follow-up was 72 weeks.
In ACTG 384, ART-naive subjects were randomized to receive didanosine and stavudine or zidovudine and lamivudine plus efavirenz, nelfinavir, or both. In the metabolic substudy A5005S (N= 329), waist, hip, thigh, and arm circumferences were measured in triplicate. DEXA scanning was performed in 157 subjects.
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Robins introduced marginal structural models (MSMs) and inverse probability of treatment weighted (IPTW) estimators for the causal effect of a time-varying treatment on the mean of repeated measures. We investigate the sensitivity of IPTW estimators to unmeasured confounding. We examine a new framework for sensitivity analyses based on a nonidentifiable model that quantifies unmeasured confounding in terms of a sensitivity parameter and a user-specified function. We present augmented IPTW estimators of MSM parameters and prove their consistency for the causal effect of an MSM, assuming a correct confounding bias function for unmeasured confounding. We apply the methods to assess sensitivity of the analysis of Hernán et al., who used an MSM to estimate the causal effect of zidovudine therapy on repeated CD4 counts among HIV-infected men in the Multicenter AIDS Cohort Study. Under the assumption of no unmeasured confounders, a 95 per cent confidence interval for the treatment effect includes zero. We show that under the assumption of a moderate amount of unmeasured confounding, a 95 per cent confidence interval for the treatment effect no longer includes zero. Thus, the analysis of Hernán et al. is somewhat sensitive to unmeasured confounding. We hope that our research will encourage and facilitate analyses of sensitivity to unmeasured confounding in other applications.
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We recently reported that zidovudine (AZT) selected for the Q509L mutation in the ribonuclease H (RNase H) domain of HIV-1 reverse transcriptase (RT), which increases resistance to AZT in combination with the thymidine analogue mutations D67N, K70R, and T215F. In the current study, we have defined the mechanism by which Q509L confers AZT resistance by performing in-depth biochemical analyses of wild type, D67N/K70R/T215F and D67N/K70R/T215F/Q509L HIV-1 RT. Our results show that Q509L increases AZT-monophosphate (AZT-MP) excision activity of RT on RNA/DNA template/primers (T/Ps) but not DNA/DNA T/Ps. This increase in excision activity on the RNA/DNA T/P is due to Q509L decreasing a secondary RNase H cleavage event that reduces the RNA/DNA duplex length to 10 nucleotides and significantly impairs the enzyme's ability to excise the chain-terminating nucleotide. Presteady-state kinetic analyses indicate that Q509L does not affect initial rates of the polymerase-directed RNase H activity but only polymerase-independent cleavages that occur after a T/P dissociation event. Furthermore, competition binding assays suggest that Q509L decreases the affinity of the enzyme to bind T/P with duplex lengths less than 18 nucleotides in the polymerase-independent RNase H cleavage mode, while not affecting the enzyme's affinity to bind the same T/P in an AZT-MP excision competent mode. Taken together, this study provides the first mechanistic insights into how a mutation in the RNase H domain of RT increases AZT resistance and highlights how the polymerase and RNase H domains of RT function in concert to confer drug resistance.
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Results indicate that the original formulations were microemulsions that displayed phase transition to a lamellar phase when brought into contact with aqueous nasal simulated mucus. The phase transition was accompanied by an increase in system elasticity and, irrespective of phase behaviour, all the systems showed a good mucoadhesive force. Thus, a viscous and mucoadhesive liquid crystalline matrix could be formed when the formulations were in contact with simulated mucus, which may prolong the residence time of zidovudine in the nasal cavity.
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A favourable clinical response, defined as reversal to a less severe ADC stage (Price and Brew's criteria), was observed after 1, 3, 6, 9 and 12 months in 15, 22, 25, 19 and 14 patients, respectively. Neither severity of ADC at entry nor ZDV dose correlated with response to treatment. Seven patients died during the 12-month follow-up. The only factor associated with longer survival was ADC severity at entry (12-month survival, 0.94 and 0.53, in patients in stages 1 or 2 and in stages 3 or 4, respectively; P < 0.01). After 6-12 months of ZDV treatment six patients who initially responded to therapy showed a relapse in initial ADC stage, and two patients a less severe neurological deterioration. Neuropsychological evaluations showed significant improvement in the Wisconsin Card-Sorting test (P = 0.006 for categories, P = 0.029 for perseverative errors), which is particularly sensitive to cognitive and frontal-lobe type functions. Brain MRI revealed a reduction of the extent of white matter lesions in six out of 13 patients, who also showed clinical improvement. SPECT scanning revealed a reduction in the extent of uptake defects concomitant with clinical response in nine out of 14 patients.
