Late Highly Active Antiretroviral Therapy Research Articles

Hospitalizations of HIV patients in a major Israeli HIV/AIDS center during the years 2000 to 2012.

To evaluate hospitalization rates and causes among human immunodeficiency virus (HIV) patients in the late highly active antiretroviral therapy (HAART) era. Data during the years 2000 to 2012 were obtained from hospital/clinical charts. Hospitalizations were defined as a ≥24 hours hospital admission. Obstetric admissions were excluded. Causes of hospitalizations were defined as acquired immune deficiency syndrome (AIDS)-defining illnesses, AIDS-related diseases (HAART adverse events, metabolic complications and non-AIDS-defining tumors/infections), and non-HIV-related diseases. Hospitalization rates are presented as admissions per 100 patient years. The number of HIV patients (58% males) in our center increased from 521 in 2000 to 1169 in 2012. 1676 hospital admissions (in 557 patients) were observed during the years of the study. The mean number of admissions per hospitalized patient was 3 ± 3.39. Hospitalization rates of HIV patients declined significantly (18.4/100 in 2000, 9/100 patient years in 2012; P = .0001), but it was higher than the rates reported in the Israeli general population (X8.76 in 2000, X6.04 in 2012). Furthermore, hospitalizations for AIDS-defining illness declined (from 46.9% to 16.1%) whereas non-HIV-related hospitalizations increased (from 31.3% to 60.1%). Lower cluster of differentiation 4 (CD4) cell counts and older age, at the time of HIV diagnosis, were associated with higher rates of admissions (especially for AIDS-defining illnesses) and mortality. Hospitalization rates of HIV patients, especially for AIDS-defining illness, continue to decline in the late HAART era despite the increasing age of the patients, though it is still higher than that of the general population. Low CD4 cell counts and older age, at the time of HIV diagnosis, are associated with readmissions and mortality.

Brain and liver pathology, amyloid deposition, and interferon responses among older HIV-positive patients in the late HAART era

BackgroundHIV+ patients on highly active antiretroviral therapy (HAART) with suppressed viral loads have a low incidence of HIV-associated dementia, but increased prevalence of milder forms of HIV-associated neurocognitive disorders (HAND). These milder forms of HAND are often associated with minimal histological abnormalities, and their pathophysiology is unclear. Comorbidities, altered amyloid metabolism, accelerated brain aging, and activated interferon responses are suspected to play a role in HAND pathogenesis in HAART–treated persons.MethodsTo investigate associations between liver disease, accelerated brain aging, and HAND in HIV+ patients in the late HAART era (2002–2015), we studied liver and brain autopsy tissues from 53 older subjects evaluated at UCLA and BWH using histopathological stains, a sensitive fluorescent amyloid stain (AmyloGlo), and targeted gene expression profiling (NanoString).ResultsThe majority of HIV+ subjects (median age 56) were on HAART (89.3%) with last pre-mortem plasma viral load <400 copies/mL (81.5%); 50% had CD4+ counts <200 cells/μL. Compared to HIV- controls (median age 65), HIV+ subjects had more cancer (p = 0.04), illicit drug use (p <0.00001), and HCV co-infection (p = 0.002), less cardiovascular disease (p = 0.03), and similar prevalence of cerebrovascular disease (~40%), hypertension, hyperlipidemia, and diabetes. Deep frontal white matter showed increased gliosis in HIV+ subjects vs. HIV- controls (p = 0.09), but no significant differences in myelin loss, blood vessel thickening, or inflammation. Liver showed more severe fibrosis/cirrhosis (p = 0.02) and less steatosis (p = 0.03) in HIV+ subjects, but no significant differences in inflammation, blood vessel thickness, or pigment deposition. There were no significant associations between liver and brain pathologies. AmyloGlo staining detected large amyloid deposits in only one HIV+ case (age 69 with Alzheimer’s disease pathology) and two HIV- controls (ages 66 and 74). White matter from HIV+ cases vs. HIV- seronegative controls showed a trend (p = 0.06) towards increased interferon response gene expression (ISG15, MX1, IFIT1, IFIT2, and IFITM1).ConclusionsGliosis and cerebrovascular disease, but not accelerated amyloid deposition, are common brain pathologies among older HIV+ patients in the late HAART era. Although HIV+ subjects had more cirrhosis, liver pathology was not associated with any consistent pattern of brain pathology. Cerebrovascular disease, interferon responses, and neuroinflammation are likely factors contributing to brain aging and HAND in older HIV+ patients on current HAART regimens.

