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Impact of highly active antiretroviral therapy on individual AIDS-defining illness incidence and survival in Australia.

OBJECTIVE: To determine the effect of highly active antiretroviral therapy (HAART) on incidence of initial AIDS-defining illnesses (ADIs) and survival after individual ADIs. METHODS: Australian AIDS notification data over the period 1993 to 2000 were examined. Analyses were based on all initial ADIs. To examine the impact of HAART, two periods of AIDS diagnosis were chosen: pre-HAART (1993-1995) and HAART (1996-2000). Comparisons between these two periods included proportion of individual ADIs, median CD4 lymphocyte counts at and survival following AIDS and individual ADIs. Median survival was based on Kaplan-Meier estimates, with examination of factors influencing survival in a Cox proportional hazards model. RESULTS: Over the period 1993 to 2000 in Australia, 5017 initial ADIs were diagnosed among 4351 AIDS cases. At AIDS diagnosis, changes from the pre-HAART (1993-1995) to HAART (1996-2000) periods included an increased proportion of Pneumocystis carinii pneumonia (PCP) (25.9% to 30.4%; p =.001), AIDS dementia complex (5.2% to 6.8%; p = 0.029), non-Hodgkin lymphoma (NHL) (4.4% to 6.3%; p =.005), and tuberculosis (0.5% to 2.7%; p <.0005). Median survival following AIDS increased from 19.6 months for AIDS cases diagnosed in 1993 to 1995 to 39.6 months for AIDS cases diagnosed in 1996 to 2000 (p <.0005). Median survival was stable for NHL (7.5-8.8 months; p =.26), but increased significantly for almost all other ADIs. CONCLUSIONS: An increased proportion of PCP relative to other ADIs suggests an increasing proportion of AIDS patients not receiving specific prophylaxis, presumably because of "late" HIV diagnosis. Survival following almost all ADIs has increased in the era of HAART, although the prognosis after NHL remains extremely poor.

AIDS-Related Opportunistic Infections↗

The association of hepatitis C prevalence, activity, and genotype with HIV infection in a cohort of New York City drug users.

Factors associated with serum HCV antibody, HCV RNA level, and HCV genotype were assessed in 557 current and former drug users. Additional assays included HIV antibody, CD4+ lymphocyte counts, HIV viral loads, and hepatitis B markers. Seventy-five percent of subjects were anti-HCV positive, of whom 75% had detectable HCV RNA (median, 5.04 x 10(5) IU/mL; range, 1020-15.7 x 10(6)). On multivariate analysis HCV seropositivity was associated with history of drug injection, HIV seropositivity, and increased age and inversely with drug snorting. Among anti-HCV-positive persons, detectable HCV RNA was independently associated with HIV seropositivity, male gender, and history of injection and inversely associated with hepatitis B surface antigen positivity. Among persons with detectable HCV RNA, higher levels were independently associated with higher HIV viral load, increased age, and genotypes 2a and 2b. These findings demonstrate an association of HCV RNA level with HIV viral load, independent of the level of immunosuppression. However, a substantial degree of the person-to-person variability in the prevalence and level of detectable HCV RNA remains unexplained.

Adult↗

Diabetes, insulin resistance, and dementia among HIV-1-infected patients.

OBJECTIVES: Metabolic complications have been associated with HIV-1 infection and with long-term use of antiretroviral (ARV) medications. In some studies, such complications have been linked to cardiovascular events, yet limited data exist concerning metabolic complications and dementia. The objective of this study was to examine the relationship between HIV-associated dementia (HAD) and diabetes among patients with HIV-1 infection. DESIGN: Cross-sectional analysis of entry data for a longitudinal cohort study. METHODS: A total of 203 participants who were enrolled in the Hawaii Aging with HIV Cohort between October 2001 and November 2003 served as the study population. Research case definitions of HAD were determined in consensus conferences by a panel that included neurologists, neuropsychologists, and a geriatrician. Diabetes was determined by self-report or a fasting glucose level > 125 mg/dL. RESULTS: Participants' ages ranged between 20-76 years at enrollment with approximately one-half aged >/=50 years. After adjustment for important covariates including age, education, ethnicity, CD4 lymphocyte count, duration of HIV infection, and protease inhibitor-based ARV therapy, we found a statistically significant association of diabetes with HAD (odds ratio 5.43, 1.66-17.70). A significant association remained after adjustment for other vascular risk factors. Among participants without diabetes, fasting glucose levels were higher with increasing impairment category. CONCLUSIONS: Within the Hawaii Aging with HIV Cohort, a longitudinal study enriched with older HIV-1-infected individuals, diabetes is associated with prevalent dementia. This finding is not fully explained by age or coexisting vascular risk factors. Evaluation of underlying mechanisms is warranted.

