didanosine and Hemophilia-A

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

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.

Topics: Adult; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Didanosine; Drug Therapy, Combination; Female; Hemophilia A; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Male; Safety; Treatment Outcome; Viremia; Zidovudine

Many cohort studies and clinical trials use repeated measurements of laboratory markers to track disease progression and to evaluate new therapies. A major problem in the analysis of such studies is that marker data are censored in some patients owing to withdrawal, loss to follow-up, or death. The objective of this paper is to evaluate the impact of selective dropouts attributable to death or disease progression on the estimates of marker change among different groups.. Data on CD4 cell count in human immunodeficiency virus 1-infected individuals from a clinical trial and a cohort study are used to illustrate this problem and a possible solution. Simulation studies are also presented.. When the rate of dropout is greater in subjects whose marker status is declining rapidly, commonly used methods, like random effects models, that ignore informative dropouts lead to overoptimistic statements about the marker trends in all compared groups, because subjects with steeper marker drops tend to have shorter follow-up times and hence are weighted less in the estimation of the group rate of the average marker decline.. The potential biases attributable to incomplete data require greater recognition in longitudinal studies. Sensitivity analyses to assess the effect of dropouts are important.

Topics: Adolescent; Adult; Bias; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Data Interpretation, Statistical; Didanosine; Hemophilia A; HIV Infections; Humans; Infant; Least-Squares Analysis; Longitudinal Studies; Middle Aged; Models, Theoretical; Patient Dropouts; Randomized Controlled Trials as Topic

We performed a pilot study to evaluate the factors associated with response to interferon (IFN) therapy for chronic hepatitis C (CHC) with human immunodeficiency virus (HIV) coinfected haemophiliacs. Seven haemophiliacs, coinfected with HIV and hepatitis C virus (HCV), received 9 mega-units (MU) of natural IFN-alpha daily during the first 2 weeks and then three times a week for 22 weeks, all injected subcutaneously. Six patients were receiving zidovudine (AZT) 600 mg day-1 and didanosine (ddI) 200 mg day(-1) during IFN therapy. This treatment was safe and well tolerated. Four patients had no detectable serum HCV-RNA at the end of therapy, but long-term, none of the seven patients achieved a sustained response, i.e. undetectable serum HCV-RNA with persistently normal serum alanine aminotransferase (ALT) 6 months after therapy. IFN did not affect CD4-positive cell counts. Most of our patients had high HCV-RNA loads and/or low CD4 counts, both unfavourable markers for IFN therapy. In conclusion, IFN therapy did not eradicate HCV from haemophiliacs coinfected with HIV.

Topics: Adult; Anti-HIV Agents; Antiviral Agents; Didanosine; Hemophilia A; Hepatitis C, Chronic; HIV Infections; Humans; Interferon-alpha; Middle Aged; Pilot Projects; Treatment Outcome; Zidovudine

We present a case of liver failure in a haemophilic patient coinfected with transfusion acquired human immunodeficiency (HIV) and hepatitis C (HCV) viruses. The case illustrates the interaction of multiple viruses with accelerated progression to end stage liver disease and ultimately death. We report the impact on the patient management of two liver biopsies, which diagnosed an initial drug induced hepatitis and subsequently an atypical HCV related hepatitis.

Topics: Anti-Bacterial Agents; Anti-HIV Agents; Clarithromycin; Didanosine; Hemophilia A; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver Failure, Acute; Male; Middle Aged; Zidovudine

A stage IIIB anaplastic seminoma which occurred in an HIV-infected hemophilia is reported. The patient with hemophilia A was 36 years old and had been seropositive for HIV antibody for 3 years. Inguinal orchiectomy and subsequent chemoradiotherapy for retroperitoneal lymphadenopathy were performed and a marker negative partial response was obtained. In spite of a low initial CD4+ lymphocyte count (90/microliter), the patient tolerated the treatment well without life-threatening opportunistic infection. Although factor VIII supplement was performed, continuous bleeding from the operative wound made postoperative care difficult.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; CD4 Lymphocyte Count; Cisplatin; Combined Modality Therapy; Didanosine; Drug Therapy, Combination; Etoposide; Factor VIII; Germinoma; Hemophilia A; Humans; Male; Orchiectomy; Saquinavir; Testicular Neoplasms; Zidovudine

We used a time-dependent input rate function in the two-compartment model to simulate drug plasma concentrations after an oral administration. The input rate term has a Gaussian-like structure with two parameters, time to maximum absorption rate (tm) and measure of the duration of the absorption process (s). This structure corresponds to the scenario in which the absorption rate of the drug into the central compartment changes unimodally with respect to time after administration with a single peak at time tm. We demonstrate the applicability of this formulation in the simulation of plasma concentration of didanosine after oral administration in two Japanese hemophiliacs. We found that we were able to simulate the time courses of the didanosine plasma concentrations in both patients using the theoretical equation with the input term included, and that we were able to determine the six parameters in the equation by the least squares estimation. Pharmacokinetic values derived from the best-fit curve were almost comparable to those reported in other literature except that the Cmax and AUC0-infinity seemed to be slightly higher than those reported elsewhere. Although we are unable to verify the accuracy of this formulation because of the lack of sufficient Japanese data, we are able to demonstrate its efficacy and convenience in the application presented here.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; AIDS-Related Complex; Anti-HIV Agents; Area Under Curve; Chromatography, High Pressure Liquid; Didanosine; Hemophilia A; Humans; Least-Squares Analysis; Mathematics

In Japan, 1531 out of 4171 hemophiliacs (36.7%) are human immunodeficiency virus (HIV)-infected, and up to 31 December 1991, 324 (21.2%) of these patients had developed AIDS. The Research Committee estimated the peak of the seroconversion period of hemophiliacs in Japan as January 1983, having presumed that new cases of seroconversion would not arise after heat treated concentrates came into general use in 1985. However, after a long 5 years window period starting in 1985, cases of seroconversion are being reported. The present mean rate of reduction in cluster difference 4 (CD4) counts of HIV infected hemophiliacs has been increasing since 1990. At present (1991), the proportion of HIV infected hemophiliacs below 20 years is believed to be approximately 40%. Concomitantly with the aging of this group, the incidence of AIDS is expected to increase in the future. Although the aforesaid factors are conducive to a rising incidence of AIDS, the rate of increase of AIDS incidence among hemophiliacs in Japan is actually decelerating. This can, hopefully, be attributed to the commencement of widespread use of periodic pentamidine inhalation therapy, or the administration of drugs such as AZT (zidovudine) or ddI (didanosine) to AIDS related complex (ARC) cases, or to asymptomatic carrier (AC) cases with CD4 counts below 350 cells for the prophylactic treatment against developing to AIDS. Oral administration of didanosine at a dosage of 400 mg/day, or didanosine at a dosage of 334 mg to 500 mg/day, has been found effective for the treatment of hemophiliacs with AIDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acquired Immunodeficiency Syndrome; Actuarial Analysis; Administration, Oral; Adolescent; Adult; Age Factors; CD4-Positive T-Lymphocytes; Child; Cluster Analysis; Didanosine; Hemophilia A; HIV Seropositivity; HIV-1; Humans; Incidence; Japan; Leukocyte Count; Population Surveillance; Risk Factors; Survival Rate