HIV-Associated Lipodystrophy: Impact of Antiretroviral Therapy

In the late 1990s, reports of unusual changes in body fat distribution named 'lipodystrophy' (LD) began to appear in HIV patients mitigating the enormous enthusiasm about improvement of survival and quality of life provided by the combinations of antiretroviral (ARV) drug classes, the so-called highly active antiretroviral therapy (HAART), which had just become available at that time. The objective of this paper is to critically review the literature on LD and to discuss the impact of newer ARV agents, namely atazanavir, darunavir and raltegravir, as well as strategies of the late HAART era, including single-tablet regimens and nucleoside-sparing regimens. Studies in which LD was measured by dual-energy x-ray absorptiometry or by abdominal computed tomography or magnetic resonance imaging scan only, were included. We were unable to identify studies depicting a negative impact of drugs or ARV regimens on limb fat loss. On the contrary, a few studies identified a negative impact of atazanavir/ritonavir or darunavir/ritonavir on trunk fat increase. It should be noted that this anthropometric measure is a poor instrument since it cannot distinguish between subcutaneous and visceral fat. We conclude that presumably the body fat changes currently observed in HIV-infected patients is the net result of competing phenomena: on one side the natural history of lipohypertrophy as a result of HIV and HAART impact, and on the other side the physiological body fat changes observed in the aging population.

Neurological opportunistic infections and neurological immune reconstitution syndrome: impact of one decade of highly active antiretroviral treatment in a tertiary hospital

Despite the reported decrease in the incidence and mortality rates of central nervous system (CNS) infections after the introduction of highly active antiretroviral therapy (HAART), few studies have focused on the global incidence and the relationship of these diseases with immune reconstitution inflammatory syndrome (IRIS) in the developed world. A descriptive cohort study of all consecutive adult HIV-infected patients with CNS opportunistic infections diagnosed between 2000 and 2010 in a tertiary hospital in Spain was carried out. Demographic, clinical, laboratory, and microbiological data were recorded. Patients were followed up until death or loss to follow-up or until 30 July 2011, when the study finished. The significance of differences in the incidence rate between early and late HAART periods was determined using the Mantel-Haenszel test. Survival distribution was estimated using the Kaplan-Meier method. A total of 110 cases of CNS infections were diagnosed. The incidence of CNS opportunistic infections decreased from 9 cases per 1000 HIV-infected patients per year in the early HAART period to 3.8 in the late HAART period (P = 0.04). Overall, the estimated mean survival time was 58.8 months (95% confidence interval 47.1-70.6 months). Of the 110 patients, 18 (16.4%) met the criteria of IRIS, 10 (55.6%) were paradoxical and eight (44.4%) were unmasking. IRIS was not associated with a higher mortality rate. The annual incidence of CNS infections decreased progressively during the period of study. The mortality rate associated with these diseases remains high despite HAART. The development of IRIS associated with neurological infections had no influence on prognosis.

Trends and causes of hospitalizations among HIV-infected persons during the late HAART era: what is the impact of CD4 counts and HAART use?