AIDS Dementia Complex↗

Fatal long-term immunosuppressive therapy with uncontrolled repeat prescription.

A case of nephrotic syndrome treated with associated cyclophosphamide and corticosteroids came to our attention after over 2 years of self-administered immunosuppressive therapy which remained unchanged and uncontrolled during this period. The self-administered therapy resulted in a severe cell-mediated immunodeficiency (as expressed by a nadir CD4 lymphocyte count of 2 cells/muL). This led to a rapid unfavorable progression of hepatitis B, which was recently acquired and subsequently evolved into a severe cholestatic and fibrosing chronic hepatitis, causing multiple end-organ failure, and ultimately, death. This process was not reversed by lamivudine therapy, hemodialysis, and the use of a Molecular Adsorbent Recirculating System. The role played by repeated drug prescriptions from general practitioners without appropriate clinical and laboratory controls, and that of our patient's depression are discussed. Current literature related to the presented case and the ongoing debate regarding repeated prescriptions are considered in this study.

Drug Administration Schedule↗

How trauma, recent stressful events, and PTSD affect functional health status and health utilization in HIV-infected patients in the south.

OBJECTIVE: In addition to biological markers of human immunodeficiency virus (HIV) disease progression, physical functioning, and utilization of health care may also be important indicators of health status in HIV-infected patients. There is insufficient understanding of the psychosocial predictors of health-related physical functioning and use of health services among those with this chronic disease. Therefore, the current study examines how trauma, severe stressful events, posttraumatic stress disorder (PTSD), and depressive symptoms are related to physical functioning and health utilization in HIV-infected men and women living in rural areas of the South. METHODS: We consecutively sampled patients from 8 rural HIV clinics in 5 southern states, obtaining 611 completed interviews. RESULTS: We found that patients with more lifetime trauma, stressful events, and PTSD symptoms reported more bodily pain, and poorer physical, role, and cognitive functioning. Trauma, recent stressful events, and PTSD explained from 12% to 27% of the variance in health-related functioning, over and above that explained by demographic variables. In addition, patients with more trauma, including sexual and physical abuse, and PTSD symptoms were at greater risk for having bed disability, an overnight hospitalization, an emergency room visit, and four or more HIV outpatient clinic visits in the previous 9 months. Patients with a history of abuse had about twice the risk of spending 5 or more days in bed, having an overnight hospital stay, and visiting the emergency room, compared with those without abuse. The effects of trauma and stress were not explained by CD4 lymphocyte count or HIV viral load; however, these effects appear to be largely accounted for by increases in current PTSD symptoms. CONCLUSION: These findings highlight the importance of addressing past trauma, stress, and current PTSD within clinical HIV care.

Adult↗

Injection drug use is an independent risk factor for iron deficiency and iron deficiency anemia among HIV-seropositive and HIV-seronegative women.

The risk factors for iron deficiency and iron deficiency anemia among female injection drug users are not well characterized. We measured hemoglobin and plasma ferritin and obtained demographic information and injection drug use history in the last 6 months in a cross-sectional study of 200 female injection drug users (134 HIV-positive and 66 HIV-negative). The women were participants in a natural history study, the AIDS Linked to Intravenous Experiences study in Baltimore, Maryland. In multivariate analyses adjusting for age, hepatitis C virus status, and HIV status, injection drug use within the last 6 months was associated with iron deficiency (odds ratio [OR] = 2.61, 95% confidence interval [CI]: 1.33 to 5.09) and iron deficiency anemia (OR = 6.65, 95% CI: 2.33 to 18.9). Among 134 HIV-positive women, injection drug use in the last 6 months was associated with iron deficiency (OR = 2.43, 95% CI: 1.08 to 5.48) and iron deficiency anemia (OR = 6.05, 95% CI: 1.82 to 20.1) in multivariate analyses adjusting for hepatitis C virus status and CD4 lymphocyte count. Injection drug use seems to be associated with iron deficiency and iron deficiency anemia. Further longitudinal studies are needed to gain insight into the nature of this association.