The synthesis of new dinucleosides of AZT and D4T is described.
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We measured plasma HIV-1 RNA serially in 552 women with HIV-1 infection who had singleton pregnancies. The status of infection in their infants was assessed by culture of blood and further classified as early (if a culture of blood obtained within the first two days of life was positive) or late (if a culture of blood obtained in the first seven days of life was negative but subsequent cultures were positive). The rates of transmission at various levels of maternal plasma HIV-1 RNA were analyzed by tests for trend, with adjustment for covariates by stratification and logistic regression.
Removal of 3'-azido-3'deoxythymidine (AZT) 3'-azido-3'-deoxythymidine 5'-monophosphate (AZTMP) from the terminated primer mediated by the human HIV-1 reverse transcriptase (RT) has been proposed as a relevant mechanism for the resistance of HIV to AZT. Here we compared wild type and AZT-resistant (D67N/K70R/T215Y/K219Q) RTs for their ability to unblock the AZTMP-terminated primer by phosphorolysis in the presence of physiological concentrations of pyrophosphate or ATP. The AZT-resistant enzyme, as it has been previously described, showed an increased ability to unblock the AZTMP-terminated primer by an ATP-dependent mechanism. We found that only mutations in the p66 subunit were responsible for this ability. We also found that three structurally divergent non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, TIBO, and a 4-arylmethylpyridinone derivative, were able to inhibit the phosphorolytic activity of the enzyme, rendering the AZT-resistant RT sensitive to AZTTP. The 4-arylmethylpyridinone derivative proved to be about 1000-fold more potent in inhibiting phosphorolysis than nevirapine or TIBO. Moreover, combinations of AZTTP with NNRTIs exhibited an exceptionally high degree of synergy in the inhibition of AZT-resistant enzyme only when ATP or PPi were present, indicating that inhibition of phosphorolysis was responsible for the synergy found in the combination. Our results not only demonstrate the importance of phosphorolysis concerning HIV-1 RT resistance to AZT but also point to the implication of this activity in the strong synergy found in some combinations of NNRTIs with AZT.
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The aim of the studv was to evaluate the capacity of poly(isohexylcyanoacrylate) nanospheres to concentrate 3'-azido 3'-deoxythymidine (AZT) in the intestinal epithelium and associated immunocompetent cells, which are known to be one of the major reservoirs of the human immunodeficiency virus (HIV).
Yearly predicted median changes in individual eGFR according to the LME model were: HBV untreated -2.05 ml/min, HBV lamivudine -0.92 ml/min, HBV adefovir -1.02 ml/min, HBV entecavir -1.00 ml/min, and HBV tenofovir -0.92 ml/min (p<0.01 for HBV untreated vs. HBV treated). In HIV-monoinfected patients: HIV untreated -0.62 ml/min, HIV treated with tenofovir -2.64 ml/min, HIV treated with zidovudine -1.0 ml/min (p=0.017 for tenofovir vs. no treatment, p<0.001 for tenofovir vs. zidovudine).
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An increasing number of AIDS cases occur each year in West Virginia despite its small urban population. From January 1984 to March 1991 at the Marshall University based multispecialty internal medicine group (the University Physicians in Internal Medicine), 66 HIV-infected persons were treated, most of whom are native West Virginians and always resided in the state. The study group consisted of 61 men and 5 women; four-fifths of the men are homosexual/bisexual and one-seventh used intravenous illicit drugs. Four women acquired infection heterosexually and one from transfusion. Twenty-eight patients never had any opportunistic infection (OI) and 38 experienced at least one OI, usually Pneumocystis carinii Pneumonia. About two-fifths of patients had CD4 counts less than 200 cells/cmm at their initial examination. Three-fourths of patients received AZT, six ddI, and most aerosolized pentamidine. Nineteen patients have died, all of whom suffered at least one OI. The mean interval until death from HIV infection and from AIDS was about 27 and 11.5 months, respectively.
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The relationship between latest CD4 count, treatment changes and time to AIDS-related complex (ARC), AIDS or death was investigated using time-updated proportional hazards models, but these models gave seriously biased estimates of the effect of ZDV. Therefore, a method based on the comparison of the randomized groups was used. A model relating a participant's events times to the treatment actually received was used to estimate what would have been observed if the deferred group had not received ZDV before ARS or AIDS, and to explore alternative policies for starting Pneumocystis carinii pneumonia (PCP) prophylaxis.
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Viral load, CD4+ and CD8+ T lymphocyte counts were assessed at intervals of 1-3 months in subjects commencing therapy between July 1996 and November 1996. Adverse events were evaluated as well as risk factors for therapeutic failures.