Declining rates of hospitalizations occurred shortly after the availability of highly active antiretroviral therapy (HAART). However, trends in the late HAART era are less defined, and data on the impact of CD4 counts and HAART use on hospitalizations are needed. We evaluated hospitalization rates from 1999 to 2007 among HIV-infected persons enrolled in a large US military cohort. Poisson regression was used to compare hospitalization rates per year and to examine factors associated with hospitalization. Of the 2429 participants, 822 (34%) were hospitalized at least once with 1770 separate hospital admissions. The rate of hospitalizations (137 per 1000 person-years) was constant over the study period [relative rate (RR) 1.00 per year change, 95% confidence interval: 0.98 to 1.02]. The hospitalization rates due to skin infections (RR: 1.50, P = 0.02), methicillin-resistant staphylococcus aureus (RR: 3.19, P = 0.03), liver disease (RR: 1.71, P = 0.04), and surgery (RR: 1.17, P = 0.04) significantly increased over time, whereas psychological causes (RR: 0.60, P < 0.01) and trauma (RR: 0.54, P < 0.01) decreased. In the multivariate model, higher nadir CD4 (RR: 0.92 per 50 cells, P < 0.01) and higher proximal CD4 counts (RR of 0.71 for 350-499 vs. <350 cells/mm(3) and RR 0.67 for > or = 500 vs. 350 cells/mm(3), both P < 0.01) were associated with lower risk of hospitalization. Risk of hospitalization was constant for proximal CD4 levels above 350 (RR: 0.94 P = 0.51, CD4 > or = 500 vs. 350-499). HAART was associated with a reduced risk of hospitalization among those with a CD4 <350 (RR: 0.72, P = 0.02) but had smaller estimated and nonsignificant effects at higher CD4 levels (RR: 0.81, P = 0.33 and 1.06, P = 0.71 for CD4 350-499 and > or = 500, respectively). Hospitalizations continue to occur at high rates among HIV-infected persons with increasing rates for skin infections, methicillin-resistant staphylococcus aureus, liver disease, and surgeries. Factors associated with a reduced risk of hospitalization include CD4 counts >350 cells per cubic millimeter and HAART use among patients with a CD4 count <350 cells per cubic millimeter.

Changing Sociodemographic and Clinical Characteristics of Tuberculosis among HIV‐Infected Patients, New York City, 1992–2005

Although highly active antiretroviral therapy (HAART) has decreased human immunodeficiency virus (HIV)-related morbidity, tuberculosis remains an important disease among HIV-infected individuals. By use of surveillance data, sociodemographic and clinical changes among HIV-infected and HIV-uninfected tuberculosis patients in New York City were evaluated using the Cochran-Armitage trend test and multivariate logistic regression across 3 periods: 1992-1995 (pre-HAART), 1996-2000 (early HAART), and 2001-2005 (late HAART). Among tuberculosis patients with known HIV status, 4345 (60%) of 7224 were HIV-infected in pre-HAART, 1943 (33%) of 5933 in early HAART, and 851 (22%) of 3815 in late HAART (P < .001 for trend). During the study period, the age of HIV-infected tuberculosis patients increased, and greater proportions were female, non-Hispanic black, Asian, and foreign born; the proportion that was non-Hispanic white decreased. The proportion that was culture-negative for Mycobacterium tuberculosis increased (from 7% pre-HAART to 21% late HAART; P < .001 for trend; early HAART vs pre-HAART adjusted odds ratio [aOR], 1.68; 95% confidence interval [CI], 1.38-2.04), and the proportion with extrapulmonary disease also increased (from 32% to 46%; P < .001 for trend). The proportion with multidrug-resistant tuberculosis decreased (from 16% to 4%; P < .001 for trend), especially from pre-HAART to early HAART (aOR, 0.31; 95% CI, 0.25-0.40). The proportion who died before tuberculosis treatment decreased (from 12% to 7%), and the proportion who died during tuberculosis treatment also decreased (from 29% to 11%) (both, P < .001 for trend). Over time, HIV-infected tuberculosis patients had AIDS longer before the diagnosis of tuberculosis (P < .001 for trend). Similar trends for culture, site of disease, and drug resistance were seen for HIV-uninfected tuberculosis patients. The sociodemographic and clinical characteristics changed substantially among HIV-infected tuberculosis patients in New York City. Awareness of these changes may speed diagnosis of tuberculosis. Future studies should evaluate HAART's effect on tuberculosis presentation among HIV-infected patients.