Adult↗

Insulin resistance is associated with cognition among HIV-1-infected patients: the Hawaii Aging With HIV cohort.

OBJECTIVE: To determine if insulin resistance (IR) is associated with lower cognitive performance among HIV-1-infected adults and to determine if advanced age magnifies risk. DESIGN: Cross-sectional analysis within the Hawaii Aging With HIV Cohort. METHODS: We calculated the homeostasis model assessment of insulin resistance (HOMA-IR) among 145 cohort participants. Values were compared to concurrent neuropsychological test performance and cognitive diagnoses. RESULTS: Hypertension, body mass index (BMI), and non-Caucasian self-identity were directly related to insulin resistance (IR); however, age, CD4 lymphocyte count, and rates of treatment with HAART were not. In logistic regression analyses and stratifying cognition status on a 3-tiered scale (normal, minor cognitive motor disorder (MCMD), and HIV-associated dementia (HAD)), we identified an increased risk of meeting a higher diagnostic category as HOMA-IR increased (OR, 1.12; 95% CI: 1.003 to 1.242 per unit of HOMA-IR, P = 0.044). In linear regression models and among nondiabetic participants, an increasing degree of IR was associated with lower performance on neuropsychological summary scores. CONCLUSIONS: IR is associated with cognitive dysfunction in this contemporary HIV-1 cohort enriched with older individuals. Metabolic dysfunction may contribute to the multifactorial pathogenesis of cognitive impairment in the era of HAART.

AIDS Dementia Complex↗

Markers of macrophage activation and axonal injury are associated with prospective memory in HIV-1 disease.

OBJECTIVE: To use clinical specimens to better understand the neuropathogenesis of prospective memory (ProM) functioning in persons with HIV-1 infection. BACKGROUND: Emergent evidence suggests that HIV-1 is associated with impaired ProM, but the underlying neuropathophysiology of this deficit is not known. METHODS: Thirty-five nondemented subjects with HIV-1 infection completed measures of both ProM (ie, memory for future intentions) and retrospective memory (RM; ie, memory for past episodes). A panel of biomarkers reflecting several possible neuropathogenic mechanisms of HIV was measured in plasma and cerebrospinal fluid, including HIV-1 RNA, total tau, monocyte chemoattractant protein-1 (MCP-1), soluble receptor for tumor necrosis factor type II, and fibroblast growth factor 1. RESULTS: After controlling for antiretroviral therapy and CD4 lymphocyte count, higher levels of MCP-1 in plasma, and soluble receptor for tumor necrosis factor type II and tau in cerebrospinal fluid were associated with ProM, but not RM. Markers of astrocytosis, growth factor depletion, and HIV-1 replication did not predict either ProM or RM. CONCLUSIONS: ProM impairment in HIV-1 may be dissociable from RM, perhaps reflecting specific neuropathogenic mechanisms of macrophage activation and axonal injury.

Adult↗

Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial.

OBJECTIVE: To demonstrate a causal relationship between herpes simplex virus 2 (HSV-2) and increased genital HIV-1-RNA shedding in women on HAART. DESIGN: A randomized, double-blind, placebo-controlled trial of herpes-suppressive therapy (valacyclovir 500 mg twice a day) in HIV-1/HSV-2-infected women taking HAART in Burkina Faso. METHODS: Participants were followed for a total of 12 biweekly visits before and after randomization. The presence and frequency of genital and plasma HIV-1 RNA, and of genital HSV-2 were assessed using summary measures, adjusting for baseline values. Random effect linear regression models were used to assess the impact of treatment on genital and plasma viral loads among visits with detectable virus. RESULTS: Sixty women were enrolled into the trial. Their median CD4 lymphocyte count was 228 cells/mul, and 83% had undetectable plasma HIV-1 RNA at baseline. Valacyclovir reduced the proportion of visits with detectable genital HSV-2 DNA [odds ratio (OR) 0.37, 95% confidence interval (CI) 0.13, 1.05], but had no significant impact on the frequency (OR 0.90, 95% CI 0.31, 2.62) or quantity (reduction of 0.33 log copies/ml, 95% CI -0.81, 0.16) of genital HIV-1 RNA. However, according to pre-defined secondary analyses restricted to women who shed HIV-1 at least once in the baseline phase, valacyclovir reduced both the proportion of visits with detectable HIV-1 shedding (OR 0.27, 95% CI 0.07, 0.99) and the quantity of genital HIV-1 RNA during these visits (-0.71 log10 copies/ml, 95% CI -1.27, -0.14). CONCLUSION: HSV-2 facilitates residual genital HIV-1 replication among dually infected women taking HAART despite HIV-1 suppression at the systemic level.

Acyclovir↗

Late listeriosis after fludarabine plus prednisone treatment.

Fludarabine plus prednisome treatment in patients with chronic lymphocytic leukaemia has recently been correlated with an increased incidence of Listeria monocytogenes infections. We observed a patient with chronic lymphocytic leukaemia who received fludarabine plus prednisone and developed a fatal listeriosis 7 months later. A further case of listeriosis has recently been described in a man who developed the infection 2 years after successful fludarabine treatment while he had a normal CD4 lymphocyte count. These cases suggest that the risk period for the development of such an unusual infection could be unexpectedly and unpredictably long. This data could be important in the evaluation of a possible antibacterial prophylaxis schedule and in the wariness about the potential danger of food known to contain L. monocytogenes.

Aged↗

[Fungi in the home and hospital environment].

From the viewpoint of 40 years of experience in the field of medical mycology with the help of current topics the competence of the medical mycologist for evaluation of a presence of fungi in the home and hospital environment is commented. The topics considered are as follows: 1. The HIV-infected person and the habitat of Cr. neoformans; the predisposition for cryptococcosis and the CD4 lymphocyte count. 2. Invasive aspergillosis after heart transplantation; by exemplary cooperation between the heart surgeon and the medical mycologist it could be demonstrated that the frequently fatal invasive aspergillosis can be avoided. 3. Attention is drawn to the currently most interesting habitats of fungi in the home environment, i.e., biological waste and compost. It has been shown that among the various fungi, the causative agents of systemic mycoses may also be found.

AIDS-Related Opportunistic Infections↗

Encephalopathy and cytomegalovirus colitis in an AIDS child.

A 2-year-old girl, who had prolonged thrush and spastic diplegia, was found to have a mother-to-child vertical transmission of human immunodeficiency virus type-1 (HIV). A brain computed tomography scan revealed a symmetrical calcification on the bilateral basal ganglia and periventricular white matter. She had an acquired immune deficiency syndrome (AIDS) encephalopathy of pure dominant pyramidal tract disorder without an intellectual deficit. Helper cell lymphocyte count (CD4) increased with the beginning of zidovudine (ZDV, also known as AZT) monotherapy but began to decrease after the 4th week to reach the baseline at 20th week. Zidovudine plus didanosine combination therapy was started at the 68th week, but because of intolerance, the combination was changed to ZDV plus lamivudine at the 98th week. By the 80th week, neither severe opportunistic infection nor deterioration of the neurological status was recognized, but chronic diarrhea appeared. The diarrhea advanced to the wasting syndrome at the age of 4 years and cytomegalovirus genome was confirmed in a biopsied specimen of the colon. Ganciclovir treatment was effective in stopping the diarrhea and increasing her bodyweight, but after the age of 5, resumption of diarrhea was followed by progressive emaciation and weakness. This work may provide some clues in treating children's AIDS.

AIDS Dementia Complex↗

Epidemiological, clinical and therapeutic features of AIDS-related Mycobacterium kansasii infection during the HIV pandemic: an 11-year follow-up study.