Suicide in HIV-Infected Individuals and the General Population in Switzerland, 1988–2008

High rates of suicide have been described in HIV-infected patients, but it is unclear to what extent the introduction of highly active antiretroviral therapy (HAART) has affected suicide rates. The authors examined time trends and predictors of suicide in the pre-HAART (1988-1995) and HAART (1996-2008) eras in HIV-infected patients and the general population in Switzerland. The authors analyzed data from the Swiss HIV Cohort Study and the Swiss National Cohort, a longitudinal study of mortality in the Swiss general population. The authors calculated standardized mortality ratios comparing HIV-infected patients with the general population and used Poisson regression to identify risk factors for suicide. From 1988 to 2008, 15,275 patients were followed in the Swiss HIV Cohort Study for a median duration of 4.7 years. Of these, 150 died by suicide (rate 158.4 per 100,000 person-years). In men, standardized mortality ratios declined from 13.7 (95% CI=11.0-17.0) in the pre-HAART era to 3.5 (95% CI=2.5-4.8) in the late HAART era. In women, ratios declined from 11.6 (95% CI=6.4-20.9) to 5.7 (95% CI=3.2-10.3). In both periods, suicide rates tended to be higher in older patients, in men, in injection drug users, and in patients with advanced clinical stage of HIV illness. An increase in CD4 cell counts was associated with a reduced risk of suicide. Suicide rates decreased significantly with the introduction of HAART, but they remain above the rate observed in the general population, and risk factors for suicide remain similar. HIV-infected patients remain an important target group for suicide prevention.

Timing of HAART Defines the Integrity of Memory B Cells and the Longevity of Humoral Responses in HIV-1 Vertically-Infected Children

Pensieroso S, Cagigi A, Palma P, et al. Proc Natl Acad Sci U S A. 2009;106(19):7939–7944PURPOSE OF THE STUDY. HIV infection induces a progressive decline in immune function that affects not only T-cell but also B-cell activities, including the progressive decline in memory B cells, markedly elevated serum immunoglobulin levels, impaired responsiveness to routine immunizations, and loss of specific antibodies previously generated. Treatment of adults with highly active antiretroviral therapy (HAART) reduces immunoglobulin levels and increases B-cell numbers. However, several studies indicate that the B-cell compartment does not recover completely and patients maintain impaired antibody responses to immunizations. The purpose of this study was to determine whether the timing of HAART initiation affected pediatric patients’ ability to generate and to maintain protective levels of antibodies to routine immunizations.STUDY POPULATION. Seventy children perinatally infected with HIV were studied with 50 healthy control subjects.METHODS. Patients and control subjects received childhood immunizations according to the national (Italian) vaccine protocol. Patients who started HAART within the first year of life were categorized as “early treated”; children treated after the first year of life were considered “late treated,” and this group was subdivided into individuals with controlled virus and those who developed virological failure. Peripheral blood cells were evaluated with standard flow cytometry for B-cell subsets, including memory B cells. Antigen-specific B-cell functions were measured with an enzyme-linked immunosorbent spot assay. Plasma antibody titers against measles, tetanus, and pneumococcal antigens were assayed with enzyme-linked immunosorbent assays.RESULTS. Early-treated patients maintained high percentages of memory B cells, compared with levels observed in healthy control subjects; patients who started HAART later showed lower percentages. Patients treated early maintained the capacity to generate antigen-specific memory B cells, and early HAART resulted in maintenance of multiple antibody levels above protective thresholds in HIV-infected children. Of concern, 25% of patients treated late failed to generate protective levels of antibodies to measles, and this number increased to >40% among those who experienced failure of antiretroviral therapy. In addition, >60% of subjects who received late HAART failed to maintain protective levels of antibodies to antigens including measles and tetanus; similar findings were noted in antibody responses to pneumococcal antigens.CONCLUSIONS. Early HAART is essential for maintenance of normal B-cell functions in perinatally HIV-infected children. Regardless of T-cell numbers and/or clinical status, the results of this study strongly indicate that newborns infected with HIV should be treated as early as possible to preserve immune functions.REVIEWER COMMENTS. Although T cells are critical for generating normal antibody responses, unique subsets of B lymphocytes are also essential in this regard. Specifically, marginal-zone B cells are required for the ability to generate polysaccharide-specific, “T-cell independent” antibodies. Infants <2 years of age are deficient in this subset of B lymphocytes. This study provides strong confirmation of many clinicians’ impressions that children who begin HAART at <1 year of age and who maintain viral suppression have normal immune functions by all measures that are clinically applied to the evaluation of this population. When to initiate HAART has been a long-term question among practitioners treating adults. Increasingly, earlier treatment (ie, at CD4+ cell counts of <500 cells per μL in adult patients) is being considered. The results of this study suggest that HAART should begin as soon as a diagnosis of HIV infection is made in perinatally exposed children.