OBJECTIVES: Optimal diagnosis and timely treatment of atypical mycobacteriosis, and especially Mycobacterium kansasii disease, remain a serious challenge for clinicians engaged in the management of the immunocompromised host. METHODS AND RESULTS: From more than 2700 hospitalizations (over 1800 patients) attributable to HIV-associated disorders over an 11-year period, 12 patients were found to have a confirmed M. kansasii infection. This reflects the recent reduction in the frequency of this HIV-related complication, which virtually disappeared after the introduction of potent antiretroviral combinations in 1996. In the early 1990s, the lack of effective antiretroviral regimens made frequent the association with AIDS, a mean CD4 lymphocyte count of nearly 20 cells/microL, and an extremely variable chest X-ray features. The recent detection of a further case was attributable to late recognition of very advanced HIV disease, complicated by multiple opportunistic disorders. CONCLUSIONS: Mycobacterium kansasii respiratory or disseminated infection continues to occur, and poses diagnostic problems in terms of late or missed identification as a result of slow culture and frequently concurrent opportunistic disease. Serious therapeutic difficulties also arise from the unpredictable in vitro antimicrobial susceptibility profile of these organisms, and from the need to start an effective combination therapy that does not interfere with other medications as soon as possible.

AIDS-Related Opportunistic Infections↗

Role of individualization of hepatitis C virus (HCV) therapy duration in HIV/HCV-coinfected individuals.

OBJECTIVE: The aim of this study was to assess the efficacy, safety and tolerability of pegylated interferon and ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients, prescribed for the same duration and at the same dosage as that used in HCV monoinfection studies. DESIGN: It was an open-label, single-centre, prospective study. METHODS: Forty-five patients coinfected with HIV and HCV with CD4 counts >200 cells/microL were treated with pegylated interferon-alpha2b 1.5 microg/kg/week and ribavirin 1000-1200 mg/day for 24-48 weeks depending on HCV genotype. Safety and tolerability were assessed weekly for the first month and monthly thereafter. Virological response was assessed at weeks 4, 12 and 24 and at the end of treatment and 12 and 24 weeks post completion of treatment. The primary endpoint was defined as undetectable HCV RNA at 24 weeks post completion of treatment [sustained virological response (SVR)]. RESULTS: The majority of patients were male and had been injecting drug users. Sixty per cent were on antiretroviral therapy. In an intention-to-treat analysis, 53% had an SVR (genotype 1, 19% and genotype 2/3, 75%). All patients who had undetectable HCV RNA at week 4 of HCV treatment [very early virological response (VEVR)] had a SVR. On multivariate analysis only HCV genotype predicted SVR. Adverse events occurred frequently. CONCLUSIONS: These results indicate that 24 weeks of HCV treatment may be adequate for HIV-infected individuals coinfected with HCV genotype 2 or 3. VEVR can predict SVR in this group and may be used to guide the subgroup of genotype 2/3 individuals who will respond to 24 weeks of treatment.

Adult↗

Effects of chronic alcohol abuse and HIV infection on brain phosphorus metabolites.

We examined the effects of human immunodeficiency virus (HIV) infection and chronic alcohol consumption on cerebral phosphorus metabolites to determine if chronic alcohol abuse is a risk factor for the progression of neurological effects of HIV infection. We studied 15 HIV- alcoholics, 8 HIV- light/nondrinkers, 32 HIV+ alcoholics, and 41 HIV+ light/nondrinking men, with both HIV+ groups having similar CD4 lymphocyte counts. We used localized 31-phosphorus magnetic resonance spectroscopy after magnetic resonance imaging to examine two brain volumes in superior white matter and subcortical gray matter. Chronic alcohol consumption was associated with reduced white matter concentrations of phosphodiester (PDE) and phosphocreatine (PCr). Also in the white matter, acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC) were associated with reduced concentrations of PDE and PCr, compared with both HIV- and clinically asymptomatic HIV+ subjects. Because no alcohol-by-HIV interactions were detected, the effects of HIV infection and alcohol abuse were cumulative. This is reflected in a successive decrease of white matter PDE and PCr concentrations in the order HIV- light/nondrinkers/HIV- alcoholics/HIV+ light/nondrinkers/HIV+ alcoholics. Subcortical gray matter PDE concentrations were lower in ARC/AIDS alcoholics than in HIV- light/nondrinking individuals. These findings suggest altered brain phospholipid metabolites and energy metabolites with alcohol abuse and HIV infection. They demonstrate that the adverse metabolic effects of HIV on the brain are augmented by chronic alcohol abuse.

AIDS Dementia Complex↗

Effect of HCV viral dynamics on treatment design: lessons learned from HIV.