Continuing declines in some but not all HIV-associated cancers in Australia after widespread use of antiretroviral therapy

To describe changes in cancer incidence in people with HIV in Australia since the introduction of highly active antiretroviral therapy (HAART). Population-based, retrospective cohort study of people with HIV (n = 20 232) using data linkage between national registers of HIV/AIDS and cancer in 1982-2004. Age-adjusted and sex-adjusted incidence rate ratios with 95% confidence intervals were calculated to compare site-specific cancer incidence during the early (1996-1999) and late (2000-2004) HAART periods with that prior to HAART (1982-1995). Five-year age-specific, sex-specific, calendar year-specific, and state-specific standardized incidence ratios with 95% confidence interval were also calculated for each period. Incidence of Kaposi sarcoma and non-Hodgkin lymphoma declined significantly (Ptrend < 0.001). Incidence of Hodgkin lymphoma was significantly higher during the early-HAART period (incidence rate ratio 2.34, 95% confidence interval 1.19-4.63) but declined thereafter (Pdiff = 0.014). Incidence of anal cancer was unchanged (Ptrend = 0.451) and remained raised more than 30-fold. Incidence declined significantly for melanoma (Ptrend = 0.041) and prostate cancer (Ptrend = 0.026), and, during the late-HAART period, was lower than in the general population for both cancers. Incidence of colorectal cancer was consistently lower than in the general population. Incidence of Kaposi sarcoma and non-Hodgkin lymphoma has continued to decline among people with HIV in Australia, though it remains very substantially elevated. Incidence of Hodgkin lymphoma may now also be declining. Incidence of anal cancer has remained stable, and it is now the third most common cancer in HIV-infected Australians. Reasons for the reduced incidence of colorectal and prostate cancer, and more recently of melanoma, are unclear.

Trends in mortality and antibiotic resistance among HIV‐infected patients with invasive pneumococcal disease

The aim of the study was to describe trends and risk factors for mortality and changes in antibiotic resistance, serotypes and clones among HIV-infected patients with invasive pneumococcal disease (IPD). A prospective study of 199 episodes of IPD occurring in a cohort of 4011 HIV-infected patients was carried out. Predictors of mortality included clinical and microbiological data. The 7-valent pneumococcal conjugate vaccine (PCV7) for children was introduced in late 2001. Time periods were classified for mortality studies as pre- (1986-1996), early (1997-2001) and late (2002-2007) highly active antiretroviral therapy (HAART) era, and for serotype studies as pre-PCV7 (1986-2001) and PCV7 (2002-2007) era. Of 199 IPD episodes, 71 (36%) occurred in HIV-infected patients with associated comorbidities (mainly liver cirrhosis; 52 of 71), which increased in recent years. The incidence of IPD decreased from the pre-HAART era to the early HAART era and then remained stable in the late HAART era (24.1, 8.4 and 7.4 episodes per 1000 patient-years, respectively). Rates of 30-day mortality have risen over the three periods (8, 19 and 25%, respectively; P = 0.017). In multiple logistic regression analysis, predictors of mortality were shock at presentation [odds ratio (OR) 7.01; 95% confidence interval (CI) 2.05-23.87] and associated comorbidities (OR 4.27; 95% CI 1.53-11.92). In the PCV7 era, IPD caused by non-PCV7 serotypes increased, and resistance to betalactams decreased. The most frequent genotypes were Spain(9V)-ST156, Spain(23F)-ST81, ST88(19F), Sweden(1)-ST304 and Spain(6B)-ST90. In the late HAART era, the incidence of IPD has not significantly decreased. Mortality from IPD has risen in association with an increase in comorbidities such as liver cirrhosis. New vaccination strategies are needed to diminish the burden of IPD in the HIV-infected population.

Incidence, Clinical Presentation, and Outcome of Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients during the Highly Active Antiretroviral Therapy Era: A Nationwide Cohort Study

Human immunodeficiency virus (HIV) infection predisposes to progressive multifocal leukoencephalopathy (PML). Here, we describe the incidence, presentation, and prognosis of PML in HIV-1-infected patients during the period before highly active antiretroviral therapy (HAART) (1995-1996) and during the early HAART (1997-1999) and late HAART (2000-2006) periods. Patients from a nationwide population-based cohort of adult HIV-1-infected individuals were included. We calculated incidence rates of PML and median survival times after diagnosis. We also described neurological symptoms at presentation and follow-up. Among 4,649 patients, we identified 47 patients with PML. The incidence rates were 3.3, 1.8, and 1.3 cases per 1000 person-years at risk in 1995-1996, 1997-1999, and 2000-2006, respectively. The risk of PML was significantly associated with low CD4(+) cell count, and 47% of cases were diagnosed by means of brain biopsy or polymerase chain reaction analysis for JC virus. The predominant neurological symptoms at presentation were coordination disturbance, cognitive defects, and limb paresis. Thirty-five patients died; the median survival time was 0.4 years (95% confidence interval [CI], 0.0-0.7) in 1995-1996 and 1.8 years (95% CI, 0.6-3.0) in both 1997-1999 and 2000-2006. CD4(+) cell count >50 cells/microL at diagnosis of PML was significantly associated with reduced mortality. The incidence of PML in HIV-infected patients decreased after the introduction of HAART. Survival after PML remains poor. In the management of PML, the main focus should be on prophylactic measures to avoid immunodeficiency.

Trends of mortality and causes of death among HIV‐infected patients in Taiwan, 1984–2005

The aim of this study was to analyse the trends of mortality and causes of death among HIV-infected patients in Taiwan from 1984 to 2005. Registered data and death certificates for HIV-infected patients from Taiwan Centers for Disease Control were reviewed. Mortality rate and causes of deaths were compared among patients whose HIV diagnosis was made in three different study periods: before the introduction of highly active antiretroviral therapy (HAART) (pre-HAART: from 1 January 1984 to 31 March 1997), in the early HAART period (from 1 April 1997 to 31 December 2001), and in the late HAART period (from 1 January 2002 to 31 December 2005). A subgroup of 1161 HIV-infected patients (11.4%) followed at a university hospital were analysed to investigate the trends of and risk factors for mortality. For 10 162 HIV-infected patients with a mean follow-up of 1.97 years, the mortality rate of HIV-infected patients declined from 10.2 deaths per 100 person-years (PY) in the pre-HAART period to 6.5 deaths and 3.7 deaths per 100 PY in the early and late HAART periods, respectively (P<0.0001). For the 1161 patients followed at a university hospital (66.8% with CD4 count <200 cells/microL), HAART reduced mortality by 89% in multivariate analysis, and the adjusted hazard ratio for death was 0.28 (95% confidence interval 0.24, 0.33) in patients enrolled in the late HAART period compared with those in the pre-HAART period. Seventy-six per cent of the deaths in the pre-HAART period were attributable to AIDS-defining conditions, compared with 36% in the late HAART period (P<0.0001). The leading causes of non-AIDS-related deaths were sepsis (14.7%) and accidental death (8.3%), both of which increased significantly throughout the three study periods. Compared with patients acquiring HIV infection through sexual contact, injecting drug users were more likely to die from non-AIDS-related causes. The mortality of HIV-infected patients declined significantly after the introduction of HAART in Taiwan. In the HAART era, AIDS-related deaths decreased significantly while deaths from non-AIDS-related conditions increased.