Viral load measurements provide an indication of viral replication, and thereby serve as a valuable tool to guide the initiation of therapy and subsequent changes. Plasma human immunodeficiency viral load strongly predicts the rate of decrease in CD4+ lymphocyte count, and progression to AIDS and death. Furthermore, the efficacy of antiretroviral therapy can be assessed by monitoring changes in plasma human immunodeficiency viral load. Similarly, viral load provides valuable information about the natural history of the hepatitis C virus infection. Hepatitis C viral load can be used to predict the likelihood of response to standard interferon-alpha treatment and other interferon-alpha regimens and to monitor treatment efficacy. Increased understanding of the natural history of the hepatitis C virus infection and the nature of resistance to interferon-alpha therapy suggests that effective treatment regimens must maintain serum levels of interferon-alpha. Ideally, interferon-alpha serum levels should provide constant pressure on the virus and should prevent viral rebound, thereby avoiding continued viral replication and minimizing the potential for emergence of resistant quasi-species. Current regimens designed to address these points include early aggressive intervention, combination drug regimens, prolonged maintenance, and novel interferons. By enabling the design and rapid assessment of new treatment regimens, viral load measurement will revolutionize the clinical management of the hepatitis C virus infection, as it has the HIV.

Antiviral Agents↗

Prognostic factors for the survival of patients with AIDS cholangiopathy.

OBJECTIVES: AIDS cholangiopathy, once considered to have extremely poor prognosis, is now rarely fatal. This study was designed to assess the survival of patients with AIDS cholangiopathy and investigate prognostic variables, especially in the era of highly active antiretroviral therapy (HAART). METHODS: Ninety-four patients with AIDS cholangiopathy were diagnosed at the San Francisco General Hospital from 1983 to 2001. The mortality status, demographic and clinical variables, and ERCP results were collected through death certificates, chart review, and endoscopic reports. RESULTS: The median survival time from the diagnosis of AIDS and AIDS cholangiopathy was 23 and 9 months, respectively. HAART significantly improved the mortality of patients with AIDS cholangiopathy (hazard ratio [HR] = 0.08, 95% confidence interval [CI] = 0.02-0.35). The presence or history of any opportunistic infection involving the digestive tract, lung, eye, nervous system, skin, or systemic involvement at the time when AIDS cholangiopathy was diagnosed was an indicator of poor prognosis (HR = 3.24, 95% CI = 1.45-7.26); this was especially true for cryptosporidial infection (HR = 2.05, 95% CI = 1.24-3.38). Patients with high serum ALP levels, especially greater than 1000 IU/L or eight times the normal value (HR = 2.69, 95% CI = 1.10-6.60), tended to have a shorter life expectancy than those with normal or slightly elevated serum ALP levels. CD4 lymphocyte counts, type of cholangiopathy, and the performance of sphincterotomy were not correlated with the survival of patients with AIDS cholangiopathy. CONCLUSIONS: HAART administration most likely accounts for the recent dramatic improvement in survival of patients with AIDS cholangiopathy. Underlying immunosuppressive status, reflected by the presence or history of any opportunistic infections, is associated with a worse outcome. Serum ALP levels might be a good clinical indicator for the prognosis of patients with AIDS cholangiopathy.

AIDS-Related Opportunistic Infections↗

Clinical aspects of Pneumocystis carinii pneumonia in HIV-infected patients: 1997.

In 1997 in Europe P. carinii pneumonia is largely a disease of individuals who are either unaware of their HIV serostatus or who decline prophylaxis despite knowing they are HIV positive. Although fibre optic bronchoscopy and bronchoalveolar lavage is the diagnostic 'gold standard' polymerase chain reaction (PCR) amplification applied to oropharyngeal washings appears to have a moderate to high diagnostic yield. With further development this may provide a truly non-invasive diagnostic test. There is a clear need for an inherently more effective regimen for prophylaxis both for those with adverse reactions (ADR) to co-trimoxazole and also for those with low CD4 lymphocyte counts. Ideally, new drug regimens should afford cross-prophylaxis against bacterial, mycobacterial and other fungal infections. Given the high frequency of ADR to co-trimoxazole when used as treatment for P. carinii pneumonia, there is also a need for effective, non-toxic alternative therapies.

AIDS-Related Opportunistic Infections↗