Risk of Recurrent Nontyphoid Salmonella Bacteremia in HIV-Infected Patients in the Era of Highly Active Antiretroviral Therapy and an Increasing Trend of Fluoroquinolone Resistance

Risk of recurrent nontyphoid Salmonella (NTS) bacteremia and trends of antimicrobial resistance of NTS remain unknown in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART). Ninety-three patients who received a diagnosis of NTS bacteremia from June 1994 through June 2006 were prospectively followed up. Incidence of recurrent NTS bacteremia was compared between the pre-HAART era (June 1994-March 1997) and the HAART era (April 1997-June 2006). Prevalence of antimicrobial resistance was compared among the NTS isolates obtained in the pre-HAART era, the early HAART era (April 1997-June 2002), and the late HAART era (July 2002-June 2006). Compared with patients enrolled in the pre-HAART era, patients who received HAART had an incidence of recurrent NTS bacteremia that was significantly reduced by 96%; the incidence of recurrent NTS bacteremia was 2.56 cases per 100 person-years in the HAART era, compared with 70.56 cases per 100 person-years in the pre-HAART era (rate ratio, 0.036; 95% confidence interval, 0.012-0.114; P<.001). In the HAART era, the incidence of recurrent NTS bacteremia did not increase among patients receiving fluoroquinolone prophylaxis for <or=30 days (1.69 cases per 100 person-years), compared with among patients receiving fluoroquinolones for >30 days (3.95 cases per 100 person-years), with a rate ratio of 0.43 (95% confidence interval, 0.07-2.58). Although resistance to ampicillin, cotrimoxazole, and chloramphenicol decreased, the proportion of NTS isolates resistant to fluoroquinolones increased from 0% in the pre-HAART era to 6.2% in the early HAART era and 34.2% in the late HAART era (P=.002). The risk of recurrent NTS bacteremia decreased significantly in the HAART era, although NTS isolates obtained from HIV-infected patients were increasingly resistant to fluoroquinolones.

Cancer Rates After Year 2000 Significantly Decrease in Children With Perinatal HIV Infection: A Study by the Italian Register for HIV Infection in Children

To evaluate the impact of highly active antiretroviral therapy (HAART) on cancer incidence in HIV-infected children throughout a 20-year period. An observational population study was conducted on 1,190 perinatally HIV-infected children enrolled onto the Italian Register for HIV Infection in Children from 1985 to 2004 and never lost to follow-up (total observation time, 10,037.66 years). Cancer rates were calculated in the pre-HAART (1985 to 1995), early HAART (1996 to 1999), and late HAART (2000 to 2004) periods and compared using Poisson regression adjusted for age. The proportion of HAART-treated children increased from 4.1% in 1996 to 60.4% in 1999 and to 81.5% in 2004. In the same time frame, the proportion of children receiving HAART for at least 2 years increased from 3.1% to 77.0%. Overall, 35 cancers occurred. Cancer rates were 4.49 (95% CI, 2.37 to 6.64), 4.09 (95% CI, 1.68 to 6.50), and 0.76 (95% CI, 0.00 to 1.80) per 1,000 children per year in 1985 to 1995, 1996 to 1999, and 2000 to 2004, respectively. Notably, there was no significant difference comparing the periods from 1985 to 1995 and 1996 to 1999 (P = .081). By contrast, cancer rates were significantly lower in the period from 2000 to 2004 than in 1996 to 1999 (P < .0001). Results were confirmed by separately analyzing data from children observed from birth (P = .418 for 1985 to 1995 v 1996 to 1999; P = .001 for 1996 to 1999 v 2000 to 2004). Dramatically reduced cancer rates were observed only in the late HAART period in parallel to the increasing proportion of children receiving HAART therapy.

Trends in AIDS and Mortality in HIV-Infected Subjects With Hemophilia From 1985 to 2003

To study trends in progression to AIDS, all-cause mortality, and cause-specific mortality (AIDS-related, liver disease, and hemorrhagic complications) over calendar periods with different exposure to highly active antiretroviral therapy (HAART) in a cohort of hemophiliacs in Spain, taking into account the competing risks of the causes of death. Multicenter cohort of HIV-infected hemophiliacs. HIV seroconversion was estimated using mathematic techniques for interval-censored data from 1979 through 1985. Rates of AIDS and cause-specific death were calculated by Poisson regression, allowing for late entry, for the periods 1985 through 1992, 1993 through 1996, 1997 through 2000 (early HAART), and 2001 through 2003 (late HAART), also allowing for competing risks. Of 585 subjects, 44% were younger than 15 years of age, 82% had severe hemophilia, 86% had type A hemophilia, and the median seroconversion date was October 1982. Calendar period and age at HIV seroconversion strongly influenced AIDS and death rates. Compared with 1993 through 1996, decreases of 75% (relative risk [RR] = 0.25, 95% confidence interval [CI]: 0.14 to 0.43) and 72% (RR = 0.28, 95% CI: 0.12 to 0.63) in the RR of AIDS were observed in early and late HAART. For all-cause mortality, 72% (RR = 0.28, 95% CI: 0.18 to 0.42) and 83% (RR = 0.17, 95% CI: 0.09 to 0.33) decreases were observed by 1997 through 2000 and 2001 through 2003. For liver-related deaths, increases were observed in the late-HAART period (RR = 2.80, 95% CI: 0.94 to 8.36) compared with 1993 through 1996, but using competing risks, this RR was substantially reduced (RR = 1.70, 95% CI: 0.57 to 5.04). Major reductions in AIDS and death rates were observed from 1997 to 2003 in hemophiliacs. These survival improvements are largely attributable to decreases in AIDS-related deaths and have been accompanied by increases in liver disease death rates, which are overestimated if competing risks are not taken into account.

Prevalence, Associated Factors, and Prognostic Determinants of AIDS‐Related Toxoplasmic Encephalitis in the Era of Advanced Highly Active Antiretroviral Therapy

Characteristics, associated factors, and survival probability of toxoplasmic encephalitis (TE) in the era of advanced highly active antiretroviral therapy (HAART) have not been fully clarified. Data for 205 individuals with acquired immunodeficiency syndrome (AIDS)-related TE were derived from the Italian Registry Investigative NeuroAIDS database, and the cases were studied longitudinally to evaluate prevalence, clinical characteristics, and survival. Moreover, the relationship between the occurrence of TE and exposure to antiretroviral therapy and to TE prophylaxis was evaluated. With an overall prevalence of 26%, TE represented the most frequent neurological disorder in the cohort. Female sex, severe immunodeficiency, and absence of primary TE prophylaxis significantly increased the risk of TE, and previous exposure to antiretroviral therapy reduced the probability of disease occurrence. Thirty-six percent of patients who had received antiretroviral therapy developed TE, although in most of these cases, the patient experienced failure of antiretroviral therapy. Of note, 66% of patients who had experienced antiretroviral therapy did not receive prophylaxis for TE at TE diagnosis. The 1-year probability of that infection with human immunodeficiency virus (HIV) would progress or that death would occur after TE was 40% and 23%, respectively. Cognitive symptoms, low CD4(+) cell count, not receiving HAART after TE, and initiating HAART >2 months after TE diagnosis were all significantly associated with an increased probability of progression of HIV infection. Not receiving HAART after diagnosis negatively affected survival. TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.